1 00:00:07,456 --> 00:00:10,893 I KNOW MOST EVERYONE 2 00:00:10,893 --> 00:00:13,429 HERE. I WILL TALK ABOUT SMALL 3 00:00:13,429 --> 00:00:18,567 CELL LUNG CANCER AND THE COMMON 4 00:00:18,567 --> 00:00:19,468 THEME WHICH IS HOW MUCH WE CAN 5 00:00:19,468 --> 00:00:21,771 LEARN FROM PATIENTS AND THE 6 00:00:21,771 --> 00:00:22,705 THEME IS YOU DON'T NEED 7 00:00:22,705 --> 00:00:24,206 THOUSANDS OF PATIENTS YOU 8 00:00:24,206 --> 00:00:26,475 PROBABLY NEED A HANDFUL OF 9 00:00:26,475 --> 00:00:28,177 PATIENTS AND YOU CAN MAKE, YOU 10 00:00:28,177 --> 00:00:30,312 KNOW, IMPORTANT DISCOVERIES AND 11 00:00:30,312 --> 00:00:32,248 OBSERVATIONS FROM A HANDFUL OF 12 00:00:32,248 --> 00:00:41,286 PATIENTS, FROM A SMALL NUMBER OF 13 00:00:41,286 --> 00:00:43,755 PATIENTS. SO I HAVE BEEN 14 00:00:43,755 --> 00:00:45,124 STUDYING SMALL CELL LUNG CANCER 15 00:00:45,124 --> 00:00:47,559 FOR THE LAST TEN YEARS AND 16 00:00:47,559 --> 00:00:51,163 GLOBALLY LUNG CANCER IS THE MOST 17 00:00:51,163 --> 00:00:55,200 COMMON CAUSE OF CANCER RELATED 18 00:00:55,200 --> 00:00:59,171 DEATHS ALMOST AS MANY OF THE 19 00:00:59,171 --> 00:01:01,840 NEXT THREE COMBINED, PROSTATE, 20 00:01:01,840 --> 00:01:04,176 COLORECTAL AND BREAST CANCER AND 21 00:01:04,176 --> 00:01:08,413 WITHIN LUNG CANCER, SMALL CELL 22 00:01:08,413 --> 00:01:11,783 LUNG CANCER TENZ TENDS TO BE 23 00:01:11,783 --> 00:01:14,219 THE MOST LETHAL TYPE. 24 00:01:14,219 --> 00:01:16,588 WE FOUND THAT THOSE DETECTED BY 25 00:01:16,588 --> 00:01:19,791 CT SCANS, MOST OF SMALL CELL 26 00:01:19,791 --> 00:01:21,827 LUNG CANCER TENDS TO BE IN THE 27 00:01:21,827 --> 00:01:24,163 ADVANCED OR METASTATIC STAGES 28 00:01:24,163 --> 00:01:26,098 AND THIS COMPARES TO THE MORE 29 00:01:26,098 --> 00:01:28,367 COMMON TYPE OF LUNG CANCER WHERE 30 00:01:28,367 --> 00:01:33,906 IF YOU DO CT SCREENING AT 31 00:01:33,906 --> 00:01:37,442 PATIENTS WITH HIGHER RISK IT 32 00:01:37,442 --> 00:01:39,411 TENDS TO BE EARLIER STAGE AND 33 00:01:39,411 --> 00:01:40,913 THE SURVIVAL HAS NOT CHANGED IN 34 00:01:40,913 --> 00:01:43,582 MANY, MANY DECADES, THIS IS 35 00:01:43,582 --> 00:01:47,553 DECADE GOING BACK TO 2001 AND 36 00:01:47,553 --> 00:01:49,922 GOES UP TO 2016 BUT EVEN BEFORE 37 00:01:49,922 --> 00:01:52,191 THAT THE TWO YEAR SURVIVAL RATE 38 00:01:52,191 --> 00:01:55,527 HAS REMAINED STEADY BETWEEN 39 00:01:55,527 --> 00:01:59,298 10-15% AND MOST PATIENTS WITH 40 00:01:59,298 --> 00:02:01,700 SCLC DIE WITHIN A YEAR OF 41 00:02:01,700 --> 00:02:03,402 DIAGNOSIS AND THE MEDIAN 42 00:02:03,402 --> 00:02:05,871 SURVIVAL IS SEVEN MONTHS. AND 43 00:02:05,871 --> 00:02:08,640 TO MAKE MATTERS WORSE SCLC WAS 44 00:02:08,640 --> 00:02:12,811 NOT ONE OF THE TUMORS INCLUDED 45 00:02:12,811 --> 00:02:19,384 IN TCLJ AND THIS IS BECAUSE IT'S 46 00:02:19,384 --> 00:02:20,819 HIGHLY METASTATIC. AS A RESULT 47 00:02:20,819 --> 00:02:23,455 MOST OF WHAT WE KNOW COMES FROM 48 00:02:23,455 --> 00:02:25,057 CELL SCOMPLIENS MOUSE MODELS AND 49 00:02:25,057 --> 00:02:28,694 THEN HUMAN BEINGS BUT THEN THE 50 00:02:28,694 --> 00:02:30,095 CONVENTIONAL OR TRADITIONAL 51 00:02:30,095 --> 00:02:30,362 RESEARCH. 52 00:02:30,362 --> 00:02:33,131 SO WE HAVE TAKE AN DIFFERENT 53 00:02:33,131 --> 00:02:36,835 APPROACH. YOU CAN CALL IT 54 00:02:36,835 --> 00:02:38,904 REVERSE TRANSLATION OR BEDSIDE 55 00:02:38,904 --> 00:02:40,172 TO BENCH OR WHATEVER YOU LIKE. 56 00:02:40,172 --> 00:02:43,208 BUT THE IDEA IS TO DERIVE 57 00:02:43,208 --> 00:02:45,844 INSIGHTS FROM PATIENTS AND TRY 58 00:02:45,844 --> 00:02:47,679 TO EXPLAIN OBSERVATIONS IN 59 00:02:47,679 --> 00:02:49,848 PATIENTS USING MECHANISTIC 60 00:02:49,848 --> 00:02:52,751 STUDIES IN MORAL SYSTEMS IN 61 00:02:52,751 --> 00:02:54,987 ANIMAL MODELS AND SO FORTH. AND 62 00:02:54,987 --> 00:02:56,188 USING THIS APPROACH, OVER THE 63 00:02:56,188 --> 00:02:59,591 LAST TEN YEARS NOW WE HAVE 64 00:02:59,591 --> 00:03:02,361 CONDUCTED, YOU KNOW, SEVERAL 65 00:03:02,361 --> 00:03:04,229 CLINICAL TRIALS AND ENROLLED A 66 00:03:04,229 --> 00:03:06,265 LOT OF PATIENTS, PERFORMED A LOT 67 00:03:06,265 --> 00:03:09,234 OF RESEARCH BIOPSIES AND 68 00:03:09,234 --> 00:03:09,868 CONDUCTED RESEARCH AUTOPSIES AND 69 00:03:09,868 --> 00:03:13,305 OUR GOAL IS FAIRLY SIMPLE. WE 70 00:03:13,305 --> 00:03:16,074 HOPE TO PROVIDE A PERSONALIZED 71 00:03:16,074 --> 00:03:17,376 PATIENT CARE WHICH ACTUALLY, YOU 72 00:03:17,376 --> 00:03:19,845 KNOW, THE CLINICAL CENTER IN CCR 73 00:03:19,845 --> 00:03:21,780 IS AN IDEAL ENVIRONMENT TO DO 74 00:03:21,780 --> 00:03:24,049 THAT. IN THE SETTING OF 75 00:03:24,049 --> 00:03:26,018 CLINICAL TRIALS, AND WE PERFORM 76 00:03:26,018 --> 00:03:28,820 IN DEPTH TUMOR MOLECULAR 77 00:03:28,820 --> 00:03:30,055 PROFILING TO COME UP WITH 78 00:03:30,055 --> 00:03:36,662 PATIENT VARIABILITIES AND THE 79 00:03:36,662 --> 00:03:38,630 HOPE IS TO ADVANCE SCLC 80 00:03:38,630 --> 00:03:40,032 THERAPIES AND UNCOVER BIOLOGY. 81 00:03:40,032 --> 00:03:41,566 BEFORE I GO INTO WHAT WE'VE 82 00:03:41,566 --> 00:03:45,037 LEARNED, WHAT DOES A TYPICAL 83 00:03:45,037 --> 00:03:46,305 SCLC LOOK LIKE? SO THIS IS A 84 00:03:46,305 --> 00:03:47,539 PATIENT OF OURS WHO PRESENTED 85 00:03:47,539 --> 00:03:49,741 WITH HIGHLY METASTATIC DISEASE, 86 00:03:49,741 --> 00:03:51,510 THIS IS A CT SCAN OF THE CHEST. 87 00:03:51,510 --> 00:03:53,812 AND YOU CAN SEE THAT THERE IS 88 00:03:53,812 --> 00:03:56,548 INVOLVEMENT OF THE LUNG. AS 89 00:03:56,548 --> 00:03:57,616 WELL AS MULTIPLE ORGANS WHICH 90 00:03:57,616 --> 00:03:59,618 YOU CANNOT SEE IN THIS SECTION. 91 00:03:59,618 --> 00:04:02,421 THESE TUMORS TEND TO BE HIGHLY 92 00:04:02,421 --> 00:04:04,222 RESPONSIVE TO A COMBINATION OF 93 00:04:04,222 --> 00:04:05,757 CHEMOTHERAPY WHICH WAS THE ONLY 94 00:04:05,757 --> 00:04:07,859 OPTION FOR THE LAST 30-40 YEARS 95 00:04:07,859 --> 00:04:09,594 OR SO AND THEN IMMUNOTHERAPIES 96 00:04:09,594 --> 00:04:12,064 WERE APPROVED ABOUT 3-4 YEARS 97 00:04:12,064 --> 00:04:14,733 AGO SO THE CURRENT STANDARD IS A 98 00:04:14,733 --> 00:04:18,337 COMBINATION OF THEME THERAPY AND 99 00:04:18,337 --> 00:04:21,340 PD-L 1 INHIBITORS. THE TUMORS 100 00:04:21,340 --> 00:04:22,841 ALMOST MELT AWAY AND YOU THINK 101 00:04:22,841 --> 00:04:24,276 THEY'RE ALMOST CURED. 102 00:04:24,276 --> 00:04:26,978 A LOT OF COMPLETE AND PARTIAL 103 00:04:26,978 --> 00:04:27,612 RESPONSES. BUT UNFORTUNATELY, 104 00:04:27,612 --> 00:04:31,116 THESE TUMORS THEY COME BACK VERY 105 00:04:31,116 --> 00:04:32,884 QUICKLY. AND RELAPSE TENDS TO 106 00:04:32,884 --> 00:04:34,686 HAPPEN USUALLY IN A MATTER OF 107 00:04:34,686 --> 00:04:37,456 WEEK TO MONTHS IN MOST PATIENTS. 108 00:04:37,456 --> 00:04:39,291 AND AT THE TIME OF RELAPSE IN 109 00:04:39,291 --> 00:04:41,393 THIS CASE YOU CAN SEE RELAPSE IN 110 00:04:41,393 --> 00:04:44,296 THE LIVER AS WELL AS IN THE 111 00:04:44,296 --> 00:04:48,467 ADRENAL. IT TENDS TO BE HIGHLY 112 00:04:48,467 --> 00:04:49,701 RESISTANT TO ADDITIONAL 113 00:04:49,701 --> 00:04:51,002 THERAPIES AND THESE ARE THE 114 00:04:51,002 --> 00:04:52,404 TREATMENTS FOR RELAPSE. THIS 115 00:04:52,404 --> 00:04:54,039 PATIENT DIED WITHIN SIX MONTHS 116 00:04:54,039 --> 00:04:55,474 OF HIS DIAGNOSIS. AND LIKE I 117 00:04:55,474 --> 00:04:57,809 SAID, THE MEDIAN SURVIVAL IS 118 00:04:57,809 --> 00:05:01,313 SEVEN MONTHS SO LIVING UP TO A 119 00:05:01,313 --> 00:05:03,582 YEAR TENDS TO BE EXCEPTION 120 00:05:03,582 --> 00:05:05,650 RATHER THAN THE RULE. PLEASE, 121 00:05:05,650 --> 00:05:16,128 PLEASE, YEAH. YES, WHEN YOU 122 00:05:16,128 --> 00:05:20,232 TREAT WITH CHEMOTHERAPY THE -- I 123 00:05:20,232 --> 00:05:22,434 WILL COME TO THE RESISTANCE IN A 124 00:05:22,434 --> 00:05:23,368 BIT BUT IT CAN BE MODELLED IN 125 00:05:23,368 --> 00:05:27,239 ANIMAL SYSTEMS. YEAH, PLEASE 126 00:05:27,239 --> 00:05:29,608 FEEL FREE TO ASK QUESTIONS IN 127 00:05:29,608 --> 00:05:31,109 BETWEEN. SO WHAT DOES IT LOOK 128 00:05:31,109 --> 00:05:32,177 LIKE UNDER THE MICROSCOPE? SO 129 00:05:32,177 --> 00:05:35,747 THIS IS A TYPICAL APPEARANCE OF 130 00:05:35,747 --> 00:05:37,015 SCLC. THE CELLS TEND TO BE 131 00:05:37,015 --> 00:05:39,484 SMALL TO MEDIUM SIZED THERE'S 132 00:05:39,484 --> 00:05:42,654 VERY MINIMAL CYTOPLASM. AND THE 133 00:05:42,654 --> 00:05:44,890 NUCLEAR FEATURES ARE VERY 134 00:05:44,890 --> 00:05:46,191 INTERESTING, THEY'RE FINELY 135 00:05:46,191 --> 00:05:49,561 DISPERSED CHROMATIN, NO DISTINCT 136 00:05:49,561 --> 00:05:52,497 NUCLEI AND WE OBSERVE WHAT'S 137 00:05:52,497 --> 00:05:54,733 CALLED NUCLEAR MOLDING THIS IS A 138 00:05:54,733 --> 00:05:56,735 SITUATION WHERE ADJACENT CELL 139 00:05:56,735 --> 00:05:59,504 NUKE LA CONFORM TO EACH OTHER. 140 00:05:59,504 --> 00:06:01,640 OF COURSE THESE TUMORS DIVIDE 141 00:06:01,640 --> 00:06:04,409 VERY RAPIDLY SO YOU SEE A LOT OF 142 00:06:04,409 --> 00:06:06,378 MITOTIC FIGURES AND THERE'S -- 143 00:06:06,378 --> 00:06:12,050 THIS TRAUMA TENDS TO BE STRAND 144 00:06:12,050 --> 00:06:12,684 AND FIE BRO VASCULAR. I WOULD 145 00:06:12,684 --> 00:06:14,619 LIKE YOU TO KEEP IN MIND THESE 146 00:06:14,619 --> 00:06:15,120 THREE FEATURES. 147 00:06:15,120 --> 00:06:16,521 THE NUCLEAR MOLDING AND WE'LL 148 00:06:16,521 --> 00:06:18,390 COME BACK TO IT IN A LITTLE BIT. 149 00:06:18,390 --> 00:06:22,794 AND THEN FINALLY WHAT MAKES A 150 00:06:22,794 --> 00:06:25,163 SCLC SO LETHAL? ONE IS THE 151 00:06:25,163 --> 00:06:27,165 EARLY AND RAPID METASTASIS. 152 00:06:27,165 --> 00:06:29,501 MOST PATIENTS ARE DIAGNOSED WITH 153 00:06:29,501 --> 00:06:30,969 ALREADY STAGE THREE STAGE FOUR 154 00:06:30,969 --> 00:06:34,105 DISEASE. IT'S THE HIGH LEVEL OF 155 00:06:34,105 --> 00:06:35,974 CHEMOTHERAPY RESISTANCE. AND 156 00:06:35,974 --> 00:06:37,843 PROBABLY AN UNDERLYING THEME 157 00:06:37,843 --> 00:06:40,178 WHICH SORT OF ENABLES THESE 158 00:06:40,178 --> 00:06:44,216 OTHER FEATURES IS THE HIGH LEVEL 159 00:06:44,216 --> 00:06:49,321 OF TUMOR HETEROGENEITY. THE 160 00:06:49,321 --> 00:06:50,922 HETEROGENEITY IS NOT DRIVEN BY 161 00:06:50,922 --> 00:06:53,058 MUTATIONAL DIFFERENCES. THIS IS 162 00:06:53,058 --> 00:06:55,927 A WHOLE GENOME SEQUENCE OF ABOUT 163 00:06:55,927 --> 00:06:59,030 100 SCLCS YOU CAN SEE ALMOST 164 00:06:59,030 --> 00:07:02,501 EVERY TUMOR IS MARKED IN RB AND 165 00:07:02,501 --> 00:07:04,102 THESE TWO ARE LOST BY VARIOUS 166 00:07:04,102 --> 00:07:05,370 MECHANISMS. BUT IF YOU LOOK AT 167 00:07:05,370 --> 00:07:08,139 THE OTHER FREQUENT MUTATIONS, 168 00:07:08,139 --> 00:07:09,941 MOST OF THEM INVOLVE MUTATIONS 169 00:07:09,941 --> 00:07:12,077 IN CHROMATIN MODIFIERS OR OTHER 170 00:07:12,077 --> 00:07:13,378 TUMOR SUPPRESSORS AND YOU 171 00:07:13,378 --> 00:07:16,548 TYPICALLY DON'T SEE THE 172 00:07:16,548 --> 00:07:18,450 MUTATIONS IN E.G.FR OR DRUG 173 00:07:18,450 --> 00:07:24,089 MUTATIONS. IF BUT RATHER, THE 174 00:07:24,089 --> 00:07:25,824 HETEROGENEITY IS DRIVEN BY 175 00:07:25,824 --> 00:07:27,192 DIFFERENCES IN TRANSCRIPTIONAL 176 00:07:27,192 --> 00:07:29,060 PROGRAMS RECENT STUDIES HAVE 177 00:07:29,060 --> 00:07:31,096 SHOWN THAT IT CAN BE DIVIDED 178 00:07:31,096 --> 00:07:33,798 INTO TWO GROUPS A LARGER GROUP 179 00:07:33,798 --> 00:07:36,968 SEEN IN ABOUT TWO-THIRDS OF SCLC 180 00:07:36,968 --> 00:07:39,971 SO THIS INCLUDES CELL LINES AND 181 00:07:39,971 --> 00:07:42,073 TUMORS. THE LARGER GROUP 182 00:07:42,073 --> 00:07:45,911 EXPRESSES NEUROENDOCRINE 183 00:07:45,911 --> 00:07:46,411 PROGRAMS AND THESE ARE 184 00:07:46,411 --> 00:07:48,914 REFLECTIVE OF THE CELLS OF 185 00:07:48,914 --> 00:07:50,448 ORIGIN, THESE ARE PART OF THE 186 00:07:50,448 --> 00:07:52,050 CELLS. SO THE LARGE PROPORTION 187 00:07:52,050 --> 00:07:54,085 OF THEM HAVE THE GENE EXPRESSION 188 00:07:54,085 --> 00:07:55,820 PROGRAMS AND A SMALLER 189 00:07:55,820 --> 00:07:57,522 PROPORTION ABOUT A THIRD OF SCLC 190 00:07:57,522 --> 00:07:59,791 THEY HAVE REDUCED OR ABSENT 191 00:07:59,791 --> 00:08:02,561 EXPRESSION OF NEUROENDOCRINE 192 00:08:02,561 --> 00:08:07,198 PROGRAMS. THEY'RE CALLED 193 00:08:07,198 --> 00:08:09,367 NON-NEUROENDOCRINE SCLC AND THEY 194 00:08:09,367 --> 00:08:12,203 LOSE THIS DURING PROGRESSION, SO 195 00:08:12,203 --> 00:08:16,274 WE THINK TRANSCRIPTOMIC IS 196 00:08:16,274 --> 00:08:19,144 LIKELY ALLOWING THIS TO BE CHEMO 197 00:08:19,144 --> 00:08:21,813 RESISTANT AND TO HAVE, YOU KNOW, 198 00:08:21,813 --> 00:08:24,015 VERY DISMAL OUTCOMES. RIGHT. 199 00:08:24,015 --> 00:08:27,519 SO WE KNOW THAT SCLC HAVE 200 00:08:27,519 --> 00:08:28,987 DISTINCT TRANSCRIPTOMIC SUBTYPES 201 00:08:28,987 --> 00:08:32,591 AND LIKE OTHER TUMOR TYPES IF WE 202 00:08:32,591 --> 00:08:34,392 CAN IDENTIFY SUBGROUP SPECIFIC 203 00:08:34,392 --> 00:08:35,527 THERAPIES THIS COULD IMPROVE 204 00:08:35,527 --> 00:08:37,162 OUTCOME. THIS IS THE BASIC 205 00:08:37,162 --> 00:08:38,296 PREMISE THAT WE'RE WORKING WITH 206 00:08:38,296 --> 00:08:42,000 BUT FOR NOW, DESPITE ALL THE 207 00:08:42,000 --> 00:08:44,002 HETEROGENEITY T TREATMENT 208 00:08:44,002 --> 00:08:44,703 STRATEGIES ARE UNIFORM. 209 00:08:44,703 --> 00:08:45,837 AND EVERY SINGLE PATIENT IS 210 00:08:45,837 --> 00:08:49,341 TREATED UNIFORMLY WITH THE SAME 211 00:08:49,341 --> 00:08:51,376 TREATMENTS WHICH WE TALKED ABOUT 212 00:08:51,376 --> 00:08:52,744 BEFORE. CHEMOTHERAPY AND THE 213 00:08:52,744 --> 00:08:54,079 RELAPSE THERE'S A COUPLE 214 00:08:54,079 --> 00:08:55,380 TREATMENTS THAT ARE APPROVED. 215 00:08:55,380 --> 00:08:58,850 ALL RIGHT, SO THAT'S THE 216 00:08:58,850 --> 00:09:01,519 INTRODUCTION SO FOR TODAY, I 217 00:09:01,519 --> 00:09:04,756 WILL PRIMARILY TALK ABOUT TWOS A 218 00:09:04,756 --> 00:09:05,490 PEB 219 00:09:05,490 --> 00:09:05,924 PEB 220 00:09:05,924 --> 00:09:06,358 PEB 221 00:09:06,358 --> 00:09:07,459 PEBLTS -- ASPECTS OF OUR WORK. 222 00:09:07,459 --> 00:09:12,063 HOW WE'RE TRYING TO OVERCOME 223 00:09:12,063 --> 00:09:13,832 CHEMORESISTANCE AND REPLICATION 224 00:09:13,832 --> 00:09:15,333 STRESS AND SECONDLY HOW WE ARE 225 00:09:15,333 --> 00:09:17,669 TRYING TO TARGET HETEROGENEITY 226 00:09:17,669 --> 00:09:19,337 IN PATIENTS AND TO UNDERSTAND 227 00:09:19,337 --> 00:09:22,707 THE DRIVERS AND CONSEQUENCES OF 228 00:09:22,707 --> 00:09:25,677 SCLC HETEROGENEITY SO THE FIRST 229 00:09:25,677 --> 00:09:28,747 PART IS REPLICATION STRESS. 