1 00:00:06,191 --> 00:00:06,658 >> GOOD AFTERNOON. 2 00:00:06,658 --> 00:00:08,560 AND WELCOME TO TODAY'S CLINICAL 3 00:00:08,560 --> 00:00:09,895 CENTER GRAND ROUNDS. 4 00:00:09,895 --> 00:00:16,902 THE HOPKINS CLOUD CME ACTIVITY 5 00:00:16,902 --> 00:00:18,403 CODE IS 57888, PLEASE TEXT THE 6 00:00:18,403 --> 00:00:19,872 CODE TO RECEIVE CREDIT FOR THIS 7 00:00:19,872 --> 00:00:20,539 LECTURE. 8 00:00:20,539 --> 00:00:21,840 WE WOULD LIKE TO TO PROVIDE 9 00:00:21,840 --> 00:00:23,642 FEEDBACK ON THIS LECTURE BY 10 00:00:23,642 --> 00:00:25,644 SCANNING THE QR CODE ON THE CMI 11 00:00:25,644 --> 00:00:25,911 SLIDE. 12 00:00:25,911 --> 00:00:28,080 FOR THOSE APPLYING TO CME, YOU 13 00:00:28,080 --> 00:00:32,317 WILL RECEIVE A LINK VIA E-MAIL 14 00:00:32,317 --> 00:00:34,419 AND IT WILL BE USED TO PROVIDE 15 00:00:34,419 --> 00:00:35,587 US IMPORTANT FEEDBACK ABOUT THIS 16 00:00:35,587 --> 00:00:36,521 PRESENTATION AND ALSO FOR A 17 00:00:36,521 --> 00:00:39,258 CHANCE FOR YOU TO PROVIDE 18 00:00:39,258 --> 00:00:41,593 INFORMATION FOR FUTURE GRAND 19 00:00:41,593 --> 00:00:42,928 ROUNDS TOPICS. 20 00:00:42,928 --> 00:00:43,862 FOLLOWING THE LECTURE, QUESTIONS 21 00:00:43,862 --> 00:00:48,066 WILL BE TAKEN FOR THE SPEAKER BY 22 00:00:48,066 --> 00:00:51,503 MICROPHONES IN THE AISLE. 23 00:00:51,503 --> 00:00:53,872 ADDITIONALLY YOU CAN SUBMIT 24 00:00:53,872 --> 00:00:55,741 QUESTIONS BY CLICKING SEND LEAVE 25 00:00:55,741 --> 00:00:57,809 FEEDBACK AT THE BOTTOM OF THE 26 00:00:57,809 --> 00:00:58,076 VIDEOCAST. 27 00:00:58,076 --> 00:01:04,383 TODAY WE ARE HONORED TO HAVE 28 00:01:04,383 --> 00:01:06,118 DR. SHRINIVASAN, HE IS A SENIOR 29 00:01:06,118 --> 00:01:07,519 INVESTIGATOR AT THE CANCER 30 00:01:07,519 --> 00:01:09,121 RESEARCH, DEPUTY DIRECTOR OF THE 31 00:01:09,121 --> 00:01:11,323 CANCER RESEARCH, AND HEAD OF THE 32 00:01:11,323 --> 00:01:13,358 INSTITUTE'S MOLECULAR CANCER 33 00:01:13,358 --> 00:01:15,394 SECTION. 34 00:01:15,394 --> 00:01:18,697 YOU'RE O LOGIC ONCOLOGY BRANCH 35 00:01:18,697 --> 00:01:20,933 WHERE HE LEADS THE STUDY FOR 36 00:01:20,933 --> 00:01:21,566 KIDNEY CANCER. 37 00:01:21,566 --> 00:01:25,570 HE EARNED HIS MEDICAL DEGREE 38 00:01:25,570 --> 00:01:29,975 FROM BANG ALOR, AND COMPLETED 39 00:01:29,975 --> 00:01:33,011 HIS Ph.D. AT THE MD ANDERSON 40 00:01:33,011 --> 00:01:34,379 SCHOOL OF MEDICINE. 41 00:01:34,379 --> 00:01:35,547 FOLLOWING HIS RESIDENCY TRAINING 42 00:01:35,547 --> 00:01:36,682 AT THE UNIVERSITY OF NEW YORK AT 43 00:01:36,682 --> 00:01:38,083 STONY BROOK AND THE UNIVERSITY 44 00:01:38,083 --> 00:01:39,885 OF TEXAS HELT SCIENCE CENTER, HE 45 00:01:39,885 --> 00:01:43,522 JOINED THE NIH WHERE HE 46 00:01:43,522 --> 00:01:46,058 COMPLETED FELLOWSHIPS ON 47 00:01:46,058 --> 00:01:48,293 ONCOLOGY AT THE NATIONAL CANCER 48 00:01:48,293 --> 00:01:49,795 INSTITUTE HE IS BOARD CERTIFIED 49 00:01:49,795 --> 00:01:55,834 IN INTERNAL MEDICINE AND MEDICAL 50 00:01:55,834 --> 00:01:59,571 ONCOLOGY. 