230 00:09:28,747 --> 00:09:29,748 REPLICATION STRESS REFERS TO, 231 00:09:29,748 --> 00:09:31,716 YOU KNOW, ANY PROBLEMS OR 232 00:09:31,716 --> 00:09:33,084 IMPEDIMENTS WITH DNA REPLICATION 233 00:09:33,084 --> 00:09:35,987 AND YOU CAN SEE HERE SOME OF THE 234 00:09:35,987 --> 00:09:38,423 FEATURES THAT DRIVE REPLICATION 235 00:09:38,423 --> 00:09:41,826 STRESS SO THESE INCLUDE ANYTHING 236 00:09:41,826 --> 00:09:44,496 THAT INTERFERES WITH THE DNA 237 00:09:44,496 --> 00:09:46,498 REPLICATION CAN CAUSE 238 00:09:46,498 --> 00:09:48,066 REPLICATION STRESS AND IN SCLC 239 00:09:48,066 --> 00:09:49,834 WE KNOW SOME OF THE KEY FEATURES 240 00:09:49,834 --> 00:09:51,236 WE TALKED ABOUT, THERE'S 241 00:09:51,236 --> 00:09:52,504 AMPLIFICATION THAT'S HIGHLY 242 00:09:52,504 --> 00:09:53,905 FREQUENT. YOU KNOW, ALL OF 243 00:09:53,905 --> 00:09:59,044 THESE ARE KNOWN FACTORS. AND 244 00:09:59,044 --> 00:10:00,311 SCLC ALSO EXHIBITS MANY 245 00:10:00,311 --> 00:10:02,147 CONSEQUENCES OF REPLICATION 246 00:10:02,147 --> 00:10:04,182 STRESS AND THESE INCLUDE ZEENOMA 247 00:10:04,182 --> 00:10:07,952 AND INSTABILITY WHICH IS 248 00:10:07,952 --> 00:10:09,821 MANIFESTED LOAD. AND THESE 249 00:10:09,821 --> 00:10:11,489 HUMANS RESPOND AND LITERALLY 250 00:10:11,489 --> 00:10:13,258 MELT AWAY WITH CHEMOTHERAPY IT'S 251 00:10:13,258 --> 00:10:16,528 ALSO A FUTURE OF TUMORS THAT ARE 252 00:10:16,528 --> 00:10:17,629 UNDER HIGH REPLICATION STRESS. 253 00:10:17,629 --> 00:10:19,631 RIGHT? SO WE HYPOTHESIZED BASED 254 00:10:19,631 --> 00:10:22,734 ON THE REPLICATION STRESS MUST 255 00:10:22,734 --> 00:10:26,838 BE A SCLC AND THE TARGETING 256 00:10:26,838 --> 00:10:28,206 STRESS YOU CAN PRODUCE SUSTAINED 257 00:10:28,206 --> 00:10:29,908 TUMOR RESPONSES IN PATIENTS. 258 00:10:29,908 --> 00:10:32,210 AND THE MAIN TRANSDUCER OF 259 00:10:32,210 --> 00:10:34,546 REPLICATION STRESS IS ATR. AND 260 00:10:34,546 --> 00:10:35,847 AT THE TIME WE WERE THINKING 261 00:10:35,847 --> 00:10:38,450 ABOUT THIS ATR INHIBITORS WAS 262 00:10:38,450 --> 00:10:40,518 STARTING TO COME INTO CLINIC AND 263 00:10:40,518 --> 00:10:43,855 WE FOUND THROUGH A CAT SCREEN 264 00:10:43,855 --> 00:10:47,792 THAT INHIBITORS OF ATR ARE 265 00:10:47,792 --> 00:10:51,496 HIGHLY TOXIC. SO WE TOOK THIS 266 00:10:51,496 --> 00:10:52,130 OBSERVATIONS INTO CLINICAL TRIAL 267 00:10:52,130 --> 00:10:53,765 WHERE WE PERFORMED A PHASE ONE 268 00:10:53,765 --> 00:10:57,302 CLINICAL TRIAL COMBINING ATR 269 00:10:57,302 --> 00:10:59,370 INHIBITOR. SO THIS WAS THE 270 00:10:59,370 --> 00:11:01,639 FIRST THAT HAD COME AROUND 271 00:11:01,639 --> 00:11:07,846 2013-14 THEN WE COMBINED THAT 272 00:11:07,846 --> 00:11:09,414 WITH TOPOTECAN. IT CAN CAUSE 273 00:11:09,414 --> 00:11:10,381 REPLICATION STRESS BY ITSELF. 274 00:11:10,381 --> 00:11:13,084 AND IT'S ALSO AN APPROVED SECOND 275 00:11:13,084 --> 00:11:15,353 LINE TREATMENT FOR SCLC PATIENTS 276 00:11:15,353 --> 00:11:19,924 SO HERE WE ARE TAKING AN SCLC 277 00:11:19,924 --> 00:11:21,359 DRUG THAT'S APPROVED, KNOWN TO 278 00:11:21,359 --> 00:11:22,393 CAUSE STRESS AND YOU'RE 279 00:11:22,393 --> 00:11:23,828 COMBINING THE INHIBITOR WHICH 280 00:11:23,828 --> 00:11:25,830 CAN MESS UP THE RESPONSE BY THE 281 00:11:25,830 --> 00:11:29,534 CELLS AND THE HOPE IS WE CAN 282 00:11:29,534 --> 00:11:32,403 DAMAGE OR SELECTIVELY KILL THE 283 00:11:32,403 --> 00:11:34,105 CELLS. SO IN TUMOR PHASE ONE 284 00:11:34,105 --> 00:11:36,107 TRIAL IS TO KNOW IF THIS IS SAFE 285 00:11:36,107 --> 00:11:37,842 IN PATIENT. THIS IS A 286 00:11:37,842 --> 00:11:39,477 COMBINATION THAT'S NEVER BEEN 287 00:11:39,477 --> 00:11:41,679 TESTED. ATR INHIBITORS HAVE 288 00:11:41,679 --> 00:11:43,515 ALSO NOT BEEN TESTED IN 289 00:11:43,515 --> 00:11:44,282 COMBINATIONS BEFORE SO WE 290 00:11:44,282 --> 00:11:46,251 OBSERVED PHARMACODYNAMIC 291 00:11:46,251 --> 00:11:51,389 ACTIVITY USING GEMMATES SIGNALS 292 00:11:51,389 --> 00:11:52,857 COMING FROM THE HAIR FOLLICLES 293 00:11:52,857 --> 00:11:56,327 AND WE FOUND THERE ARE INCREASED 294 00:11:56,327 --> 00:11:58,530 SIGNALS WITH TREATMENT OF 295 00:11:58,530 --> 00:12:00,098 TOPOTECAN BUT WHEN WE TREAT IT 296 00:12:00,098 --> 00:12:04,803 WITH THE INHIBITOR, WE FOUND 297 00:12:04,803 --> 00:12:05,303 THAT IMMEDIATELY AFTER 298 00:12:05,303 --> 00:12:07,172 ADMINISTRATION OF ATR INHIBITOR 299 00:12:07,172 --> 00:12:09,641 THERE WAS REDUCED 300 00:12:09,641 --> 00:12:10,842 PHOSPHORYLATION IN THE HAIR 301 00:12:10,842 --> 00:12:13,812 FOLLICLES AND WHEN WE COMPARED 302 00:12:13,812 --> 00:12:17,315 TO WHAT WE WERE OBSERVING IN THE 303 00:12:17,315 --> 00:12:19,651 MONONUCLEAR CELLS WHICH DON'T 304 00:12:19,651 --> 00:12:21,553 REPLICATE AS MUCH WE FOUND THE 305 00:12:21,553 --> 00:12:24,889 SIGNALS ARE MUCH REDUCED 306 00:12:24,889 --> 00:12:28,193 SUGGESTING THERE IS SOME SORT OF 307 00:12:28,193 --> 00:12:29,527 THERAPEUTIC INDEX WHERE THE 308 00:12:29,527 --> 00:12:32,363 RAPID CELLS ARE MORE DAMAGED 309 00:12:32,363 --> 00:12:34,699 THAN LESS RAPIDLY REPLICATED 310 00:12:34,699 --> 00:12:36,067 CELLS AND EVEN IN THIS EARLY 311 00:12:36,067 --> 00:12:36,935 PHASE ONE CLINICAL TRIAL WE 312 00:12:36,935 --> 00:12:39,671 FOUND THAT A SMALL NUMBER OF 313 00:12:39,671 --> 00:12:40,972 PATIENTS ABOUT THREE OR FOUR 314 00:12:40,972 --> 00:12:43,675 PATIENT, MANY OF WHOM HAD 315 00:12:43,675 --> 00:12:46,177 RESISTANCE TUMORS HAD TOO MANY 316 00:12:46,177 --> 00:12:46,411 CASES. 317 00:12:46,411 --> 00:12:48,446 SO TO TAKE AWAY FROM THE 318 00:12:48,446 --> 00:12:51,850 STUDIES, IS THAT THE INHIBITORS 319 00:12:51,850 --> 00:12:53,818 WITH TOPOTECAN IS SAFE AND 320 00:12:53,818 --> 00:12:55,854 ASSOCIATED WITH PHARMACODYNAMIC 321 00:12:55,854 --> 00:12:57,822 ACTIVITY. SO THE NEXT QUESTION 322 00:12:57,822 --> 00:13:00,158 IS IS THIS COMBINATION 323 00:13:00,158 --> 00:13:02,560 EFFECTIVE? SO FOR THAT WE 324 00:13:02,560 --> 00:13:03,228 PERFORMED A PHASE TWO CLINICAL 325 00:13:03,228 --> 00:13:05,897 TRIAL OF THE SAME COMBINATION, 326 00:13:05,897 --> 00:13:08,366 ENROLLED ABOUT 25 PATIENT WHO IS 327 00:13:08,366 --> 00:13:10,201 HAD PREVIOUSLY RECEIVED 328 00:13:10,201 --> 00:13:10,969 TREATMENT FOR SCLC. 329 00:13:10,969 --> 00:13:13,137 AND WE FOUND THAT THE 330 00:13:13,137 --> 00:13:15,173 COMBINATION IS INDEED EFFECTIVE. 331 00:13:15,173 --> 00:13:17,842 IN ABOUT 36% OF THESE PATIENTS. 332 00:13:17,842 --> 00:13:20,378 AND INTERESTINGLY EACH BAR HERE 333 00:13:20,378 --> 00:13:21,412 REPRESENTED BEST TUMOR RESPONSE 334 00:13:21,412 --> 00:13:23,481 IN A PATIENT. WE FIND THAT 335 00:13:23,481 --> 00:13:24,315 TUMOR RESPONSES WERE FOUND 336 00:13:24,315 --> 00:13:26,217 REGARDLESS OF WHETHER THE 337 00:13:26,217 --> 00:13:27,652 PATIENT HAD PLATINUM SENSITIVE 338 00:13:27,652 --> 00:13:30,021 OR NOT WHICH MEANS THAT THEY HAD 339 00:13:30,021 --> 00:13:31,556 RESPONDED TO PRIOR PLATINUM OR 340 00:13:31,556 --> 00:13:33,858 NOT. AND THEY ALSO HAD 341 00:13:33,858 --> 00:13:36,127 RESPONSES REGARDLESS OF WHETHER 342 00:13:36,127 --> 00:13:39,697 THEY HAD PRIOR TOPOISOMERASE 343 00:13:39,697 --> 00:13:42,133 INHIBITOR OR NOT. SUGGESTING 344 00:13:42,133 --> 00:13:45,036 THIS MIGHT BE SENSITIZING TUMORS 345 00:13:45,036 --> 00:13:48,106 THAT HAD PREVIOUSLY BEEN 346 00:13:48,106 --> 00:13:49,507 RESISTANT TO TOPOTECAN AND COULD 347 00:13:49,507 --> 00:13:51,576 BE APPLIED TO PATIENTS WHO HAD 348 00:13:51,576 --> 00:13:52,777 RECEIVED THIS. AND YOU CAN SEE 349 00:13:52,777 --> 00:13:53,811 THE RESPONSE IN THESE PATIENTS 350 00:13:53,811 --> 00:13:55,446 AND YOU CAN SEE THAT OF COURSE 351 00:13:55,446 --> 00:13:56,514 NOT ALL PATIENTS RESPONDED 352 00:13:56,514 --> 00:13:58,383 WITHIN THE PATIENTS WHO 353 00:13:58,383 --> 00:14:00,118 RESPONDED SOME OF THEM, MOST OF 354 00:14:00,118 --> 00:14:01,619 THEM LASTED FOR MORE THAN SIX 355 00:14:01,619 --> 00:14:03,855 MONTHS AND IN SOME CASE THE 356 00:14:03,855 --> 00:14:05,757 RESPONSES WERE MORE DURABLE 357 00:14:05,757 --> 00:14:07,458 LASTING MORE THAN 10 MONTHS AND 358 00:14:07,458 --> 00:14:09,460 12 MONTHS IN SOME INSTANCES THIS 359 00:14:09,460 --> 00:14:10,762 IS AN EXAMPLE OF A PATIENT WHO 360 00:14:10,762 --> 00:14:12,931 HAD A VERY NICE TUMOR RESPONSE. 361 00:14:12,931 --> 00:14:15,500 SHE HAD PREVIOUSLY RECEIVED A 362 00:14:15,500 --> 00:14:18,670 COMBINATION OF IMMUNOTHERAPY AND 363 00:14:18,670 --> 00:14:20,672 TOPOTECAN AND THIS WAS HER 364 00:14:20,672 --> 00:14:22,373 BASELINE SCAN. YOU CAN SEE THE 365 00:14:22,373 --> 00:14:24,409 TUMORS IN THE LIVER AS INDICATED 366 00:14:24,409 --> 00:14:26,344 HERE AND THESE SHRANK WITHIN SIX 367 00:14:26,344 --> 00:14:27,145 WEEKS OF TREATMENT AND YOU CAN 368 00:14:27,145 --> 00:14:29,080 SEE THIS TWELVE WEEKS AFTER 369 00:14:29,080 --> 00:14:30,048 TREATMENT. AND THE RESPONSE WAS 370 00:14:30,048 --> 00:14:33,318 SUSTAINED FOR ABOUT 8-10 MONTHS 371 00:14:33,318 --> 00:14:35,186 BEFORE SHE CAME OFF DUE TO 372 00:14:35,186 --> 00:14:36,087 DISEASE PROGRESSION. SO WE FIND 373 00:14:36,087 --> 00:14:38,456 THAT THE COMBINATION CAN CAUSE 374 00:14:38,456 --> 00:14:40,658 DURABLE TUMOR RESPONSES SO WE 375 00:14:40,658 --> 00:14:42,293 FOUND A COMBINATION THAT'S SAFE, 376 00:14:42,293 --> 00:14:44,662 EFFECTIVE, THE NEXT STEP IS TO 377 00:14:44,662 --> 00:14:46,464 SEE HOW DOES THIS COMBINATION 378 00:14:46,464 --> 00:14:48,399 COMPARE TO STANDARD TREATMENTS? 379 00:14:48,399 --> 00:14:49,834 RIGHT? SO THIS -- SO WE 380 00:14:49,834 --> 00:14:52,437 PERFORMED A RANDOMIZED CLINICAL 381 00:14:52,437 --> 00:14:57,308 TRIAL. 60 PARTICIPANTS WERE 382 00:14:57,308 --> 00:14:58,910 RANDOMIZED TO RECEIVE EITHER 383 00:14:58,910 --> 00:15:01,980 TOPOTECAN ALONE OR PLUS THE ATR 384 00:15:01,980 --> 00:15:03,314 INHIBITOR. AGAIN AS WITH THE 385 00:15:03,314 --> 00:15:04,983 PREVIOUS CLINICAL TRIALS THESE 386 00:15:04,983 --> 00:15:08,553 PATIENTS HAD RELAPSED SCLC. HAD 387 00:15:08,553 --> 00:15:09,821 RECEIVED ONE OR MORE TRIAL 388 00:15:09,821 --> 00:15:11,322 THERAPIES AND THIS WAS A -- THIS 389 00:15:11,322 --> 00:15:13,825 WAS ENROLLED ACROSS THE U.S. 390 00:15:13,825 --> 00:15:16,694 THE SIXTEEN CANCER CENTERS 391 00:15:16,694 --> 00:15:17,628 ENROLLED IN THIS CLINICAL TRIAL. 392 00:15:17,628 --> 00:15:19,030 SO HERE LOOKING AT THE RESPONSES 393 00:15:19,030 --> 00:15:21,833 IN THE PATIENTS IN THE LEFT IS 394 00:15:21,833 --> 00:15:23,201 PATIENTS WHO RECEIVED TOPOTECAN 395 00:15:23,201 --> 00:15:25,503 ALONE AND IN THE RIGHT IS 396 00:15:25,503 --> 00:15:26,738 PATIENTS WHO RECEIVED BOTH 397 00:15:26,738 --> 00:15:27,405 DRUGS, COMBINATION. AND YOU CAN 398 00:15:27,405 --> 00:15:30,641 SEE THE RESPONSE RATES WITH 399 00:15:30,641 --> 00:15:32,243 TOPOTECAN ALONE WAS 6%. THIS IS 400 00:15:32,243 --> 00:15:33,911 CONSISTENT WITH WHAT WE EXPECT 401 00:15:33,911 --> 00:15:37,148 WITH THE SINGLE DRUG AND WITH 402 00:15:37,148 --> 00:15:38,249 THE COMBINATION YOU SEE THE 403 00:15:38,249 --> 00:15:40,818 HIGHER RATES OF RESPONSES. AND 404 00:15:40,818 --> 00:15:42,453 THE DURATION OF THE RESPONSE WAS 405 00:15:42,453 --> 00:15:49,827 LONGER, 3.3 MONTHS, 9.3 WITH THE 406 00:15:49,827 --> 00:15:52,096 COMBINATION. THE OTHER WAS THE 407 00:15:52,096 --> 00:15:52,730 PROGRESSION-FREE SURVIVAL. WE 408 00:15:52,730 --> 00:15:55,666 DID NOT SEE A DIFFERENCE IN PFS. 409 00:15:55,666 --> 00:15:58,536 IT WAS ABOUT THREE MONTHS WITH A 410 00:15:58,536 --> 00:16:01,072 SINGLE DRUG AND 3.9 WITH A 411 00:16:01,072 --> 00:16:02,473 COMBINATION. SO THIS IS FROM 412 00:16:02,473 --> 00:16:04,375 THE TIME OF THE ENROLLMENT TO 413 00:16:04,375 --> 00:16:06,744 COMING OFF TREATMENT DUE TO 414 00:16:06,744 --> 00:16:07,945 TUMOR PROGRESSION. 415 00:16:07,945 --> 00:16:09,247 INTERESTINGLY HOWEVER WE SAW 416 00:16:09,247 --> 00:16:11,115 THAT PATIENTS HAD SIGNIFICANTLY 417 00:16:11,115 --> 00:16:12,116 LONGER OVERALL SURVIVAL WHEN 418 00:16:12,116 --> 00:16:14,852 THEY RECEIVED THE COMBINATION. 419 00:16:14,852 --> 00:16:16,521 ABOUT NINE COMPARED TO FIVE 420 00:16:16,521 --> 00:16:18,322 MONTHS AND ABOUT 3-4 MONTHS 421 00:16:18,322 --> 00:16:20,358 DIFFERENCE IN OVERALL SURVIVAL 422 00:16:20,358 --> 00:16:22,727 WHICH IS A MAJOR DIFFERENCE IN 423 00:16:22,727 --> 00:16:23,861 THE SCLC SETTING SO WE FIND THAT 424 00:16:23,861 --> 00:16:26,898 THE COMBINATION RESULTED 425 00:16:26,898 --> 00:16:28,232 IMPROVED RESPONSE, IMPROVED 426 00:16:28,232 --> 00:16:29,400 DURATION OF RESPONSES AS WELL AS 427 00:16:29,400 --> 00:16:33,271 IMPROVED OVERALL SURVIVAL. BUT 428 00:16:33,271 --> 00:16:34,472 CLEARLY AS I THINK SEE NOT EVERY 429 00:16:34,472 --> 00:16:36,707 PATIENT RESPONDS. SOME PATIENTS 430 00:16:36,707 --> 00:16:38,309 RESPOND, SOME PATIENTS DON'T 431 00:16:38,309 --> 00:16:40,278 RESPOND SO HOW DO YOU DETERMINE 432 00:16:40,278 --> 00:16:45,183 WHO IS RESPONDING? SO FOR THIS 433 00:16:45,183 --> 00:16:46,818 WE PERFORMED THE TREATMENT OF 434 00:16:46,818 --> 00:16:49,320 TUMORS OF PATIENTS WHO ENROLLED 435 00:16:49,320 --> 00:16:51,856 AND TWO OBSERVATIONS STOOD OUT. 436 00:16:51,856 --> 00:16:52,457 ONE WAS THAT THE RESPONDING 437 00:16:52,457 --> 00:16:56,327 TUMORS THAT WERE ENLISTED IN 438 00:16:56,327 --> 00:16:58,863 PATHWAYS RELATED TO THE TARGETS 439 00:16:58,863 --> 00:17:00,131 AND CHECKPOINT AS WELL AS 440 00:17:00,131 --> 00:17:01,199 MULTIPLE DNA REPAIR SUGGESTING 441 00:17:01,199 --> 00:17:04,502 THESE ARE TUMORS, THE RESPONDING 442 00:17:04,502 --> 00:17:06,270 TUMORS ARE PROBABLY UNDER HIGH 443 00:17:06,270 --> 00:17:08,439 LEVELS OF REPLICATION STRESS THE 444 00:17:08,439 --> 00:17:10,141 SECOND TAKEAWAY FROM THE 445 00:17:10,141 --> 00:17:11,809 SEQUENCING ANALYSIS WAS THE 446 00:17:11,809 --> 00:17:13,811 TUMORS THAT RESPONDED HAD HIGH 447 00:17:13,811 --> 00:17:16,280 LEVELS OF NEUROENDOCRINE 448 00:17:16,280 --> 00:17:17,782 DIFFERENTIATION. IF YOU 449 00:17:17,782 --> 00:17:20,051 REMEMBER, THIS GENERAL NAYTY 450 00:17:20,051 --> 00:17:22,353 CONSISTS OF TWO BROAD GROUPS A 451 00:17:22,353 --> 00:17:24,622 GROUP OF TUMORS THAT HAVE 452 00:17:24,622 --> 00:17:25,022 DIFFERENTIATION. 453 00:17:25,022 --> 00:17:28,292 AND THERE ARE SOME TUMORS THAT 454 00:17:28,292 --> 00:17:33,264 LOSE NEURONS. AND WHEN WE LOOK 455 00:17:33,264 --> 00:17:34,999 AT THIS KEY MARKERS INCLUDING 456 00:17:34,999 --> 00:17:36,934 DURATION OF RESPONSE AND 457 00:17:36,934 --> 00:17:37,702 PROGRESSION-FREE SURVIVAL WE 458 00:17:37,702 --> 00:17:39,871 FIND THAT PATIENTS WITH TUMORS 459 00:17:39,871 --> 00:17:41,839 THAT HAD THIS DIFFERENTIATION 460 00:17:41,839 --> 00:17:43,307 HAD SIGNIFICANTLY LONGER 461 00:17:43,307 --> 00:17:45,076 DURATION OF RESPONSE AS WELL AS 462 00:17:45,076 --> 00:17:47,178 PROGRESSION-FREE SURVIVAL 463 00:17:47,178 --> 00:17:49,814 COMPARED TO PATIENTS WHO HAD A 464 00:17:49,814 --> 00:17:57,421 NON DEG REGAGS. TO TAKE -- AWAY 465 00:17:57,421 --> 00:17:59,423 FROM THIS. THERE'S A HIGH 466 00:17:59,423 --> 00:18:01,325 REPLICATION STRESS. AND THESE 467 00:18:01,325 --> 00:18:02,360 ARE TUMORS THAT MIGHT BENEFIT. 468 00:18:02,360 --> 00:18:05,830 FROM THESE COMBINATIONS. ATR 469 00:18:05,830 --> 00:18:07,098 INHIBITOR AND SO FORTH SO HERE 470 00:18:07,098 --> 00:18:08,666 WE HAVE A DISEASE THAT'S 471 00:18:08,666 --> 00:18:09,800 CONSIDERED AS A SINGLE ENTITY. 472 00:18:09,800 --> 00:18:12,970 WE CAN USE LIMITED NUMBER OF 473 00:18:12,970 --> 00:18:14,505 PATIENTS. PRETREATMENT RNA 474 00:18:14,505 --> 00:18:15,673 SEQUENCING AND IDENTIFY WHO IS 475 00:18:15,673 --> 00:18:17,808 MORE LIKELY TO RESPOND VERSUS 476 00:18:17,808 --> 00:18:19,610 NOT. NOW, REPLICATION STRESS IS 477 00:18:19,610 --> 00:18:21,913 NOT A FEATURE THAT IS UNIQUE TO 478 00:18:21,913 --> 00:18:23,514 SCLC. THERE'S A LOT OF OTHER 479 00:18:23,514 --> 00:18:26,884 TUMORS THAT HAVE REPLICATION 480 00:18:26,884 --> 00:18:29,820 STRESS. ALL THE OTHER TUMORS 481 00:18:29,820 --> 00:18:32,557 THAT ARE WORKING RAPIDLY. THE 482 00:18:32,557 --> 00:18:36,394 OTHER QUESTION IS CAN WE DEFINE 483 00:18:36,394 --> 00:18:38,129 THIS TO IDENTIFY REPLICATION 484 00:18:38,129 --> 00:18:39,697 STRESS? THAT'S WHAT WE TRIED TO 485 00:18:39,697 --> 00:18:43,434 DO HERE SO WE USE THESE KEY 486 00:18:43,434 --> 00:18:47,738 OBSERVATIONS FROM THE EARLY IER 487 00:18:47,738 --> 00:18:51,576 DATA THAT I SHOWED. WE USED KEY 488 00:18:51,576 --> 00:18:53,744 FEATURES KNOWN TO BE FEATURED. 489 00:18:53,744 --> 00:18:56,314 SO THESE ARE ACTIVATION OF CHECK 490 00:18:56,314 --> 00:19:00,151 ONE, AND RESPONSES TO CHECK ONE 491 00:19:00,151 --> 00:19:01,352 INHIBITORS AND THESE ARE CELL 492 00:19:01,352 --> 00:19:03,221 LINE DATA AND WE IDENTIFIED AN 493 00:19:03,221 --> 00:19:06,724 18 GENE REPLICATION SIGNATURE 494 00:19:06,724 --> 00:19:08,526 WHICH IS APPLICABLE TO SCLC AND 495 00:19:08,526 --> 00:19:11,662 BEYOND AND WE VALIDATED IT. THE 496 00:19:11,662 --> 00:19:13,364 FIRST OBSERVATION WAS AN 497 00:19:13,364 --> 00:19:14,665 INCREASED REPLICATION STRESS 498 00:19:14,665 --> 00:19:16,634 CODE OR REP STRESS CODE AS WE 499 00:19:16,634 --> 00:19:20,771 CALL IT IS ASSOCIATED WITH HIGH 500 00:19:20,771 --> 00:19:23,908 LEVELS OF INTRINSIC INSTABL 501 00:19:23,908 --> 00:19:25,343 STABILITY THESE ARE ORDERED 502 00:19:25,343 --> 00:19:26,978 BASED ON THE REPLICATION STRESS. 503 00:19:26,978 --> 00:19:29,447 WE FIND THAT HIGHER REP STRESS 504 00:19:29,447 --> 00:19:32,450 CORE CELLS HAVE HIGHER 505 00:19:32,450 --> 00:19:34,518 EXPRESSION OF GAMMA AND WE 506 00:19:34,518 --> 00:19:37,822 CONFIRMED THIS USING THE DNA 507 00:19:37,822 --> 00:19:41,392 ASSAYS WHERE WE LABEL THEM WITH 508 00:19:41,392 --> 00:19:46,664 THE ANALOGS AND WE FIND THAT 509 00:19:46,664 --> 00:19:50,368 CELLS THAT LINE WITH THE STRESS 510 00:19:50,368 --> 00:19:52,703 HAVE SHORTER ORIGIN DISTANCES 511 00:19:52,703 --> 00:19:58,509 AND ALSO ASYMMETRIC FORKS AND 512 00:19:58,509 --> 00:20:00,211 FINALLY WE HAVE APPLIED THIS TO 513 00:20:00,211 --> 00:20:02,613 CELL LINES FROM ACROSS LINEAGES 514 00:20:02,613 --> 00:20:09,287 SO THESE ARE NOW GOING OND 515 00:20:09,287 --> 00:20:12,923 BEY -- 516 00:20:12,923 --> 00:20:14,325 BEYOND OTHER SCLCS TO OTHER CELL 517 00:20:14,325 --> 00:20:16,394 LINES. NOW WE HAVE PREDICTORS 518 00:20:16,394 --> 00:20:16,827 OF RESPONSE. 519 00:20:16,827 --> 00:20:17,995 WE HAVE POTENTIAL -- OF COURSE 520 00:20:17,995 --> 00:20:20,164 THESE NEED TO BE CONFIRMED IN 521 00:20:20,164 --> 00:20:21,632 LARGER STUDIES AND SO FORTH. 522 00:20:21,632 --> 00:20:22,733 THE NEXT QUESTION WE ASKED IS 523 00:20:22,733 --> 00:20:25,269 CAN WE IMPROVE THE THERAPEUTIC 524 00:20:25,269 --> 00:20:27,104 INDEX OF THESE THERAPIES? FOR 525 00:20:27,104 --> 00:20:29,807 THIS COMBINATION THAT WE TESTED 526 00:20:29,807 --> 00:20:32,310 TOPOTECAN PLUS ANOTHER. THE 527 00:20:32,310 --> 00:20:34,578 COMBINATION IS RELATIVELY SAFE 528 00:20:34,578 --> 00:20:36,180 BUT ALMOST EVERY SINGLE PATIENT 529 00:20:36,180 --> 00:20:40,318 HAS ANEMIA AND ABOUT 50% OF THE 530 00:20:40,318 --> 00:20:42,186 PATIENTS IT'S SERIOUS AND THIS 531 00:20:42,186 --> 00:20:44,021 IS TO BE EXPECTED BECAUSE 532 00:20:44,021 --> 00:20:46,390 THEY'RE A LOT MORE RAPIDLY 533 00:20:46,390 --> 00:20:49,026 PROLIFERATING CELLS. YOUR HAIR 534 00:20:49,026 --> 00:20:50,428 CELLS, EVERYTHING IS RAPIDLY 535 00:20:50,428 --> 00:20:52,263 PROLIFERATING. SO, YOU KNOW, WE 536 00:20:52,263 --> 00:20:54,231 WOULD EXPECT SOME LEVEL OF 537 00:20:54,231 --> 00:20:56,434 THERAPEUTIC INDEX BECAUSE TUMOR 538 00:20:56,434 --> 00:20:58,235 CELLS ARE MORE RAPIDLY 539 00:20:58,235 --> 00:20:59,637 PROLIFERATING. THEY'RE MORE 540 00:20:59,637 --> 00:21:00,738 RELIANT ON STRESS RESPONSES AND 541 00:21:00,738 --> 00:21:03,941 SO FORTH BUT WE DO SEE 542 00:21:03,941 --> 00:21:05,810 TOXICITIES. ONE APPROACH WE 543 00:21:05,810 --> 00:21:09,513 TRIED TO MITIGATE THE TOXICITY 544 00:21:09,513 --> 00:21:12,183 IS TO DELIVER CHEMOTHERAPY 545 00:21:12,183 --> 00:21:15,353 RATHER THAN USE CONVENTIONAL 546 00:21:15,353 --> 00:21:16,987 CHEMOTHERAPY THIS IS ONE OF THE 547 00:21:16,987 --> 00:21:27,531 EARLIER CONJUGATES WHICH TARGETS 548 00:21:28,432 --> 00:21:31,635 TROP 2 AND IT HAS A PAYLOAD. 549 00:21:31,635 --> 00:21:33,738 RATHER THAN USING TROE POE TEE 550 00:21:33,738 --> 00:21:35,806 CAN PLUS THE INHIBITOR HERE WE 551 00:21:35,806 --> 00:21:37,975 ARE USING THE ISOMERASE 552 00:21:37,975 --> 00:21:41,812 INHIBITOR USING AN ADC WITH AN 553 00:21:41,812 --> 00:21:43,314 ADR INHIBITORS AND WE FIND THERE 554 00:21:43,314 --> 00:21:45,816 IS MUCH LESS TOXICITIES SO WE 555 00:21:45,816 --> 00:21:49,253 SEE A REDUCED FREQUENCY OF 556 00:21:49,253 --> 00:21:50,354 ANEMIA. IT'S MUCH LESS 557 00:21:50,354 --> 00:21:51,889 TOLERABLE. NOT TO SAY THAT THIS 558 00:21:51,889 --> 00:21:54,358 IS COMPLETELY WITHOUT TOXICITY. 559 00:21:54,358 --> 00:21:56,660 YOU KNOW, THE TECHNOLOGY IS NOT 560 00:21:56,660 --> 00:21:58,729 EVOLVED TO A POINT WHERE WE'RE 561 00:21:58,729 --> 00:22:00,798 ABLE TO DELIVER CHEMOTHERAPY 562 00:22:00,798 --> 00:22:03,234 ALMOST EXCLUSIVELY TO THE TUMOR. 563 00:22:03,234 --> 00:22:04,268 I DON'T THINK WE'RE THERE YET 564 00:22:04,268 --> 00:22:05,803 BUT WE CAN SEE IT'S MUCH LESS 565 00:22:05,803 --> 00:22:07,371 AND IN FACT WE'RE FINDING THAT 566 00:22:07,371 --> 00:22:09,807 THE SECOND GENERATION 567 00:22:09,807 --> 00:22:13,744 COMBINATION COMBINING ADC BASE 568 00:22:13,744 --> 00:22:15,479 INHIBITORS PLUS THE OTHER 569 00:22:15,479 --> 00:22:16,580 PRODUCES TUMOR RESPONSES AND 570 00:22:16,580 --> 00:22:21,519 THIS IS A PATIENT WHO HAD 571 00:22:21,519 --> 00:22:23,354 PROSTATE CANCER AND YOU SEE 572 00:22:23,354 --> 00:22:24,021 MULTIPLE TUMORS PROGRESS AFTER 573 00:22:24,021 --> 00:22:26,457 ONE OR TWO CYCLES OF 574 00:22:26,457 --> 00:22:28,159 COMBINATION. OKAY, FINALLY WE 575 00:22:28,159 --> 00:22:30,761 ARE ASKING WHAT IS THE MOLECULAR 576 00:22:30,761 --> 00:22:33,397 BASIS OF REPLICATION STRESS? 577 00:22:33,397 --> 00:22:35,132 AND THIS IS RELATIVELY RECENT 578 00:22:35,132 --> 00:22:37,802 DATA WHICH IS UNPUBLISHED AND WE 579 00:22:37,802 --> 00:22:40,070 FIND THAT AN UNEXPECTED TARGET 580 00:22:40,070 --> 00:22:42,206 MIGHT BE DRIVING REPLICATION 581 00:22:42,206 --> 00:22:45,576 STRESS IN SCLC SO THE USUAL 582 00:22:45,576 --> 00:22:47,812 SUSPECTS ARE ON GENE 583 00:22:47,812 --> 00:22:50,414 AMPLIFICATION. LIKE THE HIGH 584 00:22:50,414 --> 00:22:52,383 AMPLIFICATION STRESS. MAYBE 585 00:22:52,383 --> 00:22:55,986 THERE IS -- IT'S AN UNEXPECTED 586 00:22:55,986 --> 00:22:57,822 TARGET. CALLED LAM ANYONE A 587 00:22:57,822 --> 00:23:01,158 WHICH IS A NUCLEAR PROTEIN. 588 00:23:01,158 --> 00:23:02,827 IT HAS MULTIPLE FUNCTIONS AND 589 00:23:02,827 --> 00:23:04,161 THE INITIAL OBSERVATION WAS THAT 590 00:23:04,161 --> 00:23:07,465 THE CELLS TEND TO HAVE REDUCED 591 00:23:07,465 --> 00:23:09,667 LEVELS OF LAM MINA EXPANSION. 592 00:23:09,667 --> 00:23:12,136 AND THIS IS COMPARED TO OTHER 593 00:23:12,136 --> 00:23:14,171 CANCERS BUT YOU CAN SEE EVEN 594 00:23:14,171 --> 00:23:15,673 WITH THE SCLC THERE IS SOMEWHAT 595 00:23:15,673 --> 00:23:17,641 OF A VARIABILITY WITH SOME CELLS 596 00:23:17,641 --> 00:23:21,779 HAVING HIGH EXPRESSION AND SOME 597 00:23:21,779 --> 00:23:24,348 HAVING LOW LMNA EXPRESSION. 598 00:23:24,348 --> 00:23:27,084 SO WE USED THE ONE WITH THE HIGH 599 00:23:27,084 --> 00:23:29,820 LMNA EXPRESSION AND WE KNOCKED 600 00:23:29,820 --> 00:23:31,489 OUT LMNA AND WE SAW THERE WAS AN 601 00:23:31,489 --> 00:23:32,990 INCREASE COMPARED TO THE 602 00:23:32,990 --> 00:23:33,257 CONTROL. 603 00:23:33,257 --> 00:23:36,694 AND THIS IS EVALUATED BY BLOOD 604 00:23:36,694 --> 00:23:38,796 AND WHEN YOU OVEREXPRESSED THE H 605 00:23:38,796 --> 00:23:41,131 1 WHICH IS A NUCLEAR THAT 606 00:23:41,131 --> 00:23:46,537 SPECIFICALLY DEGRADES RNA IN 607 00:23:46,537 --> 00:23:48,205 HYBRIDS WE FIND THERE'S A 608 00:23:48,205 --> 00:23:51,475 SOLUTION AND YOU CAN SEE THESE 609 00:23:51,475 --> 00:23:57,314 GENOME WIDE BY DNA. THAT LMNA 610 00:23:57,314 --> 00:23:59,416 KNOCK OUT HAVE SPECIFICALLY 611 00:23:59,416 --> 00:24:01,852 MORE. SO WHAT ARE THESE? THESE 612 00:24:01,852 --> 00:24:04,455 ARE RNA/DNA HYBRIDS AND THESE 613 00:24:04,455 --> 00:24:06,724 RESULT IN DISPLACEMENT OF A 614 00:24:06,724 --> 00:24:09,660 SINGLE STRAND DNA HERE AND WE 615 00:24:09,660 --> 00:24:12,930 KNOW THAT R LOOP DEGRADATION HAS 616 00:24:12,930 --> 00:24:15,533 MULTIPLE ROLES BUT DOES CAUSE 617 00:24:15,533 --> 00:24:16,967 GENOMIC INSTABILITY AND WE FIND 618 00:24:16,967 --> 00:24:20,437 THERE IS INCREASED LEVELS OF 619 00:24:20,437 --> 00:24:23,073 GAMMA H 2X WHEN YOU SILENCE LMNA 620 00:24:23,073 --> 00:24:27,978 BUT WHEN YOU SILENCE LMNA IN 621 00:24:27,978 --> 00:24:31,815 ADDITION TO AGGREGATING OTHER 622 00:24:31,815 --> 00:24:32,316 MECHANISMS. INCLUDING 623 00:24:32,316 --> 00:24:36,186 INHIBITION AND USING TOPOTECAN 624 00:24:36,186 --> 00:24:37,821 OR RNA INHIBITION YOU SEE 625 00:24:37,821 --> 00:24:39,323 THERE'S EVEN MORE DAMAGE, RIGHT? 626 00:24:39,323 --> 00:24:41,859 AND THE COMBINATION OF BOTH 627 00:24:41,859 --> 00:24:44,962 DRUGS, TOPOTECAN IN THE SETTING 628 00:24:44,962 --> 00:24:47,464 OF SI LAMINATE TENDS TO CAUSE 629 00:24:47,464 --> 00:24:49,833 MOST DAMAGE SO SUGGESTING THAT 630 00:24:49,833 --> 00:24:52,670 THE LMNA MIGHT BE REPLICATING 631 00:24:52,670 --> 00:24:54,872 STRESS AND ONE OF THE MECHANISMS 632 00:24:54,872 --> 00:24:56,740 OF THESE TWO DRUGS TO BE 633 00:24:56,740 --> 00:24:58,809 EFFECTIVE COULD BE THAT IT COULD 634 00:24:58,809 --> 00:25:00,844 BE INDUCING REPLICATION STRESS 635 00:25:00,844 --> 00:25:02,279 WHICH IS LEADING TO INCREASED 636 00:25:02,279 --> 00:25:06,116 DNA DAMAGE AND FINALLY WE FIND 637 00:25:06,116 --> 00:25:08,719 THAT PATIENTS WHO HAVE REDUCED 638 00:25:08,719 --> 00:25:10,688 LMNA LEVELS AND THEIR TUMORS 639 00:25:10,688 --> 00:25:12,189 TEND TO HAVE WORSE SURVIVAL NOW 640 00:25:12,189 --> 00:25:13,257 THE NEXT QUESTION IS, YOU KNOW, 641 00:25:13,257 --> 00:25:18,963 HOW IS LMNA REGULATED? WE SHOW 642 00:25:18,963 --> 00:25:23,167 THAT REGULATION INCLUDES THE 643 00:25:23,167 --> 00:25:25,102 CATALYTIC COMPLEX. WE KNOW IT 644 00:25:25,102 --> 00:25:30,240 ADDS GROUPS TO HISTONE THREE AT 645 00:25:30,240 --> 00:25:33,377 LYSINE 27 AND THIS CREATES GENE 646 00:25:33,377 --> 00:25:35,679 SILENCING AND WE SEE THIS BINDS 647 00:25:35,679 --> 00:25:40,584 TO LMNA AND EPIGENETIC SEQUENCES 648 00:25:40,584 --> 00:25:43,487 AND THIS SUPPRESSES THE 649 00:25:43,487 --> 00:25:46,390 METHYLATION OF THE GENE AND WHEN 650 00:25:46,390 --> 00:25:48,225 YOU TAKE SCLC CELL LINES, MOST 651 00:25:48,225 --> 00:25:51,795 HAVE REDUCED LEVELS OF LMNA. 652 00:25:51,795 --> 00:25:54,331 AND WHEN YOU USE AN H 2 653 00:25:54,331 --> 00:25:57,401 INHIBITOR IT REEXPRESSES LMNA 654 00:25:57,401 --> 00:26:00,371 AND THERE IS REDUCED H 3 655 00:26:00,371 --> 00:26:02,706 TRIMETHYLATION WITH INHIBITION. 