51 00:01:59,571 --> 00:02:02,341 DR. SHRINIVASAN, FOCUSED ON 52 00:02:02,341 --> 00:02:06,979 INDIVIDUALIZED MECHANISM BASED 53 00:02:06,979 --> 00:02:10,649 PROOF OF CONCEPT STUDIES. 54 00:02:10,649 --> 00:02:13,552 AT THE NCI, THE DOCTOR PIONEERED 55 00:02:13,552 --> 00:02:16,021 AN EVALUATION SYSTEM AND 56 00:02:16,021 --> 00:02:18,523 TREATMENT STRATEGIES IN PATIENTS 57 00:02:18,523 --> 00:02:21,660 WITH DISEASES AND CO-LED AN 58 00:02:21,660 --> 00:02:23,428 INTERNATIONAL STUDY FOR THE 59 00:02:23,428 --> 00:02:28,600 ALPHA HIP 2 INHIBITOR HAROLDING 60 00:02:28,600 --> 00:02:30,869 A PARADIME SHIFT IN THE HL. 61 00:02:30,869 --> 00:02:33,972 HE ALSO LED A NEW DEVELOPMENT OF 62 00:02:33,972 --> 00:02:36,408 WORK FOR PATIENTS WITH 63 00:02:36,408 --> 00:02:37,275 METASTATIC KIDNEY CANCER 64 00:02:37,275 --> 00:02:41,246 ESTABLISHED WITH -- EXCUSE ME -- 65 00:02:41,246 --> 00:02:46,585 MILE MATOSEIS AND RENAL CELL 66 00:02:46,585 --> 00:02:48,587 CANCER. 67 00:02:48,587 --> 00:02:49,321 DR. SHRINIVASAN IS TARGETING NEW 68 00:02:49,321 --> 00:02:52,657 AGENTS AS WELL AS NOVEL 69 00:02:52,657 --> 00:02:54,059 IMMUNOTHERAPY APPROACHES IN CELL 70 00:02:54,059 --> 00:02:56,561 AND KIDNEY CANCER, AS WELL AS 71 00:02:56,561 --> 00:03:00,899 OTHER FORMS OF SPORADIC AND 72 00:03:00,899 --> 00:03:02,167 KIDNEY HEREDITARY SYNDROMES. 73 00:03:02,167 --> 00:03:03,335 AN INTERNATIONAL SPEAKER, THE 74 00:03:03,335 --> 00:03:05,904 DOCTOR IS A AUTHOR AND CO AUTHOR 75 00:03:05,904 --> 00:03:07,806 OF 100 PUBLICATIONS AND MORE 76 00:03:07,806 --> 00:03:09,875 THAN 1 DOZEN BOOK CHAPTERS. 77 00:03:09,875 --> 00:03:12,444 HIS WORK HAS BEEN RECOGNIZED AT 78 00:03:12,444 --> 00:03:14,379 THE NCI DIRECTOR AWARD FOR 79 00:03:14,379 --> 00:03:16,014 CLINICAL AND TRANSLATIONAL 80 00:03:16,014 --> 00:03:17,949 SCIENCE LEADING TO PRACTICE 81 00:03:17,949 --> 00:03:19,151 CHANGING TREATMENTS FOR PATIENTS 82 00:03:19,151 --> 00:03:19,951 WITH KIDNEY CANCER. 83 00:03:19,951 --> 00:03:23,488 HE'S ALSO A RECIPIENT OF THAL AN 84 00:03:23,488 --> 00:03:26,158 S. RABSON AWARD WHICH RECOGNIZES 85 00:03:26,158 --> 00:03:27,292 OUTSTANDING CLINICAL 86 00:03:27,292 --> 00:03:28,593 INVESTIGATORS WHO DEMONSTRATED 87 00:03:28,593 --> 00:03:29,294 EXCEPTIONAL COMMITMENT TO 88 00:03:29,294 --> 00:03:30,429 PATIENTS AND THEIR FAMILIES. 89 00:03:30,429 --> 00:03:32,431 THE TITLE OF HIS PRESENTATION 90 00:03:32,431 --> 00:03:33,832 TODAY IS MECHANISM BASED 91 00:03:33,832 --> 00:03:35,434 TREATMENT STRATEGIES IN KIDNEY 92 00:03:35,434 --> 00:03:35,667 CANCER. 93 00:03:35,667 --> 00:03:37,869 NOW PLEASE JOIN ME IN WELCOMING 94 00:03:37,869 --> 00:03:48,280 OUR GRAND ROUNDS SPEAKER 95 00:03:49,347 --> 00:03:49,648 DR. SHRINIVASAN. 