656 00:26:02,706 --> 00:26:05,376 BUT COINCIDENTALLY WITH THIS 657 00:26:05,376 --> 00:26:07,044 INDUCTION WE SEE THAT THESE ARE 658 00:26:07,044 --> 00:26:09,480 THE EASIEST TREATMENT RESULTS IN 659 00:26:09,480 --> 00:26:11,615 RESOLUTION OF R LOOPINGS, AGAIN, 660 00:26:11,615 --> 00:26:13,584 WE FIND THESE ARE R LOOP SIGNALS 661 00:26:13,584 --> 00:26:17,855 SPECIFICALLY FOR R LOOPS USING 662 00:26:17,855 --> 00:26:20,457 RNA WHICH ACTS AS A CONTROL 663 00:26:20,457 --> 00:26:21,125 HERE. 664 00:26:21,125 --> 00:26:24,161 SO WE FIND THAT THE H 2 665 00:26:24,161 --> 00:26:26,797 INHIBITION RESTORES EXPRESSION 666 00:26:26,797 --> 00:26:28,732 AND SUPPRESSES R LOOPS AND THIS 667 00:26:28,732 --> 00:26:31,001 ACCESS MIGHT BE CONTROLLING 668 00:26:31,001 --> 00:26:32,503 REPLICATION STRESS IN SCLC CELL 669 00:26:32,503 --> 00:26:34,538 LINES AS I MENTION LMNA HAS TO 670 00:26:34,538 --> 00:26:37,541 DO WITH A LOT OF DIFFERENT 671 00:26:37,541 --> 00:26:44,281 THINGS IN ADDITION TO GENE 672 00:26:44,281 --> 00:26:47,418 SILENCING BY METHYLATION FROM 673 00:26:47,418 --> 00:26:51,955 THE AXIS SO LMNA ALSO TRAIFS 674 00:26:51,955 --> 00:26:52,623 HISTOLOGICAL FEATURES SO IF YOU 675 00:26:52,623 --> 00:26:54,892 REMEMBER FROM THE EARLIER SLIDES 676 00:26:54,892 --> 00:26:56,393 THESE ARE THE KEY HISTOLOGICAL 677 00:26:56,393 --> 00:27:00,030 FEATURES AND TWO OF THEM I 678 00:27:00,030 --> 00:27:01,598 HIGHLIGHTED WERE NUCLEAR MOLDING 679 00:27:01,598 --> 00:27:03,901 AND ABSENCE OF NUCLEI. WHEN WE 680 00:27:03,901 --> 00:27:05,669 LOOK AT THESE KNOCKOUT CELLS WE 681 00:27:05,669 --> 00:27:08,872 FIND THAT THESE KNOCKOUT CELLS 682 00:27:08,872 --> 00:27:12,242 ALSO HAVE INDISTINCT NUCLEI AND 683 00:27:12,242 --> 00:27:14,511 ALSO SHOW THEM HUGGING EACH 684 00:27:14,511 --> 00:27:16,513 OTHER AND THIS -- AND, AGAIN, 685 00:27:16,513 --> 00:27:19,183 THEY OBSERVE THE SIMILAR 686 00:27:19,183 --> 00:27:22,052 FINDINGS WHEN YOU KNOCK OUT LMNA 687 00:27:22,052 --> 00:27:24,221 THEY TEND TO BE INDISTINCT AND 688 00:27:24,221 --> 00:27:26,156 THESE FINDINGS SUGGEST THAT THE 689 00:27:26,156 --> 00:27:29,159 LOW LMNA EXPRESSION MIGHT ALSO 690 00:27:29,159 --> 00:27:30,627 EXPLAIN THIS HISTOLOGICAL 691 00:27:30,627 --> 00:27:32,396 FEATURES OF SCLC INCLUDING THE 692 00:27:32,396 --> 00:27:36,233 NUCLEAR MOLDING, LACK OF 693 00:27:36,233 --> 00:27:38,736 DISTINCT NUCLEI AS WELL AS 694 00:27:38,736 --> 00:27:41,105 CYTOPLASM BECAUSE IT ALSO 695 00:27:41,105 --> 00:27:43,807 REGULATES CYTOPLASMIC, THE 696 00:27:43,807 --> 00:27:45,142 AMOUNT THROUGH ITS CONNECTION 697 00:27:45,142 --> 00:27:47,177 WITH THIS LINK COMPLEX WHICH 698 00:27:47,177 --> 00:27:49,847 CONNECTS IT TO THE SAY TO 699 00:27:49,847 --> 00:27:50,614 SKELETAL THROUGH THIS LINK 700 00:27:50,614 --> 00:27:53,050 COMPLEX AND THE KEY PLAYERS YOU 701 00:27:53,050 --> 00:27:54,218 SEE ARE SUM ONE AND NECESSARY 702 00:27:54,218 --> 00:27:57,955 PRINT THROUGH THEM, IT ALSO 703 00:27:57,955 --> 00:28:00,157 CONNECTS -- IT ALSO MAINTAINS 704 00:28:00,157 --> 00:28:10,701 SAY TO SKELETAL INTEGRITY. YES 705 00:28:12,970 --> 00:28:13,737 >> AUDIENCE: (SPEAKER FAR FROM 706 00:28:13,737 --> 00:28:13,937 MIC). 707 00:28:13,937 --> 00:28:16,573 >> VERY GOOD POINT. WE HAVE 708 00:28:16,573 --> 00:28:17,841 USED IN COLLABORATION WITH THE 709 00:28:17,841 --> 00:28:20,010 LAB HERE WE HAVE LOOKED AT ONE 710 00:28:20,010 --> 00:28:24,248 MODEL OF AGING. SO THIS IS 711 00:28:24,248 --> 00:28:29,052 YOUNG AND OLD FIBROBLASTSES FROM 712 00:28:29,052 --> 00:28:30,888 THE SAME INDIVIDUAL DERIVED FROM 713 00:28:30,888 --> 00:28:32,923 WHEN THEY'RE IN THEIR 20S AND 714 00:28:32,923 --> 00:28:35,025 WHEN THEY'RE IN THEIR 60S AND 715 00:28:35,025 --> 00:28:36,760 70S AND WE FIND THAT CONSISTENT 716 00:28:36,760 --> 00:28:38,762 WITH WHAT WE'RE SEEING OLDER 717 00:28:38,762 --> 00:28:41,832 FIBROBLASTS HAVE A REDUCED LMNA 718 00:28:41,832 --> 00:28:43,834 EXPRESSION AND OLDER HAVE AN 719 00:28:43,834 --> 00:28:45,836 INCREASED NUMBER OF R LOOPS SO 720 00:28:45,836 --> 00:28:48,238 THERE SEEMS TO BE A COMMON 721 00:28:48,238 --> 00:28:49,840 MECHANISM BETWEEN SCLC AND 722 00:28:49,840 --> 00:28:51,208 MODELS OF AGING. 723 00:28:51,208 --> 00:28:55,813 WHERE REDUCED LMNA IN THE CLC IT 724 00:28:55,813 --> 00:28:58,949 IS MEDIATED REGULATION. BUT IN 725 00:28:58,949 --> 00:29:01,518 THE OTHER IT CAN BE MUTATIONS IN 726 00:29:01,518 --> 00:29:03,253 LMNA BUT IT CAUSES GENOMIC 727 00:29:03,253 --> 00:29:05,355 INSTABILITY. WE THINK THAT'S AN 728 00:29:05,355 --> 00:29:06,423 INTERESTING ANGLE BECAUSE, YOU 729 00:29:06,423 --> 00:29:09,827 KNOW, THERE'S A LOT OF GENOME 730 00:29:09,827 --> 00:29:11,094 INSTABILITY BUT I'M NOT AN 731 00:29:11,094 --> 00:29:13,597 EXPERT BUT TALKING TO EXPERT I 732 00:29:13,597 --> 00:29:15,098 DON'T THINK WE KNOW FULLY 733 00:29:15,098 --> 00:29:17,835 CLEARLY WHAT EXACTLY CAUSES 734 00:29:17,835 --> 00:29:21,605 GENOME INSTABILITY IN THIS. 735 00:29:21,605 --> 00:29:22,239 >> AUDIENCE: (SPEAKER FAR FROM 736 00:29:22,239 --> 00:29:26,443 MIC). 737 00:29:26,443 --> 00:29:37,254 >> ANDREISH: WE'VE HAD DISCUSSI 738 00:29:37,254 --> 00:29:38,956 WITH TOM ABOUT THIS. THANK YOU. 739 00:29:38,956 --> 00:29:41,191 LMNA HAS A LOT OF DIFFERENT 740 00:29:41,191 --> 00:29:42,259 FUNCTIONS. ANOTHER IMPORTANT 741 00:29:42,259 --> 00:29:47,431 FUNCTION OF LMNA IS NUCLEAR 742 00:29:47,431 --> 00:29:49,566 DEFORMABILITY. WE KNOW THAT 743 00:29:49,566 --> 00:29:51,335 NUCLEAR DEFORMABILITY IS A RATE 744 00:29:51,335 --> 00:29:53,136 LIMITED STEP IN THE MIGRATION OF 745 00:29:53,136 --> 00:29:55,672 CANCER CELLS THROUGH CONFINED 746 00:29:55,672 --> 00:29:57,107 SPACES THROUGH METASTASIS SO 747 00:29:57,107 --> 00:29:59,509 HERE WE HAVE DONE SOME 748 00:29:59,509 --> 00:30:00,844 EXPERIMENTS IN COLLABORATION 749 00:30:00,844 --> 00:30:02,613 WITH WATER MAIN LAB WHERE WE 750 00:30:02,613 --> 00:30:05,349 HAVE DONE THIS, YOU KNOW, THIS 751 00:30:05,349 --> 00:30:07,150 SQUISHING ASSAY OR CONFINEMENT 752 00:30:07,150 --> 00:30:10,287 ASSAY WITH CONSTRAINTS SCLC TO A 753 00:30:10,287 --> 00:30:15,292 HEIGHT OF THREE MICRONS AND THIS 754 00:30:15,292 --> 00:30:16,760 SIMULATES THE DEFINED MATRIX 755 00:30:16,760 --> 00:30:27,237 THAT THE CELLS FACE DURING 756 00:30:27,738 --> 00:30:28,305 METAST 757 00:30:28,305 --> 00:30:29,840 METASTASES. AND NOW TO TEST 758 00:30:29,840 --> 00:30:31,375 WHETHER THERE'S ENHANCED 759 00:30:31,375 --> 00:30:34,611 DEFORMABILITY IN LMNA KNOCK OUT 760 00:30:34,611 --> 00:30:37,848 CELLS HAS THIS THROUGH CONFINED 761 00:30:37,848 --> 00:30:39,116 SPACES. WE HAVE DONE THIS IN 762 00:30:39,116 --> 00:30:41,451 ANOTHER EXPERIMENT. THIS IS THE 763 00:30:41,451 --> 00:30:43,887 ASPIRATION ASSAY. WE FIND THAT 764 00:30:43,887 --> 00:30:45,923 LMNA KNOCK OUT CELLS TEND TO BE 765 00:30:45,923 --> 00:30:47,925 DRAWN FURTHER INTO THESE NARROW 766 00:30:47,925 --> 00:30:49,726 SPACE WHICH ARE ABOUT THREE 767 00:30:49,726 --> 00:30:52,195 MICRON SIZE COMPARED TO THE 768 00:30:52,195 --> 00:30:53,764 CONTROL CELLS. SO THEY ARE 769 00:30:53,764 --> 00:30:56,266 TAKEN IN MUCH MORE RAPIDLY. AND 770 00:30:56,266 --> 00:30:58,769 FURTHER, IF YOU NOTICE LIKE, FOR 771 00:30:58,769 --> 00:31:01,371 EXAMPLE, THIS TIME POINT 60 772 00:31:01,371 --> 00:31:03,106 SECONDS COMPARED TO THE CONTROL 773 00:31:03,106 --> 00:31:04,808 CELLS THEY GO IN MUCH MORE 774 00:31:04,808 --> 00:31:06,243 RAPIDLY COMPARED TO THE CONTROL 775 00:31:06,243 --> 00:31:08,378 CELLS AND THIS IS QUANTIFICATION 776 00:31:08,378 --> 00:31:09,746 HERE SUGGESTING THAT NOT ONLY 777 00:31:09,746 --> 00:31:11,481 ARE THEY MORE DEFORMABLE THEY 778 00:31:11,481 --> 00:31:18,522 TEND OF THE -- TO HAVE INCREASED 779 00:31:18,522 --> 00:31:22,426 TRANSIT. BUT TO FURTHER ADDRESS 780 00:31:22,426 --> 00:31:26,229 THIS, WE HAVE THESE LMNA 781 00:31:26,229 --> 00:31:29,132 KNOCKOUT CELLS AND WE FIND THAT 782 00:31:29,132 --> 00:31:30,267 IT'S INTERESTINGLY THE LATENCY 783 00:31:30,267 --> 00:31:32,636 IS UNCHANGED SO THAT IS THE TIME 784 00:31:32,636 --> 00:31:35,772 TO DEVELOP METASTASIS IS CHANGED 785 00:31:35,772 --> 00:31:37,407 WITH KNOCKOUT COMPARED TO 786 00:31:37,407 --> 00:31:37,841 CONTROL. 787 00:31:37,841 --> 00:31:40,310 AS WELL AS THE OTHER IS CHANGED. 788 00:31:40,310 --> 00:31:42,179 THE NUMBER OF MICE THAT DEVELOP 789 00:31:42,179 --> 00:31:44,848 ME IT'S A TA SI IS SIMILAR IN 790 00:31:44,848 --> 00:31:46,116 BOTH GROUPS. 791 00:31:46,116 --> 00:31:48,251 BUT WE FIND THERE'S MUCH MORE 792 00:31:48,251 --> 00:31:51,288 NUMBER IN LMNA KNOCKOUT CELLS 793 00:31:51,288 --> 00:31:53,824 COMPARED TO INTACT CELLS 794 00:31:53,824 --> 00:31:55,926 SUGGESTING THAT YOU KNOW LMNA 795 00:31:55,926 --> 00:31:58,862 MAY NOT BE AFFECTING THE EARLY 796 00:31:58,862 --> 00:32:01,531 STAGES OF METASTASIS BUT MAYBE 797 00:32:01,531 --> 00:32:02,265 LATER IN THE LOCAL ENVIRONMENT 798 00:32:02,265 --> 00:32:04,701 AND SO FORTH. SO THIS IS AN 799 00:32:04,701 --> 00:32:05,869 AREA THAT WE ARE PURSUING. 800 00:32:05,869 --> 00:32:09,840 COULD YOU MODULATE THESE LEVELS 801 00:32:09,840 --> 00:32:12,776 TO VARY THE LEVELS OF LMNA AND 802 00:32:12,776 --> 00:32:14,711 THAT COULD RESULT IN PHENOTYPES 803 00:32:14,711 --> 00:32:16,780 AND SO FORTH. SO TO GIVE YOU A 804 00:32:16,780 --> 00:32:19,383 QUICK OVERVIEW SO FAR, SO WE'VE 805 00:32:19,383 --> 00:32:21,685 GONE FROM, YOU KNOW, HYPOTHESIS 806 00:32:21,685 --> 00:32:24,254 AND SOME CELL LINE SCREENS THAT 807 00:32:24,254 --> 00:32:25,655 THE COMBINATION OF ATR COULD BE 808 00:32:25,655 --> 00:32:28,058 EFFECTIVE IN A CLC PATIENTS. WE 809 00:32:28,058 --> 00:32:30,994 WENT FROM PHASE ONE TRIAL TO 810 00:32:30,994 --> 00:32:33,897 PHASE TWO TRIAL SHOWING 811 00:32:33,897 --> 00:32:35,465 EFFICACY, CONDUCTED A TRIAL, AND 812 00:32:35,465 --> 00:32:37,501 DEVELOPED SIGNALS THAT CAN BE 813 00:32:37,501 --> 00:32:39,002 EXPLORED TO OTHER TUMORS THAT 814 00:32:39,002 --> 00:32:40,404 ARE UNDER HIGH REPLICATION 815 00:32:40,404 --> 00:32:43,073 STRESS AND THEN MORE RECENTLY 816 00:32:43,073 --> 00:32:44,775 WE'VE DONE MECHANISTIC WORK TO 817 00:32:44,775 --> 00:32:46,843 SOMEHOW THAT LMNA MIGHT BE 818 00:32:46,843 --> 00:32:48,612 DRIVING THIS STRESS NOT ONLY 819 00:32:48,612 --> 00:32:49,846 REPLICATION STRESS BUT ALSO SOME 820 00:32:49,846 --> 00:32:52,249 KEY HISTOLOGICAL FEATURES 821 00:32:52,249 --> 00:32:54,451 INCLUDING NUCLEAR PATTERNS AND 822 00:32:54,451 --> 00:32:57,554 MOLDING AND SO ON AS WELL AS THE 823 00:32:57,554 --> 00:32:59,122 HIGH FREQUENCY OF ME AT THE TA 824 00:32:59,122 --> 00:33:01,391 SIS. SOME OF IT IS STILL 825 00:33:01,391 --> 00:33:02,159 ONGOING. 826 00:33:02,159 --> 00:33:04,327 SO TO, YOU KNOW, SUMMARIZE THIS 827 00:33:04,327 --> 00:33:06,530 SORT OF INITIAL PART WE FIND 828 00:33:06,530 --> 00:33:10,333 THAT SCLC CELLS HAVE HIGH 829 00:33:10,333 --> 00:33:11,902 VARIABILITY BETWEEN PATIENTS AND 830 00:33:11,902 --> 00:33:13,804 THEY RESPOND TO REPLICATION 831 00:33:13,804 --> 00:33:16,173 STRESS TARGETED AGENTS, LMNA 832 00:33:16,173 --> 00:33:17,407 MIGHT BE A KEY DETERMINANT OF A 833 00:33:17,407 --> 00:33:18,742 RESPONSE AND SO ON. SO WHAT 834 00:33:18,742 --> 00:33:20,944 ABOUT THESE TUMORS THAT ARE 835 00:33:20,944 --> 00:33:22,679 UNDER LOW APPLICATION STRESS? 836 00:33:22,679 --> 00:33:24,581 WHAT IS GOING ON WITH THEM? SO 837 00:33:24,581 --> 00:33:26,583 WE'VE DONE ANOTHER CLINICAL 838 00:33:26,583 --> 00:33:32,322 TRIAL HERE ASSIST -- IT'S AN 839 00:33:32,322 --> 00:33:33,623 IMMUNOTHERAPY TRIAL. VERY FEW 840 00:33:33,623 --> 00:33:34,925 PATIENTS RESPONDED IN THIS 841 00:33:34,925 --> 00:33:35,158 TRIAL. 842 00:33:35,158 --> 00:33:36,193 THIS WAS A NEGATIVE CLINICAL 843 00:33:36,193 --> 00:33:39,062 TRIAL AND USING SAMPLES FROM 844 00:33:39,062 --> 00:33:41,364 PATIENTS, PRETREATMENT TUMOR RNA 845 00:33:41,364 --> 00:33:42,032 SEQUENCING WE FOUND THAT IN THIS 846 00:33:42,032 --> 00:33:44,734 CASE TUMORS THAT RESPOND TO 847 00:33:44,734 --> 00:33:46,203 TREATMENT TO IMMUNOTHERAPY IN 848 00:33:46,203 --> 00:33:48,271 THIS CASE AS ONE WOULD EXPECT 849 00:33:48,271 --> 00:33:50,574 THESE TUMORS ARE ENRICHED IN 850 00:33:50,574 --> 00:33:52,409 IMMUNE RELATED PATHWAYS BUT ALSO 851 00:33:52,409 --> 00:33:55,412 IN THE NEURONAL SYSTEM IN 852 00:33:55,412 --> 00:33:57,848 CONTRAST TO THE PREVIOUS DNA 853 00:33:57,848 --> 00:34:00,283 REPAIR TARGETED THERAPIES 854 00:34:00,283 --> 00:34:01,852 SUGGESTIONING IT IS THESE TUMORS 855 00:34:01,852 --> 00:34:03,987 THAT THEY ARE RESPONDING TO. 856 00:34:03,987 --> 00:34:07,090 AND A FELLOW AT THAT TIME TOOK 857 00:34:07,090 --> 00:34:10,894 THESE CELLS, INDUCED NOT IN 858 00:34:10,894 --> 00:34:14,764 THESE NEUROENDOCRINE CELLS. BUT 859 00:34:14,764 --> 00:34:18,902 WE ALSO FOUND THAT WITH THIS 860 00:34:18,902 --> 00:34:20,937 INDUCTION OF NEURAL ENDOCRINE 861 00:34:20,937 --> 00:34:21,638 FEATURES SO YOU CAN SEE THIS IN 862 00:34:21,638 --> 00:34:23,740 THE CELLS, THERE'S ALSO 863 00:34:23,740 --> 00:34:28,044 INCREASED UPREGULATION OF 864 00:34:28,044 --> 00:34:28,545 ANTIGEN PROCESSING AND 865 00:34:28,545 --> 00:34:29,679 PRESENTATION MACHINERY SO 866 00:34:29,679 --> 00:34:30,981 THERE'S A SUGGESTION THAT THE 867 00:34:30,981 --> 00:34:33,750 LOW ENDOCRINE FEATURE IS A 868 00:34:33,750 --> 00:34:35,185 RESULT OF INCREASED IMMUNE 869 00:34:35,185 --> 00:34:37,587 ACTIVATION. THESE ARE THE 870 00:34:37,587 --> 00:34:39,022 PATIENTS WHO THEY ARE MOST 871 00:34:39,022 --> 00:34:40,390 LIKELY TO RESPOND TO 872 00:34:40,390 --> 00:34:41,057 IMMUNOTHERAPY. SO AS I 873 00:34:41,057 --> 00:34:42,626 MENTIONED EARLIER IT'S DIFFICULT 874 00:34:42,626 --> 00:34:44,928 TO BIOPSY THESE PATIENTS AND 875 00:34:44,928 --> 00:34:48,899 WE'RE FORGE NOT -- FORTUNATE 876 00:34:48,899 --> 00:34:51,668 HERE THAT WE HAVE A GREAT IR 877 00:34:51,668 --> 00:34:54,671 DEPARTMENT THAT CAN BIOPSY IN 878 00:34:54,671 --> 00:34:55,305 SHORT NOTICE. 879 00:34:55,305 --> 00:34:57,841 BUT IT WOULD BE NICE TO HAVE A 880 00:34:57,841 --> 00:34:58,575 NONINVASIVE APPROACH TO PROTECT 881 00:34:58,575 --> 00:35:02,879 THESE TUMORS. HERE WE WORKED IN 882 00:35:02,879 --> 00:35:06,816 COLLABORATION TO APPLY THE 883 00:35:06,816 --> 00:35:08,351 TECHNIQUE. THIS IS A FAIRLY 884 00:35:08,351 --> 00:35:10,253 SIMPLE APPROACH. YOU DO THIS 885 00:35:10,253 --> 00:35:12,422 USING ONE OR TWO PATIENTS' 886 00:35:12,422 --> 00:35:14,824 PLASMA YOU CAN LOOK AT ANY MARK 887 00:35:14,824 --> 00:35:16,960 BUT IN THIS CASE THEY LOOK AT 888 00:35:16,960 --> 00:35:21,665 THE TRIMETHYLATION WHICH MARKS 889 00:35:21,665 --> 00:35:23,667 THE ABILITY TO TRANSCRIBE AND 890 00:35:23,667 --> 00:35:25,835 YOU GET A GENE COUNT AND 891 00:35:25,835 --> 00:35:28,171 COMPARED TO THE CONTROLS, SCLC 892 00:35:28,171 --> 00:35:29,839 SAMPLES HAVE SIGNIFICANTLY 893 00:35:29,839 --> 00:35:31,341 INCREASED NUMBERS OF MULTIPLE 894 00:35:31,341 --> 00:35:37,714 MARKERS LIKE DLL 3 AND THIS 895 00:35:37,714 --> 00:35:39,783 PLASMA SCORE IT CORRELATES 896 00:35:39,783 --> 00:35:41,318 POSITIVELY WITH CT SCAN BASED 897 00:35:41,318 --> 00:35:44,854 TUMOR VOLUME. PATIENTS WITH 898 00:35:44,854 --> 00:35:47,390 HIGH SCORES HAVE POORER OUTCOMES 899 00:35:47,390 --> 00:35:48,525 BUT MOST IMPORTANTLY THIS IS 900 00:35:48,525 --> 00:35:52,128 VERY POWERFUL APPROACH BECAUSE 901 00:35:52,128 --> 00:35:55,865 YOU CAN REALLY TELL FROM 902 00:35:55,865 --> 00:35:57,801 CIRCUL 903 00:35:57,801 --> 00:35:58,501 CIRCULA 904 00:35:58,501 --> 00:36:01,171 CIRCULATING P-SEQ IT'S TO THE 905 00:36:01,171 --> 00:36:03,039 GENE LEVEL. NOT ALL HAVE THIS 906 00:36:03,039 --> 00:36:03,673 LEVEL OF ACCORDANCE BUT ABOUT 907 00:36:03,673 --> 00:36:06,176 20% OF THE GENES, ESPECIALLY 908 00:36:06,176 --> 00:36:09,846 GENES WHICH ARE VERY 909 00:36:09,846 --> 00:36:11,214 TUMOR-SPECIFIC SUCH AS SLK 1 AND 910 00:36:11,214 --> 00:36:13,817 NEUROD 1. SO YOU CAN SEE THE 911 00:36:13,817 --> 00:36:17,721 AKOR -- ACCORDANCE. 