96 00:03:49,648 --> 00:03:50,615 [ APPLAUSE ] 97 00:03:50,615 --> 00:03:53,251 >> THANK YOU DOCTOR FOR THAT 98 00:03:53,251 --> 00:03:53,885 VERY KIND INTRODUCTION. 99 00:03:53,885 --> 00:04:00,225 I AM GOING TO SAY HLRCC, INSTEAD 100 00:04:00,225 --> 00:04:02,094 OF THE FULL NAME SO THAT ALL OF 101 00:04:02,094 --> 00:04:03,562 YOU CAN FOLLOW IT. 102 00:04:03,562 --> 00:04:04,963 IT'S MUCH EASIER THAN SAYING THE 103 00:04:04,963 --> 00:04:05,464 LONG WORDS. 104 00:04:05,464 --> 00:04:07,866 IT'S A GREAT PLEASURE FOR ME TO 105 00:04:07,866 --> 00:04:09,267 BE HERE TODAY TO TELL YOU A 106 00:04:09,267 --> 00:04:11,369 LITTLE BIT ABOUT THE WORK WE'VE 107 00:04:11,369 --> 00:04:16,808 BEEN DOING AT THE NCI LEADING TO 108 00:04:16,808 --> 00:04:19,344 SOME DISCOVERIES IN KIDNEY 109 00:04:19,344 --> 00:04:21,713 CANCER AND HOW HE MANAGE KIDNEY 110 00:04:21,713 --> 00:04:22,747 CANCER. 111 00:04:22,747 --> 00:04:24,182 OVER THE NEXT 45-50 MINUTES OR 112 00:04:24,182 --> 00:04:26,251 SO, I WILL LEAD YOU THROUGH SOME 113 00:04:26,251 --> 00:04:28,453 ASPECTS OF WHAT WE'VE DONE AND 114 00:04:28,453 --> 00:04:30,021 HOPEFULLY WE WILL HAVE QUESTIONS 115 00:04:30,021 --> 00:04:31,490 FOR DISCUSSIONS AFTER THAT, 116 00:04:31,490 --> 00:04:32,791 SOMETIMES FOR QUESTIONS FOR 117 00:04:32,791 --> 00:04:37,028 DISCUSSION AFTER THAT. 118 00:04:37,028 --> 00:04:40,265 SO IF YOU'RE LOOKING AT KIDNEY 119 00:04:40,265 --> 00:04:42,901 CANCER IN THE 1980S, WHAT WE 120 00:04:42,901 --> 00:04:44,402 KNEW ABOUT KIDNEY CANCER WAS 121 00:04:44,402 --> 00:04:46,371 VERY LIMITED AND FROM A 122 00:04:46,371 --> 00:04:46,972 CLASSIFICATION PERSPECTIVE, 123 00:04:46,972 --> 00:04:48,707 CLASSIFICATION IS VERY, VERY 124 00:04:48,707 --> 00:04:49,407 SIMPLE. 125 00:04:49,407 --> 00:04:53,411 YOU HAD ADENOMAS OR YOU HAD 126 00:04:53,411 --> 00:04:54,946 RENAL SUBCARCINOMAS, AND OTHER 127 00:04:54,946 --> 00:04:56,581 CATEGORY WHICH RECOGNIZED THERE 128 00:04:56,581 --> 00:04:57,816 WERE KIDNEY CANCERS THAT LOOK 129 00:04:57,816 --> 00:05:00,051 DIFFERENT FROM THE MORE COMMON 130 00:05:00,051 --> 00:05:00,819 CONVENTIONAL KIDNEY CANCERS BUT 131 00:05:00,819 --> 00:05:05,557 NOT A LOT MORE WAS KNOWN ABOUT 132 00:05:05,557 --> 00:05:05,957 IT. 133 00:05:05,957 --> 00:05:07,659 OVER THE YEARS, OVER THE NEXT 134 00:05:07,659 --> 00:05:09,361 DECADE OR DECADE AND A HALF, 135 00:05:09,361 --> 00:05:12,864 PATHOLOGISTS MADE A LOT OF 136 00:05:12,864 --> 00:05:14,432 STRIDES IN RECOGNIZING THAT 137 00:05:14,432 --> 00:05:16,968 THERE WERE INDEED MANY DIFFERENT 138 00:05:16,968 --> 00:05:20,038 HISTOLOGIC TYPES OF KIDNEY 139 00:05:20,038 --> 00:05:20,272 CANCER. 