912 00:36:17,721 --> 00:36:20,757 YOU CAN CONFER A LOT OF PROGRAMS 913 00:36:20,757 --> 00:36:21,825 AND THIS IS SPECIFICALLY 914 00:36:21,825 --> 00:36:24,561 IMPORTANT BUT IT'S NOT DRIVEN BY 915 00:36:24,561 --> 00:36:26,830 MUTATIONS BUT BY GENE EXPRESSION 916 00:36:26,830 --> 00:36:28,298 PROGRAMS. THIS CAN BE 917 00:36:28,298 --> 00:36:28,965 POTENTIALLY USE AND FEEL WE'RE 918 00:36:28,965 --> 00:36:31,401 DOING STUDY UPS WITH THIS. IN 919 00:36:31,401 --> 00:36:33,803 AN IDEAL WORLD IF YOU TAKE THESE 920 00:36:33,803 --> 00:36:36,673 PATIENTS, TREAT THEM WITH STRESS 921 00:36:36,673 --> 00:36:39,542 TARGETED THERAPIES, AND TREAT 922 00:36:39,542 --> 00:36:41,811 THEM WITH IMMUNE ACTIVATORS, 923 00:36:41,811 --> 00:36:43,179 EVERYTHING WOULD BE GREAT, ALL 924 00:36:43,179 --> 00:36:45,548 PATIENTS WOULD BE CURED BUT 925 00:36:45,548 --> 00:36:47,217 UNFORTUNATELY, THIS IS NOT TRUE 926 00:36:47,217 --> 00:36:49,719 BECAUSE THERE'S A LOT OF 927 00:36:49,719 --> 00:36:51,187 HETEROGENEITY AND IT'S A MAIN 928 00:36:51,187 --> 00:36:53,657 CAUSE OF TREATMENT FAILURE SO 929 00:36:53,657 --> 00:36:56,259 HOW DO WE TARGET THIS IN SCLC? 930 00:36:56,259 --> 00:36:57,560 SO IN THE NEXT TEN MINUTES OR SO 931 00:36:57,560 --> 00:36:59,829 I WILL TRY TO HIGHLIGHT SOME OF 932 00:36:59,829 --> 00:37:01,064 OUR EFFORTS. AND I THINK YOU 933 00:37:01,064 --> 00:37:03,800 CAN SORT OF THINK ABOUT IT IN 934 00:37:03,800 --> 00:37:07,437 THIS FRAMEWORK, ONE YOU EVER TO 935 00:37:07,437 --> 00:37:08,938 -- YOU HAVE TO TAKE APPROACHES. 936 00:37:08,938 --> 00:37:11,841 AND WE TALKED ABOUT HOW IT 937 00:37:11,841 --> 00:37:14,644 ENFORCES A NEUROENDOCRINE 938 00:37:14,644 --> 00:37:16,546 DIFFERENTIATION AND YOU HAVE TO 939 00:37:16,546 --> 00:37:18,548 COME UP WITH DRUG COMBINATIONS 940 00:37:18,548 --> 00:37:19,382 TO TARGET POPULATIONS AND 941 00:37:19,382 --> 00:37:21,851 SIMILAR TO THIS IS HOW LEUKEMIA 942 00:37:21,851 --> 00:37:25,121 AND LYMPHOMAS ARE BEING CURED. 943 00:37:25,121 --> 00:37:26,423 YOU COMBINE DRUGS AS MUCH AS THE 944 00:37:26,423 --> 00:37:29,559 PATIENT CAN TOLERATE, TO 945 00:37:29,559 --> 00:37:30,260 HOPEFULLY TARGET MULTIPLE 946 00:37:30,260 --> 00:37:32,495 DIFFERENT CLONES AND, YOU KNOW, 947 00:37:32,495 --> 00:37:34,764 TAKE CARE OF THE CANCER VOLUME. 948 00:37:34,764 --> 00:37:36,866 SO THE FIRST APPROACH IS 949 00:37:36,866 --> 00:37:40,403 CONSTRAINING PLASTICITY WE 950 00:37:40,403 --> 00:37:43,573 TALKED ABOUT ECH 2 INHIBITOR 951 00:37:43,573 --> 00:37:46,543 WHICH IS ALREADY APPROVED FOR A 952 00:37:46,543 --> 00:37:47,711 FEW DIFFERENT INDICATIONS AND 953 00:37:47,711 --> 00:37:50,480 ESSENTIALLY WHAT IT DOES IS IT 954 00:37:50,480 --> 00:37:54,284 REDUCES OR IT INHIBITS 955 00:37:54,284 --> 00:37:57,287 METHYLATION AT 27. NOW WE'RE 956 00:37:57,287 --> 00:37:59,389 DOING A PHASE ONE, TWO CLINICAL 957 00:37:59,389 --> 00:38:01,291 TRIAL. IN THIS CASE WE GIVE IT 958 00:38:01,291 --> 00:38:05,528 EVERYDAY FOR FIFTEEN DAYS. AND 959 00:38:05,528 --> 00:38:06,796 THE HOPE IS THAT IT IS 960 00:38:06,796 --> 00:38:10,500 PROGRAMMING IN THE TUMOR SO THAT 961 00:38:10,500 --> 00:38:14,037 IT REPROGRAMS AND IS MORE 962 00:38:14,037 --> 00:38:17,006 IMMUNOGENIC AND AT THE END WE 963 00:38:17,006 --> 00:38:19,075 TREAT WITH CHEMOTHERAPY. SO 964 00:38:19,075 --> 00:38:20,910 THIS IS AN ONGOING TRIAL BUT I 965 00:38:20,910 --> 00:38:23,113 JUST WANT TO SHARE A PRE/POST 966 00:38:23,113 --> 00:38:24,013 TREATMENT BIOPSY OF THE SAME 967 00:38:24,013 --> 00:38:28,451 PATIENT FROM THE SAME SITE. 968 00:38:28,451 --> 00:38:31,688 BEFORE AS THE MET TO STAT AND 969 00:38:31,688 --> 00:38:33,390 AFTER. SO YOU CAN SEE THERE ARE 970 00:38:33,390 --> 00:38:37,827 TWO. ONE IS MOSTLY FIBROTIC 971 00:38:37,827 --> 00:38:38,061 TISSUE. 972 00:38:38,061 --> 00:38:39,662 AND THIS IS THE CHALLENGE WE 973 00:38:39,662 --> 00:38:41,831 FACE AND HERE WE HAVE DONE 974 00:38:41,831 --> 00:38:43,433 SPATIAL TRANSCRIPTOMICS AND WE 975 00:38:43,433 --> 00:38:45,602 CAN IDENTIFY THE TUMOR CELLS IN 976 00:38:45,602 --> 00:38:47,203 PRETREATMENT AS WELL AS 977 00:38:47,203 --> 00:38:47,937 POSTTREATMENT TUMORS AND YOU CAN 978 00:38:47,937 --> 00:38:49,305 SEE AT LEAST IN THIS ONE SINGLE 979 00:38:49,305 --> 00:38:51,241 CASE YOU LOOK AT THE EXPRESSION 980 00:38:51,241 --> 00:38:53,977 OF ALC 1 WHICH IS A MARKER. 981 00:38:53,977 --> 00:38:55,545 PRETREATMENT COMPARED TO 982 00:38:55,545 --> 00:38:57,514 POSTTREATMENT WE HYPOTHESIZE 983 00:38:57,514 --> 00:39:01,151 THERE IS REDUCTION IN THIS 984 00:39:01,151 --> 00:39:03,453 NEUROENDOCRINE WITH AS THE ME TO 985 00:39:03,453 --> 00:39:05,855 STAT SUGGESTING THIS COULD BE 986 00:39:05,855 --> 00:39:08,658 MODULATING THE TUMOR, 987 00:39:08,658 --> 00:39:09,492 EPIGENETICALLY PROGRAMMING AND 988 00:39:09,492 --> 00:39:12,629 THAT IT MIGHT THEN RESPOND TO 989 00:39:12,629 --> 00:39:13,997 IMMUNOTHERAPY. SO THIS IS AN 990 00:39:13,997 --> 00:39:16,566 ONGOING TRIAL. ANOTHER APPROACH 991 00:39:16,566 --> 00:39:18,268 WHICH WE COULD TRY IS RATIONAL 992 00:39:18,268 --> 00:39:20,403 COMBINATIONS THAT TARGET 993 00:39:20,403 --> 00:39:21,438 HETEROGENEITY. THESE ARE SOME 994 00:39:21,438 --> 00:39:23,440 OF THE CELL SURFACE TARGETS THAT 995 00:39:23,440 --> 00:39:26,576 HAVE BEEN EXPLORED. D 7H 3 AND 996 00:39:26,576 --> 00:39:28,178 SO FORTH AND AS YOU KNOW THERE 997 00:39:28,178 --> 00:39:31,514 ARE MULTIPLE WAYS TO TARGET 998 00:39:31,514 --> 00:39:34,017 THESE CELL SURFACE PROGRAMS NOW. 999 00:39:34,017 --> 00:39:38,388 THERE'S T-CELL ENGAGES AND THEN 1000 00:39:38,388 --> 00:39:40,523 CHIMERIC ANTIGEN RECEPTORS IN 1001 00:39:40,523 --> 00:39:42,358 THIS WAY WE ARE TARGETING TWO 1002 00:39:42,358 --> 00:39:48,865 CELL SURFACE PRO TEENS, DL 3 AND 1003 00:39:48,865 --> 00:39:51,100 TROP2 WHICH IS EXPRESSED 1004 00:39:51,100 --> 00:39:54,537 UNIQUELY IN THE ENDO CLINIC 1005 00:39:54,537 --> 00:39:54,771 CELLS. 1006 00:39:54,771 --> 00:39:58,741 HOW DO YOU TARGET THESE OR ANY 1007 00:39:58,741 --> 00:40:01,578 OR NON ANY. SO WE'RE DOING A -- 1008 00:40:01,578 --> 00:40:03,079 PHASE ONE PHASE TWO CLINICAL 1009 00:40:03,079 --> 00:40:05,248 TRIAL WHERE WE ARE COMBINING A 1010 00:40:05,248 --> 00:40:07,584 BISPECIFIC ENGAGER THAT TARGETS 1011 00:40:07,584 --> 00:40:11,187 DLL 3. WHICH IS RECENTLY 1012 00:40:11,187 --> 00:40:13,923 APPROVED AND WE'RE COMBINING 1013 00:40:13,923 --> 00:40:18,261 THIS WITH AN ADC 3. SO THIS IS 1014 00:40:18,261 --> 00:40:21,831 A TRIAL WHICH WE HOPE WILL OPEN 1015 00:40:21,831 --> 00:40:28,671 NEXT -- EARLY NEXT YEAR. BY YOU 1016 00:40:28,671 --> 00:40:33,810 COULD ALSO THINK ABOUT TARGETS. 1017 00:40:33,810 --> 00:40:36,045 WE ARE ASKING PATIENTS HOW MANY 1018 00:40:36,045 --> 00:40:37,413 TARGETED TREATMENTS ARE NEEDED 1019 00:40:37,413 --> 00:40:39,983 TO ELIMINATE MOST TUMOR CELLS 1020 00:40:39,983 --> 00:40:41,451 WHILE WE SPARE NORMAL CELLS 1021 00:40:41,451 --> 00:40:48,091 BECAUSE AS I MENTIONED BEFORE 1022 00:40:48,091 --> 00:40:48,424 AA 1023 00:40:48,424 --> 00:40:49,158 DSH 1024 00:40:49,158 --> 00:40:50,727 ADCS ARE ANY OF THESE 1025 00:40:50,727 --> 00:40:52,362 APPROACHES. ANOTHER APPROACH IS 1026 00:40:52,362 --> 00:40:55,765 WE CAN TARGET ANTIGENS THAT ARE 1027 00:40:55,765 --> 00:40:57,567 OBSERVED ACROSS SITES. DOING 1028 00:40:57,567 --> 00:40:58,968 CLINICAL TRIALS OF COMBINATIONS 1029 00:40:58,968 --> 00:41:00,403 ARE EVEN MORE CHALLENGING, 1030 00:41:00,403 --> 00:41:02,872 TRYING TO GET DRUGS FROM TWO 1031 00:41:02,872 --> 00:41:04,674 DIFFERENT COMPANIES AND COMBINE 1032 00:41:04,674 --> 00:41:06,976 THEM. SO CAN WE IDENTIFY 1033 00:41:06,976 --> 00:41:08,144 TARGETS THAT ARE OBSERVED ACROSS 1034 00:41:08,144 --> 00:41:09,846 DIFFERENT SUBTYPES AND YOU CAN 1035 00:41:09,846 --> 00:41:13,249 SEE THIS IS PDX DATA THAT HAVE 1036 00:41:13,249 --> 00:41:14,751 BEEN STAINED FOR SOME OF THEIR 1037 00:41:14,751 --> 00:41:16,085 MARKERS. YOU CAN SEE THEY SEEM 1038 00:41:16,085 --> 00:41:18,588 TO BE A CONSERVED TARGET ACROSS 1039 00:41:18,588 --> 00:41:19,689 MULTIPLE DIFFERENT TUMORS 1040 00:41:19,689 --> 00:41:22,492 COMPARED TO DLL 3. SOME TUMORS 1041 00:41:22,492 --> 00:41:23,560 HAVE IT AND SOME DON'T. 1042 00:41:23,560 --> 00:41:26,629 SO FOLLOWING THIS OBSERVATION, 1043 00:41:26,629 --> 00:41:30,667 WE ARE STARTING A CELL TRIAL 1044 00:41:30,667 --> 00:41:33,503 FOCUSING ON B 7H 3. THIS IS A 1045 00:41:33,503 --> 00:41:34,971 COLLABORATION WITH ST. JUDE 1046 00:41:34,971 --> 00:41:37,473 WHICH HAVE DEVELOPED THE VECTOR 1047 00:41:37,473 --> 00:41:38,975 AND SHARED IT WITH AND THE 1048 00:41:38,975 --> 00:41:40,176 MANUFACTURING THAT WILL HAPPEN 1049 00:41:40,176 --> 00:41:42,845 AT NIHCCE THE GOAL IS WE CAN 1050 00:41:42,845 --> 00:41:44,647 COLLECT AND LOOK AFTER THESE 1051 00:41:44,647 --> 00:41:45,715 PATIENTS EVEN WHILE THEY'RE 1052 00:41:45,715 --> 00:41:46,416 GETTING THEIR INITIAL TREATMENTS 1053 00:41:46,416 --> 00:41:48,117 OR EVEN AT THE TIME OF DIAGNOSIS 1054 00:41:48,117 --> 00:41:51,187 THEY CAN HAVE T-CELLS HARVESTED 1055 00:41:51,187 --> 00:41:57,827 AND MODIFIED USING THE 1056 00:41:57,827 --> 00:42:00,296 CONSTRUCTS TO BE ADMINISTERED 1057 00:42:00,296 --> 00:42:02,398 LATER. SO THIS IS VERY 1058 00:42:02,398 --> 00:42:03,800 CHALLENGING PROTOCOL DEVELOPED 1059 00:42:03,800 --> 00:42:05,201 BY ONE OF OUR CLINICAL FELLOWS 1060 00:42:05,201 --> 00:42:06,269 ESPECIALLY BECAUSE THIS IS A 1061 00:42:06,269 --> 00:42:08,605 TUMOR THAT RAPIDLY GROWS, RIGHT? 1062 00:42:08,605 --> 00:42:11,441 YOU DON'T HAVE A LOT OF TIME 1063 00:42:11,441 --> 00:42:12,275 BETWEEN PROGRESS AND TREATMENT 1064 00:42:12,275 --> 00:42:13,676 AND USUALLY IN A MATTER OF WEEKS 1065 00:42:13,676 --> 00:42:15,612 YOU HAVE TO GET THE PATIENT 1066 00:42:15,612 --> 00:42:17,780 STARTED. SO THIS IS AN ON -- 1067 00:42:17,780 --> 00:42:19,749 THIS IS ONGOING EFFORT AND WE 1068 00:42:19,749 --> 00:42:22,285 HOPE TO START THE PROTOCOL EARLY 1069 00:42:22,285 --> 00:42:24,220 NEXT YEAR AGAIN. AND FROM A 1070 00:42:24,220 --> 00:42:25,021 PATIENT'S PERSPECTIVE, YOU KNOW, 1071 00:42:25,021 --> 00:42:27,323 ONE OF THE MAIN CHALLENGES IS, 1072 00:42:27,323 --> 00:42:29,225 YOU KNOW, WHICH OF THE -- OR 1073 00:42:29,225 --> 00:42:30,293 FROM A PHYSICIAN'S PERSPECTIVE 1074 00:42:30,293 --> 00:42:31,561 OR CHALLENGES, YOU KNOW, YOU 1075 00:42:31,561 --> 00:42:32,996 HAVE SO MANY OF THESE TARGETS, 1076 00:42:32,996 --> 00:42:35,498 WHICH IS THE TARGET THAT IS MOST 1077 00:42:35,498 --> 00:42:37,834 APPROPRIATE FOR ME? OR MOST 1078 00:42:37,834 --> 00:42:39,102 APPROPRIATE FOR MY TUMOR? WITH 1079 00:42:39,102 --> 00:42:42,071 EACH GROUP WE'RE TRYING TO 1080 00:42:42,071 --> 00:42:44,440 LAUNCH THIS PATIENT MINOR 1081 00:42:44,440 --> 00:42:46,909 APPROACH WHERE WE HAVE AN OPTION 1082 00:42:46,909 --> 00:42:49,012 TO MATCH PATIENTS AND THE TARGET 1083 00:42:49,012 --> 00:42:51,080 ANTIGENS SO, AGAIN, THIS IS AN 1084 00:42:51,080 --> 00:42:52,882 APPROACH WHERE, THIS IS A 1085 00:42:52,882 --> 00:42:55,084 PLATFORM WHERE WE CAN UPLOAD RNA 1086 00:42:55,084 --> 00:42:56,219 SEQUENCING DATA FROM A PATIENT 1087 00:42:56,219 --> 00:42:57,654 AND THE QUESTION IS, WHAT IS IS 1088 00:42:57,654 --> 00:42:59,389 THE BEST CELL SURFACE TARGET FOR 1089 00:42:59,389 --> 00:43:05,828 A GIVEN PATIENT? IS IT TROP 2 1090 00:43:05,828 --> 00:43:10,733 OR ANOTHER THAT SPREADS ACROSS 1091 00:43:10,733 --> 00:43:18,241 TUMOR CELLS? BUT AT THE END OF 1092 00:43:18,241 --> 00:43:20,510 THE DAY THESE APPROACHES ARE 1093 00:43:20,510 --> 00:43:21,811 GREAT BUT TO TARGET THIS WE HAVE 1094 00:43:21,811 --> 00:43:24,213 TO GET A BETTER DETERMINANT. 1095 00:43:24,213 --> 00:43:25,715 WE'VE DONE TWO STUDIES IN THIS 1096 00:43:25,715 --> 00:43:28,151 AREA, ONE FOCUSING ON INTRINSIC 1097 00:43:28,151 --> 00:43:31,521 FEATURES AS I MENTIONED SCLC 1098 00:43:31,521 --> 00:43:34,190 STARTS FROM AN ENDOCRINE CELL OF 1099 00:43:34,190 --> 00:43:37,226 ORIGIN BUT OVER TIME IT 1100 00:43:37,226 --> 00:43:41,431 PROGRESSES TO A 1101 00:43:41,431 --> 00:43:42,065 NON-NEUROENDOCRINE STATEMENT. 1102 00:43:42,065 --> 00:43:43,933 SO THE QUESTION IS WHAT IS THIS 1103 00:43:43,933 --> 00:43:46,369 DRIVING THE TRANSITION AND IN 1104 00:43:46,369 --> 00:43:49,839 ANIMAL MODELS PEOPLE FIND IT IS 1105 00:43:49,839 --> 00:43:51,207 THIS UPREGULATION THAT DRIVES 1106 00:43:51,207 --> 00:43:53,843 THE TRANSITION AND IN ONE OF OUR 1107 00:43:53,843 --> 00:43:55,745 RECENT STUDIES WE FOUND THAT 1108 00:43:55,745 --> 00:44:00,383 EXTROE SEW MALL DNA MIGHT HAVE 1109 00:44:00,383 --> 00:44:02,685 THE BURST THAT ALLOWS IT TO ANY 1110 00:44:02,685 --> 00:44:05,555 TO NOT ANY STATE. ANOTHER IS 1111 00:44:05,555 --> 00:44:07,657 THE FEATURES. WHAT ARE THE 1112 00:44:07,657 --> 00:44:11,961 TUMOR EXTRINSIC FEATURES DRIVING 1113 00:44:11,961 --> 00:44:12,895 THIS HETEROGENEITY. WE FIND 1114 00:44:12,895 --> 00:44:15,331 THAT THE MICROENVIRONMENT CAN 1115 00:44:15,331 --> 00:44:16,599 SHAPE SUBTYPES. AND I WANT TO 1116 00:44:16,599 --> 00:44:17,800 HIGHLIGHT THAT, YOU KNOW, IN 1117 00:44:17,800 --> 00:44:22,371 BOTH THESE STUDIES, ESPECIALLY 1118 00:44:22,371 --> 00:44:24,874 STUDIES OF INTRATUMOR 1119 00:44:24,874 --> 00:44:26,342 HETEROGENEITY IT IS HARD TO GET 1120 00:44:26,342 --> 00:44:29,979 THIS FROM A PATIENT WHO IS 1121 00:44:29,979 --> 00:44:31,147 ALIVE. WE HAVE THIS PROTOCOL 1122 00:44:31,147 --> 00:44:37,687 WHICH IS REALLY AN AMAZING 1123 00:44:37,687 --> 00:44:40,356 OPPORTUNITY TO GET TUMOR 1124 00:44:40,356 --> 00:44:42,125 BIOPSIES FROM DIFFERENT SITES 1125 00:44:42,125 --> 00:44:43,726 AND THIS IS A COLLABORATION 1126 00:44:43,726 --> 00:44:47,163 WORKING WITH MULTIPLE GROUPS 1127 00:44:47,163 --> 00:44:50,566 PARTICULARLY IN THE PATHOLOGY 1128 00:44:50,566 --> 00:44:51,834 WHERE PATIENTS COME INTO THE 1129 00:44:51,834 --> 00:44:53,402 HOSPITAL AND THEY SPEND THEIR 1130 00:44:53,402 --> 00:44:54,504 LAST DAYS OR HOURS IN THE 1131 00:44:54,504 --> 00:44:56,405 HOSPITAL AND AS SOON AS THEY 1132 00:44:56,405 --> 00:44:59,509 PASS, WORKING WITH THE PATHOLOGY 1133 00:44:59,509 --> 00:45:01,844 TEAM, WE DO A RAPID AUTOPSY 1134 00:45:01,844 --> 00:45:03,946 USUALLY WITHIN AN HOUR OR TWO 1135 00:45:03,946 --> 00:45:05,815 AND OBTAIN MULTI-REGION 1136 00:45:05,815 --> 00:45:07,517 SEQUENCING AND SO ON. SO, 1137 00:45:07,517 --> 00:45:09,819 AGAIN, THIS IS A VERY USEFUL 1138 00:45:09,819 --> 00:45:14,557 TOOL TO ASSESS INTRATUMOR 1139 00:45:14,557 --> 00:45:16,325 HETEROGENEITY AND USING THIS TO 1140 00:45:16,325 --> 00:45:17,326 STUDY THE ENVIRONMENT WE ASK 1141 00:45:17,326 --> 00:45:21,664 THIS QUESTION, HOW IS THE TUMOR 1142 00:45:21,664 --> 00:45:25,234 DIFFERENT FROM NE AND NON-NE 1143 00:45:25,234 --> 00:45:27,937 TUMORS AND THIS IS LOOKING AT 1144 00:45:27,937 --> 00:45:28,905 LIGAND INTERCEPTORS AND THIS IS 1145 00:45:28,905 --> 00:45:33,709 USING AN OLDER PLATFORM. WE 1146 00:45:33,709 --> 00:45:35,778 FIND THAT NON-NE TUMORS TEND TO 1147 00:45:35,778 --> 00:45:37,847 HAVE MUCH MORE INTERACTIONS WITH 1148 00:45:37,847 --> 00:45:40,716 THIS TRAUMA COMPARED TO ANY 1149 00:45:40,716 --> 00:45:41,517 OTHER TUMORS. 1150 00:45:41,517 --> 00:45:43,753 YOU WONDER WHAT ARE THESE ACTION 1151 00:45:43,753 --> 00:45:46,556 AND WE FIND THAT FDF ARE MUCH 1152 00:45:46,556 --> 00:45:51,027 MORE ENRICHED AND NON-NE TUMORS 1153 00:45:51,027 --> 00:45:57,834 AND WE HAVE DONE SOME INTRO -- 1154 00:45:57,834 --> 00:46:01,571 INVITRO STUDIES. WE HAVE A 1155 00:46:01,571 --> 00:46:03,673 TRIAL TO HOPEFULLY INTERFERE 1156 00:46:03,673 --> 00:46:07,443 WITH THIS NE AND NON-NE 1157 00:46:07,443 --> 00:46:08,678 REACTIONS WITH THIS TRAUMA AND 1158 00:46:08,678 --> 00:46:11,180 THIS IS AN ONGOING EFFORT AND IN 1159 00:46:11,180 --> 00:46:12,882 THE SPACE WE HAVE FOUND THAT 1160 00:46:12,882 --> 00:46:15,651 THIS CAN BE DRIVEN BY EXTRA 1161 00:46:15,651 --> 00:46:17,453 CHROMOSOMAL DNA SO HERE, WHEN WE 1162 00:46:17,453 --> 00:46:20,223 LOOK AT S SKRSHGSLC CELL LINES 1163 00:46:20,223 --> 00:46:22,325 WAS WE SEE THERE ARE SOME CELL 1164 00:46:22,325 --> 00:46:24,360 LICENSE WITH EXCEPTIONALLY HIGH 1165 00:46:24,360 --> 00:46:26,028 LEVELS OF GAINS. 1166 00:46:26,028 --> 00:46:28,431 AND THIS IS COMMONLY SEEN FOR 1167 00:46:28,431 --> 00:46:30,900 THE GENES. AND THESE TEND TO BE 1168 00:46:30,900 --> 00:46:33,302 MORE INTERESTED IN CELL LINES 1169 00:46:33,302 --> 00:46:34,503 COMPARED TO TUMORS. WHEN HE DID 1170 00:46:34,503 --> 00:46:37,106 THIS WORK, HE PROBED FURTHER, HE 1171 00:46:37,106 --> 00:46:39,609 FOUND THESE FOCAL AMPLIFICATIONS 1172 00:46:39,609 --> 00:46:41,644 COVER SMALL PORTIONS OF THE 1173 00:46:41,644 --> 00:46:43,346 GENOME ABOUT 15,000 TO A MILLION 1174 00:46:43,346 --> 00:46:45,748 BASE PAIRS AND FINALLY WE 1175 00:46:45,748 --> 00:46:48,351 CONCLUDED THAT THESE ARE ECD 1176 00:46:48,351 --> 00:46:50,186 AMPLIFICATIONS WHICH ARE FOCAL 1177 00:46:50,186 --> 00:46:52,488 AMPLIFICATIONS THAT INVOLVE 1178 00:46:52,488 --> 00:46:55,424 SEGMENTS FROM DISTINCT LOCI THAT 1179 00:46:55,424 --> 00:46:56,759 ARE ARRANGED IN A SINGLE 1180 00:46:56,759 --> 00:46:58,961 AMPLIFIED REGION IF YOU'RE NOT 1181 00:46:58,961 --> 00:47:00,396 FAMILIAR, THERE'S A LOT OF 1182 00:47:00,396 --> 00:47:03,132 ATTENTION THESE DAYS. I THINK 1183 00:47:03,132 --> 00:47:05,501 THEY ARE VERY COOL TO, FROM A 1184 00:47:05,501 --> 00:47:06,802 BIOLOGY STANDPOINT BUT OF COURSE 1185 00:47:06,802 --> 00:47:08,437 VERY LETHAL. THEY ARE FORMED 1186 00:47:08,437 --> 00:47:11,641 WHEN THERE'S DNA DAMAGE. SO ANY 1187 00:47:11,641 --> 00:47:16,646 FORM OF DNA CAN FORM THIS. AND 1188 00:47:16,646 --> 00:47:19,115 REARRANGEMENT INTO A SINGLE 1189 00:47:19,115 --> 00:47:21,250 REGION. SO THERE'S MULTIPLE 1190 00:47:21,250 --> 00:47:22,351 MECHANISMS. IF YOU HAVE A 1191 00:47:22,351 --> 00:47:24,086 DOUBLE STRAND REARRANGEMENT YOU 1192 00:47:24,086 --> 00:47:26,255 CAN HAVE A SIMPLE DNA. BUT YOU 1193 00:47:26,255 --> 00:47:28,591 CAN ALSO HAVE MASSIVE DNA DAMAGE 1194 00:47:28,591 --> 00:47:33,863 OR CHROMOSOME SHATTERING WHICH 1195 00:47:33,863 --> 00:47:36,933 CAN RESULT IN COMPLEX EC DNA BUT 1196 00:47:36,933 --> 00:47:39,402 WHY ARE THEY SO COMPLICATED 1197 00:47:39,402 --> 00:47:40,836 BECAUSE THEY DON'T HAVE 1198 00:47:40,836 --> 00:47:44,507 CENTRALNESS. THEY HAVE UNEQUAL 1199 00:47:44,507 --> 00:47:45,741 SEGREGATION THAT MEANS THEY CAN 1200 00:47:45,741 --> 00:47:47,510 CONCENTRATE IN SOME CELLS MORE 1201 00:47:47,510 --> 00:47:48,978 THAN OTHERS. AND THERE ARE 1202 00:47:48,978 --> 00:47:52,581 OTHER FUTURES OF EC DNA THAT 1203 00:47:52,581 --> 00:47:57,820 DRIVE HIGH ONCOGENE EXPRESSION. 1204 00:47:57,820 --> 00:48:00,389 THERE'S ENHANCERS AND CON TESTS 1205 00:48:00,389 --> 00:48:02,725 AS WELL AS HIGHER CHROMATIN 1206 00:48:02,725 --> 00:48:04,827 ACCESSIBILITY AND THIS IS ONE 1207 00:48:04,827 --> 00:48:06,395 EXAMPLE. IN THE SCLC CELL LINE 1208 00:48:06,395 --> 00:48:15,471 THERE'S TWO DNA'S. HERE YOU CAN 1209 00:48:15,471 --> 00:48:17,106 SEE THE SINGLE STRUCTURE. AND 1210 00:48:17,106 --> 00:48:18,574 WHEN WE DO SEQUENCE WE FIND 1211 00:48:18,574 --> 00:48:20,309 THAT, YOU KNOW, EACH COLUMN HERE 1212 00:48:20,309 --> 00:48:24,380 IS A SINGLE CELL. THERE'S A LOT 1213 00:48:24,380 --> 00:48:32,021 OF VARIABILITY IN THE 1214 00:48:32,021 --> 00:48:33,022 HETEROGENEITY. SO YOU CAN 1215 00:48:33,022 --> 00:48:35,624 IMAGINE THE COMPLEXITY OF THESE 1216 00:48:35,624 --> 00:48:39,328 CELLS THAT HAVE, YOU KNOW, SOME 1217 00:48:39,328 --> 00:48:41,263 DNA AND SOME DON'T HAVE EC DNA 1218 00:48:41,263 --> 00:48:43,332 SO THIS IS PROBABLY ONE FEATURE 1219 00:48:43,332 --> 00:48:46,469 THAT DRIVES THE HETEROGENEITY 1220 00:48:46,469 --> 00:48:48,304 AND THEY ALSO HAVE 1221 00:48:48,304 --> 00:48:50,206 COAMPLIFICATION OF REGULATORY 1222 00:48:50,206 --> 00:48:50,773 ELEMENTS. PROBABLY MOST 1223 00:48:50,773 --> 00:48:52,842 INTERESTING GOING BACK TO THIS 1224 00:48:52,842 --> 00:48:55,211 AUTOPSY OF THIS PATIENT WHO HAD 1225 00:48:55,211 --> 00:48:57,179 MULTIPLE SAMPLES. AND WE 1226 00:48:57,179 --> 00:49:00,116 PERFORMED WHOLE GENOME 1227 00:49:00,116 --> 00:49:03,686 SEQUENCING AND WE FOUND THAT MYC 1228 00:49:03,686 --> 00:49:06,389 IS FOUND IN DIFFERENT LEVELS. 1229 00:49:06,389 --> 00:49:09,825 SO WE HAD THE MYC AMPLIFIED 1230 00:49:09,825 --> 00:49:11,894 COMPARED TO LUNG AND ADRENAL 1231 00:49:11,894 --> 00:49:14,397 WHERE MYC IS MUCH MORE SMALLER 1232 00:49:14,397 --> 00:49:17,967 AMPLIFIED AND WHEN WE HOOK AT -- 1233 00:49:17,967 --> 00:49:20,903 LOOK AT THE DNA WE SEE THIS AS A 1234 00:49:20,903 --> 00:49:24,106 STAINING REGION WHICH IS WITHIN 1235 00:49:24,106 --> 00:49:29,545 CHROMOSOME BUT IN THESE OTHER 1236 00:49:29,545 --> 00:49:31,814 LINES IT'S AN EC DNA. THERE'S 1237 00:49:31,814 --> 00:49:36,986 HIGHER LEVELS OF TRANSCRIPTIONAL 1238 00:49:36,986 --> 00:49:39,255 OUTPUT AND WE SEE THAT LIVER, 1239 00:49:39,255 --> 00:49:41,791 WHERE IT'S AMPLIFIED, THE TUMOR 1240 00:49:41,791 --> 00:49:45,594 HAS AN ASCL 1 END STATE BUT WHEN 1241 00:49:45,594 --> 00:49:48,297 IT GOES TO THE LUNG, YOU CAN SEE 1242 00:49:48,297 --> 00:49:51,333 THAT YOU START TO SEE THIS. SO 1243 00:49:51,333 --> 00:49:53,335 THIS SEEMS TO BE SUBTYPES THAT 1244 00:49:53,335 --> 00:49:55,704 SUGGESTS THIS IS ENHANCED BY THE 1245 00:49:55,704 --> 00:49:57,406 META STATIC SITES. THE QUESTION 1246 00:49:57,406 --> 00:49:59,508 THAT'S IMPORTANT FOR US IS TO 1247 00:49:59,508 --> 00:50:00,576 SEE IF IT CAN BE TARGETED. 1248 00:50:00,576 --> 00:50:02,511 AND THERE'S A LOT OF INTEREST. 1249 00:50:02,511 --> 00:50:04,613 THERE'S A RECENT PAPER SHOWING 1250 00:50:04,613 --> 00:50:07,817 THAT YOU CAN ENHANCE, THERE'S 1251 00:50:07,817 --> 00:50:08,484 MUCH MORE TRANSCRIPTION 1252 00:50:08,484 --> 00:50:09,819 HAPPENING AND ONE WAY TO TARGET 1253 00:50:09,819 --> 00:50:12,822 IT IS BY ENHANCING TRANSCRIPTION 1254 00:50:12,822 --> 00:50:14,256 REPLICATION CONFLICTS AND HERE 1255 00:50:14,256 --> 00:50:16,926 THEY USED CHECK ONE INHIBITORS 1256 00:50:16,926 --> 00:50:17,893 AND USING THE SAME APPROACH CHIP 1257 00:50:17,893 --> 00:50:21,831 THAT I MENTIONED EARLIER, YOU 1258 00:50:21,831 --> 00:50:24,700 CAN REALLY IDENTIFY EC DNA'S IN 1259 00:50:24,700 --> 00:50:29,171 MA. -- PLASMA. 1260 00:50:29,171 --> 00:50:30,940 YOU CAN SEE THE WHOLE GENOME 1261 00:50:30,940 --> 00:50:32,141 SEQUENCES AT THE TOP AND YOU CAN 1262 00:50:32,141 --> 00:50:35,377 SEE ALMOST MATCHED PROFILES FOR 1263 00:50:35,377 --> 00:50:37,847 BOTH CF AS WELL AS WHOLE 1264 00:50:37,847 --> 00:50:40,850 SEQUENCES AND OF COURSE IT'S -- 1265 00:50:40,850 --> 00:50:43,686 IT LEADS TO FATALITY, AND THIS 1266 00:50:43,686 --> 00:50:45,187 TENDS TO HAVE MUCH WORSE 1267 00:50:45,187 --> 00:50:47,890 OUTCOMES AND ABOUT 20% OF SCLCS 1268 00:50:47,890 --> 00:50:49,925 HAVE EC DNA REPLICATION. TO 1269 00:50:49,925 --> 00:50:51,427 CONCLUDE, WE ARE TRYING TO 1270 00:50:51,427 --> 00:50:53,195 COMBINE THE DUAL POWERS OF 1271 00:50:53,195 --> 00:50:54,463 CLINICAL OBSERVATION. AND I 1272 00:50:54,463 --> 00:50:57,299 THINK THE POWER OF CLINICAL 1273 00:50:57,299 --> 00:50:59,068 OBSERVATION IS SOMEWHAT 1274 00:50:59,068 --> 00:51:00,369 UNDERESTIMATED THESE DAYS. IT'S 1275 00:51:00,369 --> 00:51:01,837 STILL VERY POWERFUL EVEN IN THE 1276 00:51:01,837 --> 00:51:03,973 AGE OF GENOMICS WE'RE TRYING TO 1277 00:51:03,973 --> 00:51:06,375 COMBINE IT WITH THE POWERS OF 1278 00:51:06,375 --> 00:51:08,477 GENOMICS AND WE'RE FINDING THAT 1279 00:51:08,477 --> 00:51:09,812 SCLC, A SINGLE DISEASE IS REALLY 1280 00:51:09,812 --> 00:51:15,451 A GROUP OF DECIDINGS -- DISEASES 1281 00:51:15,451 --> 00:51:22,558 THAT HAS UNIQUE VULNERABILITIES. 1282 00:51:22,558 --> 00:51:24,293 WE TALKED ABOUT MECHANISMS THAT 1283 00:51:24,293 --> 00:51:28,264 DRIVE THESE INCLUDING LMNA 1284 00:51:28,264 --> 00:51:31,200 SUPPRESSION BY ECH 2 WHICH MAY 1285 00:51:31,200 --> 00:51:33,802 EXPLAIN THE OTHER FEATURES AND 1286 00:51:33,802 --> 00:51:38,007 NOTCH MEDIA UPREGULATION IN THIS 1287 00:51:38,007 --> 00:51:39,875 CASE. SOME, YOU KNOW, SUBTYPES 1288 00:51:39,875 --> 00:51:41,243 WHICH WE DIDN'T TALK ABOUT WE 1289 00:51:41,243 --> 00:51:43,345 FOUND THAT NEVER SMOKERS, THEY 1290 00:51:43,345 --> 00:51:46,482 HAVE THEIR OWN GENOMIC FEATURES 1291 00:51:46,482 --> 00:51:47,650 AND THERE'S A COMPONENT OF 1292 00:51:47,650 --> 00:51:52,421 MUTATED SCLC THAT JUST GERMLINE 1293 00:51:52,421 --> 00:51:53,889 MUTATIONS IN KEY DNA REPAIRED 1294 00:51:53,889 --> 00:51:56,292 GENES AND THIS IS IMPORTANT 1295 00:51:56,292 --> 00:51:58,627 BECAUSE SCLC IS -- VERY CLOSELY 1296 00:51:58,627 --> 00:51:59,962 ASSOCIATED WITH SMOKING. ALMOST 1297 00:51:59,962 --> 00:52:03,566 ALL PATIENTS HAVE SMOKED AT SOME 1298 00:52:03,566 --> 00:52:04,833 POINT OR SECONDHAND SMOKE 1299 00:52:04,833 --> 00:52:08,437 EXPOSURE. WE TALKED ABOUT 1300 00:52:08,437 --> 00:52:09,471 DRIVERS OF SCLC. AND WE'RE NOT 1301 00:52:09,471 --> 00:52:13,809 AT A POINT WHERE WE CAN TARGET 1302 00:52:13,809 --> 00:52:16,478 THEM YET AND THE DRIVER AND 1303 00:52:16,478 --> 00:52:19,081 THERE ARE APPROACHES THAT YOU 1304 00:52:19,081 --> 00:52:21,217 CAN USE TO TARGET THEM AND THEN 1305 00:52:21,217 --> 00:52:24,386 NONINVASIVE SUBTYPES AND ONE WAY 1306 00:52:24,386 --> 00:52:25,621 TO TARGET HETEROGENEITY IN 1307 00:52:25,621 --> 00:52:28,224 PATIENTS IS BY USING 1308 00:52:28,224 --> 00:52:34,196 COMBINATIONS, BY STRAINING 1309 00:52:34,196 --> 00:52:38,167 PLASTICITY. THIS IS A VALUE OF 1310 00:52:38,167 --> 00:52:41,136 DEATH. THIS IS WHERE PATIENTS, 1311 00:52:41,136 --> 00:52:42,671 DRUGS, IDEAS DIE BUT WE FOUND 1312 00:52:42,671 --> 00:52:43,973 ONE APPROACH TO BRIDGE THIS 1313 00:52:43,973 --> 00:52:45,507 DIVIDE IS TO REALLY FOCUS ON THE 1314 00:52:45,507 --> 00:52:46,675 PATIENT AND OF COURSE, YOU KNOW, 1315 00:52:46,675 --> 00:52:52,014 I WANT TO THANK THE PATIENTS, 1316 00:52:52,014 --> 00:52:58,120 AND THANK CLINICAL GROUP AND TO 1317 00:52:58,120 --> 00:52:59,888 HAVE A GREAT CLINICAL GROUP AND 1318 00:52:59,888 --> 00:53:01,090 WE'RE FORTUNATE FOR THAT. WE 1319 00:53:01,090 --> 00:53:02,358 HAVE A GREAT RESEARCH GROUP AS 1320 00:53:02,358 --> 00:53:04,426 WELL AS THE NUMBER OF 1321 00:53:04,426 --> 00:53:05,060 COLLABORATORS BOTH WITHIN THE 1322 00:53:05,060 --> 00:53:07,496 BRANCH AND OUTSIDE THE BRANCH. 1323 00:53:07,496 --> 00:53:09,832 NUMBER OF FORMER FELLOWS WHOSE 1324 00:53:09,832 --> 00:53:12,635 WORK I HIGHLIGHTED AND OF COURSE 1325 00:53:12,635 --> 00:53:15,371 TECH TRANSFERS, STATISTICS AND 1326 00:53:15,371 --> 00:53:17,606 OF COURSE THANK YOU ALL FOR 1327 00:53:17,606 --> 00:53:18,173 COMING AND HAPPY HOLIDAYS. 1328 00:53:18,173 --> 00:53:28,617 >> AUDIENCE: (APPLAUSE). 1329 00:53:30,252 --> 00:53:32,021 >> AUDIENCE: THAT WAS GREAT, 1330 00:53:32,021 --> 00:53:33,922 THANK YOU. MIGHT BE A QUESTION. 1331 00:53:33,922 --> 00:53:36,458 I WAS UNDER THE QUESTION P 53 1332 00:53:36,458 --> 00:53:40,129 WAS A MAJOR EFFECT OF DEATH 1333 00:53:40,129 --> 00:53:42,464 AFTER STRESS. BUT YOU TOLD US 1334 00:53:42,464 --> 00:53:44,166 THEY HAD MUTATIONS. WHAT DO YOU 1335 00:53:44,166 --> 00:53:46,235 KNOW ABOUT THE MECHANISM OF 1336 00:53:46,235 --> 00:53:48,137 DOWNSTREAM OF REPLICATION STRESS 1337 00:53:48,137 --> 00:53:50,439 IN THESE CELLS? IS THERE 1338 00:53:50,439 --> 00:53:51,740 REMAINING? IS THERE SOME OTHER 1339 00:53:51,740 --> 00:53:53,709 MECHANISM WHAT DO YOU KNOW ABOUT 1340 00:53:53,709 --> 00:53:53,942 THAT? 1341 00:53:53,942 --> 00:53:55,544 >> ANISH: THAT'S A GOOD 1342 00:53:55,544 --> 00:53:58,314 QUESTION. SO I DON'T KNOW, IN 1343 00:53:58,314 --> 00:54:00,082 THE MECHANISMS, SO INDEED IT IS 1344 00:54:00,082 --> 00:54:06,088 P 53 MEDIATED. SO I'M THINKING 1345 00:54:06,088 --> 00:54:10,259 THAT, YOU KNOW, YEAH I DON'T 1346 00:54:10,259 --> 00:54:13,062 KNOW THE NON P 53 MECHANISMS 1347 00:54:13,062 --> 00:54:15,898 THAT MEDIATES THAT, YEAH. 1348 00:54:15,898 --> 00:54:20,069 >> AUDIENCE: ANISH, REALLY 1349 00:54:20,069 --> 00:54:21,537 BEAUTIFUL LECTURE, THANK YOU. I 1350 00:54:21,537 --> 00:54:23,839 HAD A QUESTION ABOUT THE 1351 00:54:23,839 --> 00:54:25,040 REPLICATION STRESS ASPECT OF 1352 00:54:25,040 --> 00:54:28,210 YOUR WORK. OBVIOUSLY A LOT OF 1353 00:54:28,210 --> 00:54:29,812 TUMORS ARE REPRODUCING QUICKLY, 1354 00:54:29,812 --> 00:54:32,381 THEY HAVE A LOT OF REPLICATION 1355 00:54:32,381 --> 00:54:36,885 STRESS. THOSE THAT RECUR AFTER 1356 00:54:36,885 --> 00:54:38,087 CHEMOTHERAPY, DOES IT STAND TO 1357 00:54:38,087 --> 00:54:40,289 REASON THAT THEY WOULD HAVE LESS 1358 00:54:40,289 --> 00:54:41,090 REPLICATION STRESS OR THERE ARE 1359 00:54:41,090 --> 00:54:43,726 OTHER MECHANISMS OF RESISTANCE 1360 00:54:43,726 --> 00:54:45,227 THAT COME UP? 1361 00:54:45,227 --> 00:54:47,429 >> ANISH: RIGHT SO WE'RE NOT 1362 00:54:47,429 --> 00:54:48,697 COMPREHENSIVELY LOOKED AT 1363 00:54:48,697 --> 00:54:50,966 MECHANISMS OF RESISTANCE THAT 1364 00:54:50,966 --> 00:54:53,635 OCCUR AFTER TREATMENT. SO ONE 1365 00:54:53,635 --> 00:54:56,105 OF THEM COULD BE DOWNREGULATION 1366 00:54:56,105 --> 00:54:58,640 OF REPLICATION STRESS RELATED 1367 00:54:58,640 --> 00:55:01,810 PATHWAYS. ONE COULD BE EMT, YOU 1368 00:55:01,810 --> 00:55:04,146 KNOW, SO WE HAVE SEEN THIS IN 1369 00:55:04,146 --> 00:55:06,215 SOME, AGAIN, IT'S VERY DIFFICULT 1370 00:55:06,215 --> 00:55:08,183 TO GET PRE/POST TREATMENT 1371 00:55:08,183 --> 00:55:09,284 BIOPSIES AND THAT'S REALLY A 1372 00:55:09,284 --> 00:55:10,619 MAJOR CHALLENGE SO EMT COULD BE 1373 00:55:10,619 --> 00:55:11,987 ONE AND HOW WE KNOW THAT IS WHEN 1374 00:55:11,987 --> 00:55:15,491 WE DO CIRCULATING TUMOR CELLS, 1375 00:55:15,491 --> 00:55:17,259 WE CAN PROFILE THEM USING 1376 00:55:17,259 --> 00:55:20,129 EPITHELIUM MARKERS, EP CAM AND 1377 00:55:20,129 --> 00:55:21,663 MAC ONE AND SO FORTH. WE FIND 1378 00:55:21,663 --> 00:55:24,266 THAT CTCS THAT ARE OBTAINED AT 1379 00:55:24,266 --> 00:55:27,369 THE TIME OF RELAPSE OR AT THE 1380 00:55:27,369 --> 00:55:28,237 TIME OF DISEASE PROGRESSION, 1381 00:55:28,237 --> 00:55:29,805 THEY TEND TO LOSE THESE 1382 00:55:29,805 --> 00:55:31,707 EPITHELIAL MARKERS SO MAYBE THAT 1383 00:55:31,707 --> 00:55:35,677 IS ONE MECHANISM. RIGHT. AND 1384 00:55:35,677 --> 00:55:38,080 THEN DRUG REFLEX TRANSPORTERS. 1385 00:55:38,080 --> 00:55:39,515 WE HAVE NOT FOUND IT BUT OTHER 1386 00:55:39,515 --> 00:55:42,251 PEOPLE HAVE. ABC 1, THEY CAN BE 1387 00:55:42,251 --> 00:55:44,820 AMPLIFIED ON DNA'S, THAT COULD 1388 00:55:44,820 --> 00:55:48,056 BE A THIRD MECHANISM. 1389 00:55:48,056 --> 00:55:52,361 BUT I THINK THE CELLS ARE SO 1390 00:55:52,361 --> 00:55:54,296 PLASTIC, SO TRANSCRIPTIONALLY 1391 00:55:54,296 --> 00:55:57,266 PLASTIC I FEEL MORE SO THAN 1392 00:55:57,266 --> 00:56:00,068 MUTATIONS IT IS, OR GENOMIC 1393 00:56:00,068 --> 00:56:01,603 ALTERATIONS, IT IS 1394 00:56:01,603 --> 00:56:03,138 TRANSCRIPTOMIC CHANGES INCLUDING 1395 00:56:03,138 --> 00:56:06,809 EMT AND POTENTIALLY OTHERS THAT 1396 00:56:06,809 --> 00:56:09,478 MIGHT BE DRIVING THIS RESISTANCE 1397 00:56:09,478 --> 00:56:10,646 AND FOR INSTANCE, PEOPLE HAVE 1398 00:56:10,646 --> 00:56:12,347 SHOWN THAT TUMORS OBTAINED AT 1399 00:56:12,347 --> 00:56:15,584 THE TIME OF RELAPSE THEY TEND TO 1400 00:56:15,584 --> 00:56:17,953 BE MORE NEUROENDOCRINE SO THAT 1401 00:56:17,953 --> 00:56:20,322 COMES WITH MORE FEATURES, 1402 00:56:20,322 --> 00:56:23,959 REDUCED REPLICATION STRESS, 1403 00:56:23,959 --> 00:56:24,560 CHEMOTHERAPY RESISTANCE AND 1404 00:56:24,560 --> 00:56:25,828 RADIOTHERAPY RESISTANCE I THINK 1405 00:56:25,828 --> 00:56:29,131 IT'S GOING TO BE A LITTLE BIT OF 1406 00:56:29,131 --> 00:56:29,798 EVERYTHING. 1407 00:56:29,798 --> 00:56:31,400 >> AUDIENCE: SO THE OTHER, IF 1408 00:56:31,400 --> 00:56:37,873 CAN I ASK ANOTHER QUESTION, I 1409 00:56:37,873 --> 00:56:42,478 WANTED TO FOLLOW UP WITH LMNA. 1410 00:56:42,478 --> 00:56:44,780 ONE OF THE FEATURES IS THAT ONE 1411 00:56:44,780 --> 00:56:45,714 OF THE TREATMENTS FOR PROJEER YA 1412 00:56:45,714 --> 00:56:51,587 HAS BEEN INHIBITORS WHICH BY THE 1413 00:56:51,587 --> 00:56:54,323 WAY WERE PERFORMED FOR TREATING 1414 00:56:54,323 --> 00:56:56,425 TUMORS. WHAT WOULD YOU EXPECTS 1415 00:56:56,425 --> 00:56:58,160 FOR ISOLATION INHIBITORS TO DO 1416 00:56:58,160 --> 00:57:00,462 IN YOUR SYSTEM AND MIGHT THEY 1417 00:57:00,462 --> 00:57:04,199 SENSITIZE MORE CELLS TO THE 1418 00:57:04,199 --> 00:57:05,133 REPLICATION STRESS TREATMENTS? 1419 00:57:05,133 --> 00:57:08,303 >> ANISH: SO WE'VE NOT TRIED THE 1420 00:57:08,303 --> 00:57:10,405 FAR THAT CELL TRANSFERASE 1421 00:57:10,405 --> 00:57:12,074 INHIBITORS IN THIS CASE BUT I 1422 00:57:12,074 --> 00:57:14,209 THINK THOSE AGENTEDS MIGHT BE 1423 00:57:14,209 --> 00:57:17,346 MORE SPECIFIC TO THE SETTING OF 1424 00:57:17,346 --> 00:57:21,817 PROJAR YA WHERE THERE'S AN LMNA 1425 00:57:21,817 --> 00:57:22,551 MUTATION. 1426 00:57:22,551 --> 00:57:24,286 BUT IN THIS CASE WE SEE IT'S 1427 00:57:24,286 --> 00:57:26,221 PROBABLY A SUPPRESSION OF LMNA 1428 00:57:26,221 --> 00:57:27,723 AND MAYBE THE AGENTS MIGHT BE A 1429 00:57:27,723 --> 00:57:31,894 WAY TO REACTIVATE LMNA RATHER 1430 00:57:31,894 --> 00:57:33,262 THAN USING FAR THAT CELL 1431 00:57:33,262 --> 00:57:36,098 INHIBITORS. I THINK, YOU KNOW, 1432 00:57:36,098 --> 00:57:37,833 THE CONSEQUENCE IS PROBABLY 1433 00:57:37,833 --> 00:57:40,135 SIMILAR THAT AS A DYSFUNCTIONAL 1434 00:57:40,135 --> 00:57:41,803 LMNA BUT MAYBE THE MECHANISMS 1435 00:57:41,803 --> 00:57:44,439 ARE SLIGHTLY DIFFERENT AND THE 1436 00:57:44,439 --> 00:57:45,807 DRUGS MIGHT NOT NECESSARILY 1437 00:57:45,807 --> 00:57:50,512 TRANSLATE. 1438 00:57:50,512 --> 00:57:51,780 >> AUDIENCE: HEY, I AM A BIG 1439 00:57:51,780 --> 00:57:55,484 FAN. SO I AM BIASED. AMAZING 1440 00:57:55,484 --> 00:57:58,520 WORK. BUT ALSO AMAZING 1441 00:57:58,520 --> 00:58:01,823 CHALLENGES. I MEAN, SO 1442 00:58:01,823 --> 00:58:03,325 CHALLENGING AND DIFFICULT TO 1443 00:58:03,325 --> 00:58:06,094 MAKE IT END? 1444 00:58:06,094 --> 00:58:07,829 >> ANISH: YEAH, WE HAVE A 1445 00:58:07,829 --> 00:58:09,998 PERSONAL THERAPIST FOR THE 1446 00:58:09,998 --> 00:58:10,299 GROUP. 1447 00:58:10,299 --> 00:58:10,899 >> AUDIENCE: YOU KNOW I HAVE 1448 00:58:10,899 --> 00:58:12,467 SOME SKILLS IN THAT DOMAIN. 1449 00:58:12,467 --> 00:58:15,203 CHEAP IS CHEAP. I KNOW. I 1450 00:58:15,203 --> 00:58:18,473 KNOW. YEAH, SO JUST A FEW 1451 00:58:18,473 --> 00:58:21,476 COMMENTS AS FAR AS I STILL 1452 00:58:21,476 --> 00:58:29,818 REMEMBER, SO ONE, YOU REMEMBER 1453 00:58:29,818 --> 00:58:32,854 SJ. WE HAVE A PREDICTOR OF 1454 00:58:32,854 --> 00:58:33,689 EXTRACELLULAR DNA FROM THE 1455 00:58:33,689 --> 00:58:37,092 SLIDES. IT'S ACTUALLY, WE HAVE 1456 00:58:37,092 --> 00:58:38,594 ALL THAT. SO THAT'S ONE 1457 00:58:38,594 --> 00:58:41,129 DIMENSION. I MENTION IT BECAUSE 1458 00:58:41,129 --> 00:58:44,032 I WILL NOT REMEMBER. THE SECOND 1459 00:58:44,032 --> 00:58:51,540 THING IS, THAT WE CAN LOOK AT 1460 00:58:51,540 --> 00:58:52,474 THE PREDICTED SPATIAL 1461 00:58:52,474 --> 00:58:57,112 DESTRUCTION. -- SPATIAL 1462 00:58:57,112 --> 00:58:57,479 DISTRIBUTION. 1463 00:58:57,479 --> 00:59:00,182 WE SHOULD DO THAT. 1464 00:59:00,182 --> 00:59:01,817 THIRDLY, YOU KNOW I COULDN'T 1465 00:59:01,817 --> 00:59:04,286 HELP THINKING ABOUT THIS MAYBE 1466 00:59:04,286 --> 00:59:06,622 SOME ANALOGY, MAYBE IT'S TOO 1467 00:59:06,622 --> 00:59:08,256 SIMPLISTIC TO NEURAL BLASTOMA 1468 00:59:08,256 --> 00:59:12,461 SO, YOU KNOW, ALSO FROM THE -- 1469 00:59:12,461 --> 00:59:17,165 FROM -- CAROL IS HERE? OH. 1470 00:59:17,165 --> 00:59:21,803 YEAH, SO CAROL JUST SENT HER 1471 00:59:21,803 --> 00:59:24,406 FELLOWS SENT US SOME POSTER, MY 1472 00:59:24,406 --> 00:59:26,975 NAME WAS IN IT, I'M CLUELESS BUT 1473 00:59:26,975 --> 00:59:29,811 I READ IT WITH MY INTEREST AND 1474 00:59:29,811 --> 00:59:36,885 APPARENT LY CAROL CAN SAY MORE 1475 00:59:36,885 --> 00:59:39,121 BETWEEN THESE. AND MAKE HIGHLY 1476 00:59:39,121 --> 00:59:43,992 INVOLVED -- I WONDER ABOUT THIS 1477 00:59:43,992 --> 00:59:53,035 ANALOGY AND YOU SHOULD TALK TO 1478 00:59:53,035 --> 00:59:55,704 CAROL. THE WORK YOU D DID YOU 1479 00:59:55,704 --> 00:59:57,639 HAVE TO DO COUNCIL CELL CAPTURE? 1480 00:59:57,639 --> 00:59:59,174 >> ANISH: IT'S A FAIRLY SIMPLE 1481 00:59:59,174 --> 01:00:00,976 PROCEDURE. THEY LOOK AT PLASMA 1482 01:00:00,976 --> 01:00:03,111 AND THEY HAVE THE ANTIBODIES 1483 01:00:03,111 --> 01:00:05,714 AGAINST THE PARTICULAR HIS TOME 1484 01:00:05,714 --> 01:00:08,250 MODIFICATION. THEY CAPTURE AND 1485 01:00:08,250 --> 01:00:09,284 THEY DO SEQUENCING. SO THERE'S 1486 01:00:09,284 --> 01:00:11,286 NO CANCER CELLS INVOLVED. 1487 01:00:11,286 --> 01:00:13,622 IT'S JUST PLASMA THAT'S ISOLATED 1488 01:00:13,622 --> 01:00:15,891 FROM PATIENTS. SO WE DOUBLE 1489 01:00:15,891 --> 01:00:17,426 SPIN PLASMA THAT'S COLLECTED IN 1490 01:00:17,426 --> 01:00:21,129 TUBES AND THEY LOOK AT THIS HIS 1491 01:00:21,129 --> 01:00:22,898 TOME MODIFICATION DIRECTLY. 1492 01:00:22,898 --> 01:00:24,700 >> AUDIENCE: WHEN YOU SAY IT'S 1493 01:00:24,700 --> 01:00:28,336 COLLATED WITH 26 TRANSCRIPT, IT 1494 01:00:28,336 --> 01:00:29,271 EXCITED ME. YOU MEAN CELLS IN 1495 01:00:29,271 --> 01:00:31,673 THE TUMOR BUT YOU MEAN WHAT? 1496 01:00:31,673 --> 01:00:36,845 TUMOR CELLS, BULK EXPRESSION? 1497 01:00:36,845 --> 01:00:37,879 >> ANISH: THE EXPRESSION IS CUE 1498 01:00:37,879 --> 01:00:44,119 MORE CELLS. TWO CIRCULATING 1499 01:00:44,119 --> 01:00:45,821 SUB-SEQ BASED EXPRESSION OF THAT 1500 01:00:45,821 --> 01:00:46,388 GIVEN GENE. 1501 01:00:46,388 --> 01:00:47,556 >> AUDIENCE: BUT IS IT BULK 1502 01:00:47,556 --> 01:00:49,357 EXPRESSION OF THE TUMOR TME OR 1503 01:00:49,357 --> 01:00:52,160 THE EXPRESSION OF TUMOR CELLS? 1504 01:00:52,160 --> 01:00:53,061 >> ANISH: TUMOR CELL. 1505 01:00:53,061 --> 01:00:54,763 >> AUDIENCE: WOW SO THAT'S 1506 01:00:54,763 --> 01:00:56,765 AMAZING. WE SHOULD TALK BECAUSE 1507 01:00:56,765 --> 01:00:59,167 WE CAN -- THAT'S AMAZING. 1508 01:00:59,167 --> 01:01:00,869 >> ANISH: I THINK IT'S A REALLY 1509 01:01:00,869 --> 01:01:01,803 POWERFUL TOOL WE WORKED WITH A 1510 01:01:01,803 --> 01:01:04,840 LOT OF DIFFERENT APPROACHES IN 1511 01:01:04,840 --> 01:01:06,007 CIRCULATING FREE DNA STARTING 1512 01:01:06,007 --> 01:01:11,646 FROM LOOKING AT MUTATIONS, 1513 01:01:11,646 --> 01:01:12,547 METHYLATION, MODIFICATIONS IN 1514 01:01:12,547 --> 01:01:14,549 PLASMA, FLAG MEN TOMICS, BASED 1515 01:01:14,549 --> 01:01:16,418 IN THE POSITIONING AND SO FORTH 1516 01:01:16,418 --> 01:01:17,853 BUT BY FAR, THIS IS PROBABLY THE 1517 01:01:17,853 --> 01:01:23,091 BEST APPROACH. TO INFER TUMOR 1518 01:01:23,091 --> 01:01:24,259 GENE EXPRESSION PROGRAM AGAIN, 1519 01:01:24,259 --> 01:01:26,962 IF IT'S A GENE THAT'S EXPRESSED 1520 01:01:26,962 --> 01:01:28,830 IN NORMAL TISSUE, LIKE, FOR 1521 01:01:28,830 --> 01:01:30,832 EXAMPLE, IF YOU'RE LOOKING AT 1522 01:01:30,832 --> 01:01:32,467 ENVIRONMENT YOU DON'T SEE THE 1523 01:01:32,467 --> 01:01:33,068 CONCORDANCE BECAUSE NORMAL 1524 01:01:33,068 --> 01:01:35,137 TISSUE IS SHEDDING IT AND YOU 1525 01:01:35,137 --> 01:01:40,175 DON'T SEE THAT. BUT IF IT'S A 1526 01:01:40,175 --> 01:01:41,276 TUMOR-SPECIFIC GENE WE CAN 1527 01:01:41,276 --> 01:01:43,278 DETECT THAT. 1528 01:01:43,278 --> 01:01:45,347 >> AUDIENCE: BUT WE CAN INFER 1529 01:01:45,347 --> 01:01:48,483 THROUGH THE BIOMARKERS DIRECTLY 1530 01:01:48,483 --> 01:01:49,417 THROUGH THE BLOOD FOR MANY DRUGS 1531 01:01:49,417 --> 01:01:52,020 AND TARGETS AND FINE 1532 01:01:52,020 --> 01:01:55,924 SENSITIVITIES. WITHOUT A NEED 1533 01:01:55,924 --> 01:02:00,495 FOR BAY BIOPSY. 1534 01:02:00,495 --> 01:02:03,565 >> ANISH: YES, AND WE SHOULD 1535 01:02:03,565 --> 01:02:06,501 TALK. THIS EPITHELIAL, YOU 1536 01:02:06,501 --> 01:02:09,204 KNOW, IT'S VERY EVIDENT IN 1537 01:02:09,204 --> 01:02:11,106 NEUROBLASTOMA, IT HAS A LOT OF 1538 01:02:11,106 --> 01:02:12,007 COMMONALITIES, THE CELL OF 1539 01:02:12,007 --> 01:02:13,475 ORIGIN IS NOT THE SAME BUT THERE 1540 01:02:13,475 --> 01:02:16,678 IS A LOT OF COMMONALITIES, CELL 1541 01:02:16,678 --> 01:02:19,948 STATE TRANSITIONS, DRUG 1542 01:02:19,948 --> 01:02:21,817 SENSITIVITY, YES. 1543 01:02:21,817 --> 01:02:23,451 >> AUDIENCE: BUT IT IS MUCH MORE 1544 01:02:23,451 --> 01:02:25,187 STILL RESPONSIBLE TO THERAPY. 1545 01:02:25,187 --> 01:02:27,155 OF COURSE IT IS EXTENSIVE SO 1546 01:02:27,155 --> 01:02:30,492 WHY, YOU AND CAROL SHOULD -- I 1547 01:02:30,492 --> 01:02:32,260 CAN SERVE COFFEE, I'LL BRING YOU 1548 01:02:32,260 --> 01:02:35,664 AND CAROL TO THE SAME ROOM. WE 1549 01:02:35,664 --> 01:02:38,834 MUSTN'T -- WHY, I STILL DIDN'T 1550 01:02:38,834 --> 01:02:40,735 COME OUT FROM THE -- YOUR TALK 1551 01:02:40,735 --> 01:02:43,572 WITH AN UNDERSTANDING WHY IS IT 1552 01:02:43,572 --> 01:02:44,673 SO DIFFICULT TO TREAT? 1553 01:02:44,673 --> 01:02:45,807 >> ANISH: I THINK THE COMMON 1554 01:02:45,807 --> 01:02:49,544 THEME IS HETEROGENEITY AND -- 1555 01:02:49,544 --> 01:02:53,014 >> AUDIENCE: BUT MANY ARE -- 1556 01:02:53,014 --> 01:02:54,349 >> ANISH: THIS IS PROBABLY AN 1557 01:02:54,349 --> 01:02:55,417 EXTREME CASE. 1558 01:02:55,417 --> 01:02:57,619 >> AUDIENCE: I THINK IT'S THE 1559 01:02:57,619 --> 01:02:58,954 DYNAMICS OF THE RESISTANCE BUT 1560 01:02:58,954 --> 01:03:00,488 WHAT DO I KNOW? THANK YOU SO 1561 01:03:00,488 --> 01:03:00,722 MUCH. 1562 01:03:00,722 --> 01:03:10,098 >> ANISH: THANK YOU. 1563 01:03:10,098 --> 01:03:12,234 >> AUDIENCE: TERRIFIC WORK AND 1564 01:03:12,234 --> 01:03:15,003 IT'S SO NICE OF YOU TO SHOW THE 1565 01:03:15,003 --> 01:03:17,806 BENCH TO BEDSIDE EFFORTS MY 1566 01:03:17,806 --> 01:03:19,207 QUESTION IS ABOUT THE 1567 01:03:19,207 --> 01:03:21,276 HETEROGENEITY. SPECIFICALLY, 1568 01:03:21,276 --> 01:03:24,312 YOU MENTIONED THAT THIS IDEA 1569 01:03:24,312 --> 01:03:27,582 THAT I THINK WE'VE -- MY TEAM 1570 01:03:27,582 --> 01:03:28,450 HAS BEEN PRETTY INTERESTED IN 1571 01:03:28,450 --> 01:03:30,185 LOOKING AT, WHAT IS THE 1572 01:03:30,185 --> 01:03:32,254 HETEROGENEITY AT THE EARLIEST 1573 01:03:32,254 --> 01:03:38,126 POINT OF METASTASIS, BEFORE YOU 1574 01:03:38,126 --> 01:03:41,796 HAVE THIS BULK TUMOR AND THESE 1575 01:03:41,796 --> 01:03:43,665 COLONIZING CELLS WHAT IS THE 1576 01:03:43,665 --> 01:03:44,332 NECESSARY HETEROGENEITY THERE? 1577 01:03:44,332 --> 01:03:48,136 HOW DO THEY INTERACT WITH EACH 1578 01:03:48,136 --> 01:03:49,804 OTHER? IS IT MORE COOPERATIVE 1579 01:03:49,804 --> 01:03:51,072 THAN SURVIVAL OF THE FITTEST AND 1580 01:03:51,072 --> 01:03:52,674 FROM THERE, WHAT ARE OBVIOUSLY 1581 01:03:52,674 --> 01:03:55,777 THE CROSS TALK BETWEEN THE 1582 01:03:55,777 --> 01:03:56,344 MICROENVIRONMENT AND THAT 1583 01:03:56,344 --> 01:03:57,245 ALTHOUGH PERHAPS THEY'RE 1584 01:03:57,245 --> 01:03:58,647 PARALLEL EVENTS. YOU KNOW, THE 1585 01:03:58,647 --> 01:03:59,414 EVOLUTION OF THE 1586 01:03:59,414 --> 01:04:00,282 MICROENVIRONMENT AND THE 1587 01:04:00,282 --> 01:04:02,784 EVOLUTION OF THE TUMOR MAYBE 1588 01:04:02,784 --> 01:04:06,521 HAPPENING CONCURRENTLY BUT NOT 1589 01:04:06,521 --> 01:04:09,257 NECESSARILY SYNERGISTICALLY. 1590 01:04:09,257 --> 01:04:10,792 ALTHOUGH MAYBE. SO MY QUESTION 1591 01:04:10,792 --> 01:04:13,695 IS YOU DID MENTION ABOUT TARGETS 1592 01:04:13,695 --> 01:04:20,035 TO THAT. AND TRYING TO WORK 1593 01:04:20,035 --> 01:04:22,137 WITH THEM ABOUT WHAT IS THE GOAL 1594 01:04:22,137 --> 01:04:23,738 NUMBER OF TARGETS? I WONDER 1595 01:04:23,738 --> 01:04:25,807 ABOUT THAT TOO. IF WE THINK 1596 01:04:25,807 --> 01:04:26,808 IT'S COOPERATIVE THAT EACH SUB 1597 01:04:26,808 --> 01:04:28,710 CLONE ACTUALLY IS BETTER IN A 1598 01:04:28,710 --> 01:04:30,512 GROUP OF OTHER DIFFERENT CLONES, 1599 01:04:30,512 --> 01:04:33,515 YOU KNOW, LIKE TEAMWORK MAKES 1600 01:04:33,515 --> 01:04:35,050 THE DREAM WORK ALMOST. 1601 01:04:35,050 --> 01:04:36,251 RATHER THAN ONE CLONE HAVING TO 1602 01:04:36,251 --> 01:04:37,819 BE DOMINANT THAN WHAT IS THE 1603 01:04:37,819 --> 01:04:40,055 NUMBER THAT YOU WOULD NEED, WHAT 1604 01:04:40,055 --> 01:04:41,823 ARE THE TARGETS BECAUSE I THINK 1605 01:04:41,823 --> 01:04:44,659 THE DAYS -- AND YOU KNOW, THE 1606 01:04:44,659 --> 01:04:45,961 DAYS OF THAT SINGLE APPROACH 1607 01:04:45,961 --> 01:04:47,896 WHICH WE'RE DOING WITH 1608 01:04:47,896 --> 01:04:49,364 IMMUNOTHERAPY BY THE WAY, THIS 1609 01:04:49,364 --> 01:04:51,633 IS A GREAT TARGET BUT IT'S ONLY 1610 01:04:51,633 --> 01:04:53,335 ONE, MAYBE OVER -- AND I WANT TO 1611 01:04:53,335 --> 01:04:54,602 KNOW ARE WE GETTING CLOSER TO 1612 01:04:54,602 --> 01:04:56,771 KNOWING THE NUMBER AND DOES IT 1613 01:04:56,771 --> 01:04:59,741 MATTER THEN THE CONTINUUM? 1614 01:04:59,741 --> 01:05:00,942 TARGETING SOMETHING 1615 01:05:00,942 --> 01:05:03,378 NEUROENDOCRINE-LIKE OR SOMETHING 1616 01:05:03,378 --> 01:05:05,080 TARGETING SOMETHING IN BETWEEN 1617 01:05:05,080 --> 01:05:08,383 AND WHAT IS THAT CRITICAL 1618 01:05:08,383 --> 01:05:08,650 NUMBER? 1619 01:05:08,650 --> 01:05:09,918 >> ANISH: THANK YOU. ALL GREAT 1620 01:05:09,918 --> 01:05:11,519 THOUGHTS. WE HAVE NOT REALLY 1621 01:05:11,519 --> 01:05:13,021 TRIED TO ADDRESS THE EARLIER 1622 01:05:13,021 --> 01:05:14,823 STAGES OF METASTASIS AND THE 1623 01:05:14,823 --> 01:05:18,526 CHALLENGES. WE MOST LIE DEAL -- 1624 01:05:18,526 --> 01:05:20,028 MOSTLY DEAL WITH PATIENTS. WE 1625 01:05:20,028 --> 01:05:21,563 WORK WITH MODEL SYSTEMS AND 1626 01:05:21,563 --> 01:05:23,064 THERE ARE NOT MODEL SYSTEMS AT 1627 01:05:23,064 --> 01:05:26,568 THE EARLY STAGES OF METASTASIS 1628 01:05:26,568 --> 01:05:27,068 DEVELOPMENT IN SCLC. 1629 01:05:27,068 --> 01:05:28,970 DEFINITELY, YOU DON'T GET 1630 01:05:28,970 --> 01:05:31,506 PATIENTS AT THAT EARLY STAGES 1631 01:05:31,506 --> 01:05:33,141 OUR TUMOR SAMPLES ARE AT THAT 1632 01:05:33,141 --> 01:05:34,542 EARLY STAGES THAT'S A BIG 1633 01:05:34,542 --> 01:05:36,011 CHALLENGE TO UNDERSTAND THE 1634 01:05:36,011 --> 01:05:37,312 COOPERATIVITY AT THE EARLIEST 1635 01:05:37,312 --> 01:05:38,913 STAGES BUT, YOU KNOW, THAT'S WHY 1636 01:05:38,913 --> 01:05:42,417 I HAVE THIS, BECAUSE THE EARLIER 1637 01:05:42,417 --> 01:05:45,053 STAGES OF SMOKING, IF YOU STOP 1638 01:05:45,053 --> 01:05:49,524 SMOKE SOMETHING -- SMOKING? 1639 01:05:49,524 --> 01:05:51,326 I READ THERE'S NOT MUCH ON THIS 1640 01:05:51,326 --> 01:05:52,727 DISEASE. IT STARTED TO BE 1641 01:05:52,727 --> 01:05:54,496 REPORTED AS SMOKING CAME UP. 1642 01:05:54,496 --> 01:05:57,132 IT'S IMPORTANT TO GO AS EARLY AS 1643 01:05:57,132 --> 01:06:00,235 YOU CAN BUT BEFORE THE 1644 01:06:00,235 --> 01:06:01,269 METASTASIS FORMATION IT'S 1645 01:06:01,269 --> 01:06:02,237 DIFFICULT TO INTERCEPT THEM 1646 01:06:02,237 --> 01:06:03,938 EITHER BY DEVELOPING MODEL OR IN 1647 01:06:03,938 --> 01:06:06,608 OUR CASE BY FOLLOWING PATIENTS. 1648 01:06:06,608 --> 01:06:08,043 >> AUDIENCE: SO WE'RE NOT CLOSE 1649 01:06:08,043 --> 01:06:09,844 WE ARE PATIENTS BY SCREENING 1650 01:06:09,844 --> 01:06:12,747 MAYBE BY BLOOD SCREENING, BY 1651 01:06:12,747 --> 01:06:15,450 IMAGING? WE'RE NOT CLOSER. 1652 01:06:15,450 --> 01:06:16,918 >> ANISH: NOT REALLY. WE LOOKED 1653 01:06:16,918 --> 01:06:19,888 AT CT SCANS, SMOKERS SCREENED BY 1654 01:06:19,888 --> 01:06:22,724 CT SCANS FOR IT TO BE EFFECTIVE, 1655 01:06:22,724 --> 01:06:26,761 TO DEFECT IT WE HAVE TO DETECT 1656 01:06:26,761 --> 01:06:29,497 IT BEFORE IT SHOWS UP ON A CT 1657 01:06:29,497 --> 01:06:33,101 SCAN. THERE'S A LOT OF HOPE 1658 01:06:33,101 --> 01:06:33,902 WITH BLOOD BASED TESTING AND 1659 01:06:33,902 --> 01:06:38,506 WE'LL SEE WHAT SHA SOME -- THAT 1660 01:06:38,506 --> 01:06:38,840 SHOWS. 1661 01:06:38,840 --> 01:06:41,242 TO YOUR SECOND POINT IN TERMS OF 1662 01:06:41,242 --> 01:06:42,410 MESSING WITH INTERACTIONS, YOU 1663 01:06:42,410 --> 01:06:44,012 KNOW, THERE'S A LOT OF 1664 01:06:44,012 --> 01:06:44,646 INTERACTIONS. BUT THE QUESTION 1665 01:06:44,646 --> 01:06:46,915 IS, LIKE, WHAT ARE THE KEY 1666 01:06:46,915 --> 01:06:48,516 INTERACTIONS? IS THERE LIKE ONE 1667 01:06:48,516 --> 01:06:50,151 OR TWO KEY INTERACTIONS THAT ONE 1668 01:06:50,151 --> 01:06:55,023 CAN TARGET? AND I THINK YOU 1669 01:06:55,023 --> 01:06:57,459 KNOW, PROBABLY THE DATA IS A 1670 01:06:57,459 --> 01:07:01,262 GOOD STARTING POINT. WE MAY 1671 01:07:01,262 --> 01:07:05,834 NEED TO EXPERIMENT. IS SGF THE 1672 01:07:05,834 --> 01:07:08,636 MOST IMPORTANT VULNERABILITY? I 1673 01:07:08,636 --> 01:07:09,370 WOULD IMAGINE THAT YOU HAVE 1674 01:07:09,370 --> 01:07:11,072 DRIVER INTERACTIONS AND MAYBE 1675 01:07:11,072 --> 01:07:14,509 JUST PASSING THEIR INTERACTIONS. 1676 01:07:14,509 --> 01:07:15,643 AND YOU KNOW, EITHER 1677 01:07:15,643 --> 01:07:16,578 EXPERIMENTALLY YOU PROBABLY HAVE 1678 01:07:16,578 --> 01:07:18,513 TO FIGURE OUT WHICH ONES ARE, 1679 01:07:18,513 --> 01:07:20,915 YOU KNOW, TARGETABLE, WHICH ONES 1680 01:07:20,915 --> 01:07:23,885 WE HAVE A DRUG AGAINST AND STUFF 1681 01:07:23,885 --> 01:07:24,519 LIKE THAT. 1682 01:07:24,519 --> 01:07:27,355 >> AUDIENCE: ARE YOU SUCCESSFUL 1683 01:07:27,355 --> 01:07:29,357 AT GETTING POSTTREATMENT 1684 01:07:29,357 --> 01:07:29,858 BIOPSIES. 1685 01:07:29,858 --> 01:07:32,227 >> ANISH: VERY DIFFICULT. 1686 01:07:32,227 --> 01:07:34,262 >> AUDIENCE: THAT WOULD HELP. 1687 01:07:34,262 --> 01:07:34,963 >> ANISH: THANK YOU. 1688 01:07:34,963 --> 01:07:37,632 >> THANKS ANISH, THAT WAS REALLY 1689 01:07:37,632 --> 01:07:40,201 FASCINATING AND YES, WE HAVE 1690 01:07:40,201 --> 01:07:41,870 SPOKEN ABOUT THE SIMILARITIES. 1691 01:07:41,870 --> 01:07:43,171 THERE IS A LOT. ALTHOUGH THERE 1692 01:07:43,171 --> 01:07:47,842 ARE SOME MAJOR DIFFERENCES. SO 1693 01:07:47,842 --> 01:07:54,516 I WAS REALLY INTRIGUED WITH THE 1694 01:07:54,516 --> 01:07:55,283 EXPERIMENTS AND THINGS LIKE 1695 01:07:55,283 --> 01:08:02,557 THAT. WE'VE RECENTLY FOUND THAT 1696 01:08:02,557 --> 01:08:04,526 INHIBITORS CAN ACTUALLY PREVENT 1697 01:08:04,526 --> 01:08:06,694 TRANSITION OF THE CELLS INTO 1698 01:08:06,694 --> 01:08:09,497 DIFFERENT PHENOTYPIC TYPES AND 1699 01:08:09,497 --> 01:08:12,000 THERE IS A COMPOUND THAT'S INN 1700 01:08:12,000 --> 01:08:13,801 CLINICAL TRIALS. HAVE YOU 1701 01:08:13,801 --> 01:08:15,336 EVALUATE THAT HAD IN YOUR MODELS 1702 01:08:15,336 --> 01:08:18,773 TO SEE IF YOU CAN -- 1703 01:08:18,773 --> 01:08:20,441 >> ANISH: THANK YOU. WE HAVE 1704 01:08:20,441 --> 01:08:22,710 NOT EVALUATED THAT COMPOUND BUT 1705 01:08:22,710 --> 01:08:25,813 I KNOW OTHER GROUPS HAVE USED 1706 01:08:25,813 --> 01:08:27,916 THIS INHIBITORS. SPECIFICALLY 1707 01:08:27,916 --> 01:08:31,686 IN THE CNC I THINK IT'S MARKED 1708 01:08:31,686 --> 01:08:34,189 BY EXPRESSION. AND THAT IS, YOU 1709 01:08:34,189 --> 01:08:36,558 KNOW, IS A SPECIFIC 1710 01:08:36,558 --> 01:08:38,459 VULNERABILITY SO I THINK 1711 01:08:38,459 --> 01:08:41,162 EPIGENETIC MODULATION THEY'RE 1712 01:08:41,162 --> 01:08:45,033 USING IS EH 2 OR THE OTHER COULD 1713 01:08:45,033 --> 01:08:46,267 POTENTIALLY REPRESENT AN AVENUE 1714 01:08:46,267 --> 01:08:48,636 TO GET AT THESE TUMORS. 1715 01:08:48,636 --> 01:08:50,104 >> AUDIENCE: AND DO YOU SEE WITH 1716 01:08:50,104 --> 01:08:53,441 PROGRESSIVE THERAPY? I MEAN, I 1717 01:08:53,441 --> 01:08:55,210 WONDER IF YOU -- IT SEEMED AS 1718 01:08:55,210 --> 01:08:57,312 THOUGH -- YOUR TRIALS WERE 1719 01:08:57,312 --> 01:08:59,781 TREATING RELAPSE PATIENTS. AND 1720 01:08:59,781 --> 01:09:03,117 SO MY QUESTION, HAVE THERE BEEN 1721 01:09:03,117 --> 01:09:05,220 CONSIDERATIONS OF TRYING THIS 1722 01:09:05,220 --> 01:09:06,588 UPFRONT SO THAT YOU DON'T GIVE 1723 01:09:06,588 --> 01:09:15,730 THE PATIENTS A BUNCH OF HIGH 1724 01:09:15,730 --> 01:09:17,165 DOSE CHEMOTHERAPY AND YOU SET 1725 01:09:17,165 --> 01:09:19,834 YOURSELF UP FOR OTHER THINGS 1726 01:09:19,834 --> 01:09:20,535 DOWN THE LINE. 1727 01:09:20,535 --> 01:09:22,637 >> ANISH: AS YOU KNOW IT'S 1728 01:09:22,637 --> 01:09:24,505 DIFFICULT TO SUBTRACT. ONCE 1729 01:09:24,505 --> 01:09:25,573 SOMETHING IS ESTABLISHED IT'S 1730 01:09:25,573 --> 01:09:26,941 DIFFICULT. REALLY RUNNING UP 1731 01:09:26,941 --> 01:09:29,811 AGAINST A MOUNTAIN TO TRY TO 1732 01:09:29,811 --> 01:09:30,812 SUBTRACT SO FOR EXAMPLE WITH 1733 01:09:30,812 --> 01:09:32,680 CHEMOTHERAPY COMBINATION OF 1734 01:09:32,680 --> 01:09:37,885 CARBOPLATIN IS THE STANDARD 1735 01:09:37,885 --> 01:09:40,221 REGIMEN BUT WE KNOW THAT 1736 01:09:40,221 --> 01:09:41,055 CARBOPLATIN IS SUBSTANTIALLY 1737 01:09:41,055 --> 01:09:44,325 LESS EFFECTIVE. IT REALLY 1738 01:09:44,325 --> 01:09:45,793 DOESN'T CONTRIBUTE THAT THE 1739 01:09:45,793 --> 01:09:47,528 SYNERGY OF THE COMBINATION BUT 1740 01:09:47,528 --> 01:09:49,831 IT DOES CONTRIBUTE TO A LOT OF 1741 01:09:49,831 --> 01:09:51,766 TOXICITY. IF I HAVE TO START A 1742 01:09:51,766 --> 01:09:54,535 CLINICAL TRIAL SAYING I'M GOING 1743 01:09:54,535 --> 01:09:57,438 TO REDUCE THE CARBOPLATIN THE 1744 01:09:57,438 --> 01:10:00,642 BAR IS SO HIGH EVEN THOUGH THESE 1745 01:10:00,642 --> 01:10:03,177 INITIAL REGIMENS ARE NOT -- 1746 01:10:03,177 --> 01:10:05,580 >> AUDIENCE: THIS I CAN TELL YOU 1747 01:10:05,580 --> 01:10:08,683 WAS THE -- WHEN I STARTED AT A 1748 01:10:08,683 --> 01:10:09,684 BIOLOGIST AT A CLINICAL 1749 01:10:09,684 --> 01:10:10,785 DEPARTMENT AND I KEPT SAYING WHY 1750 01:10:10,785 --> 01:10:12,654 CAN'T WE CHANGE IT UPFRONT AND 1751 01:10:12,654 --> 01:10:14,088 THEY CONTINUALLY SAID BECAUSE 1752 01:10:14,088 --> 01:10:16,024 THE TUMORS RESPOND HOWEVER IF 1753 01:10:16,024 --> 01:10:19,427 YOU CONTINUE TO HAVE 80% RELAPSE 1754 01:10:19,427 --> 01:10:22,163 OR, YOU KNOW, AS YOU SAY, THIS, 1755 01:10:22,163 --> 01:10:24,532 THEN IT'S JUST AS UNETHICAL TO 1756 01:10:24,532 --> 01:10:27,001 CONTINUE TO DO THE SAME THING. 1757 01:10:27,001 --> 01:10:33,908 AND I THINK WE REALLY OWE IT TO 1758 01:10:33,908 --> 01:10:35,743 TRY CHANGE THAT MINDSET IN SOME 1759 01:10:35,743 --> 01:10:38,146 WAY. I DO KNOW IN THE COMMUNITY 1760 01:10:38,146 --> 01:10:41,883 THEY HAVE TAKEN THINGS OUT TO 1761 01:10:41,883 --> 01:10:45,853 DECREASE THE LONG-TERM 1762 01:10:45,853 --> 01:10:49,824 TOXICITIES ASSOCIATED WITH OUR 1763 01:10:49,824 --> 01:10:52,760 SURVIVO 1764 01:10:52,760 --> 01:10:54,696 SURVIVORS. ITS INCUMBENT UPON 1765 01:10:54,696 --> 01:10:56,631 US BECAUSE IT WAS GOOD. BUT IF 1766 01:10:56,631 --> 01:10:57,732 THE RELAPSE RATES CONTINUE TO BE 1767 01:10:57,732 --> 01:11:01,069 THE SAME AND THE DEATH RATES THE 1768 01:11:01,069 --> 01:11:05,173 SAME, THEN IT'S NOT, YOU KNOW. 1769 01:11:05,173 --> 01:11:09,210 >> ANISH: TOTALLY AGREE. IT MAY 1770 01:11:09,210 --> 01:11:11,579 HAVE TO COME FROM A PATIENT 1771 01:11:11,579 --> 01:11:13,081 STANDPOINT. THERE ARE NOT MUCH 1772 01:11:13,081 --> 01:11:15,049 SURVIVORS AND NOT MUCH IN TERMS 1773 01:11:15,049 --> 01:11:15,717 OF PATIENT ADVOCACY AND STUFF 1774 01:11:15,717 --> 01:11:19,420 LIKE THAT. BUT, YEAH. 1775 01:11:19,420 --> 01:11:20,621 >> AUDIENCE: OKAY, THANKS, 1776 01:11:20,621 --> 01:11:22,290 ANYWAY, IT'S GREAT AND WE NEED 1777 01:11:22,290 --> 01:11:23,091 TO CONTINUE TALKING. THINK 1778 01:11:23,091 --> 01:11:26,828 THERE'S A LOT OF PEOPLE 1779 01:11:26,828 --> 01:11:29,230 INTERESTED IN NEUROENDOCRINE 1780 01:11:29,230 --> 01:11:30,832 TUMORS AND DIFFERENT TYPES OF 1781 01:11:30,832 --> 01:11:33,234 TUMORS LIKE PROSTATE. I THINK 1782 01:11:33,234 --> 01:11:34,135 THERE'S SOMETHING INTERESTING. 1783 01:11:34,135 --> 01:11:37,872 PEOPLE HAVE BEEN FOCUSED ON 1784 01:11:37,872 --> 01:11:39,440 EPITHELIAL BUT ENDOCRINE ARE THE 1785 01:11:39,440 --> 01:11:42,276 BAD GUYS OF ALL THE TUMORS. 1786 01:11:42,276 --> 01:11:43,378 THANKS A LOT. 1787 01:11:43,378 --> 01:11:45,847 >> ANISH: THANK YOU, EVERYONE. 1788 01:11:45,847 --> 01:11:56,290 >> AUDIENCE: (APPLAUSE).