140 00:05:20,272 --> 00:05:23,441 THEY DEFINE CLEAR CELL KIDNEY 141 00:05:23,441 --> 00:05:25,510 CANCER WHICH IS WHAT PEOPLE 142 00:05:25,510 --> 00:05:27,245 TYPICALLY REFER TO AS KIDNEY 143 00:05:27,245 --> 00:05:28,880 CANCER, THE MOST COMMON FORM 144 00:05:28,880 --> 00:05:31,750 ACCOUNTING FOR 75% OF ALL KIDNEY 145 00:05:31,750 --> 00:05:32,117 TUMORS. 146 00:05:32,117 --> 00:05:34,719 AND THEN THIS APPLIED 147 00:05:34,719 --> 00:05:35,387 ILLEGALSARY KIDNEY CANCER WHICH 148 00:05:35,387 --> 00:05:38,123 IS THE WAY IT WAS CLASSIFIED 149 00:05:38,123 --> 00:05:40,859 PREVIOUSLY THE MOST COMMON 150 00:05:40,859 --> 00:05:42,360 KIDNEY MALIGNANCY AND 151 00:05:42,360 --> 00:05:43,929 PATHOLOGISTS WERE FURTHER ABLE 152 00:05:43,929 --> 00:05:45,764 TO DISTINGUISH BASED ON 153 00:05:45,764 --> 00:05:46,398 HISTOLOGIC FEATURES, TYPES 1 AND 154 00:05:46,398 --> 00:05:47,866 WHAT THE REST OF THE WORLD 155 00:05:47,866 --> 00:05:51,069 CALLED TYPE 2 BUT WE CALL 156 00:05:51,069 --> 00:05:53,605 NONTYPE 1 BECAUSE WE HAVE AN 157 00:05:53,605 --> 00:05:56,708 OUTSTANDING KIDNEY CANCER 158 00:05:56,708 --> 00:05:58,243 PATHOLOGIST, DR. MARINO, WHO 159 00:05:58,243 --> 00:05:59,978 POINTED OUT VERY ASTUTELY AND 160 00:05:59,978 --> 00:06:04,316 NOW WE KNOW IT'S ABSOLUTELY 161 00:06:04,316 --> 00:06:06,651 TRUE, THAT WHILE TYPE 1 APPEARS 162 00:06:06,651 --> 00:06:08,820 TO BE HOMOGEANOUS IN ITS 163 00:06:08,820 --> 00:06:09,955 APPEARANCE AND CLINICAL 164 00:06:09,955 --> 00:06:11,423 CHARACTERISTICS, TYPE 2 IS 165 00:06:11,423 --> 00:06:14,159 REALLY A VERY HETEROGENEOUS 166 00:06:14,159 --> 00:06:16,294 GROUP OF MALACY, SO WE USE THE 167 00:06:16,294 --> 00:06:17,862 TERM NONTYPE 1 AND I WILL TELL 168 00:06:17,862 --> 00:06:19,998 YOU IN A MINUTE OR 2 HOW THAT 169 00:06:19,998 --> 00:06:20,832 EVOLVED WITH TIME AS WELL. 170 00:06:20,832 --> 00:06:23,068 AND THEN THERE ARE OTHER FORMS 171 00:06:23,068 --> 00:06:26,471 OF KIDNEY CANCER, CHROMA PHOBE, 172 00:06:26,471 --> 00:06:27,639 AND OTHERS MEDULARY AND OTHERS 173 00:06:27,639 --> 00:06:29,474 THAT MAKE UP THE REST. 174 00:06:29,474 --> 00:06:32,510 BUT IT WAS WITH THE ADVENT OF 175 00:06:32,510 --> 00:06:33,678 MORE EXTENSIVE GENETIC 176 00:06:33,678 --> 00:06:34,512 EVALUATION AND GENETIC TESTING 177 00:06:34,512 --> 00:06:40,885 THAT WE REALLY STARTED TO 178 00:06:40,885 --> 00:06:41,987 UNDERSTAND HOW COMPLEX KIDNEY 179 00:06:41,987 --> 00:06:43,688 CANCER WAS AND HOW IT WAS WE 180 00:06:43,688 --> 00:06:47,459 USED A TERM TO DESCRIBE A 181 00:06:47,459 --> 00:06:48,493 REALLY, REALLY DESPERATE 182 00:06:48,493 --> 00:06:49,694 ENTITIES BECAUSE THEY ALL ARISE 183 00:06:49,694 --> 00:06:50,395 IN THE KIDNEY. 184 00:06:50,395 --> 00:06:52,764 HERE IS SHOWING THE 185 00:06:52,764 --> 00:06:55,500 REPRESENTATION OF SOME FORM OF 186 00:06:55,500 --> 00:06:56,568 THE CONDITIONS THAT WE RECOGNIZE 187 00:06:56,568 --> 00:06:59,137 AND AS WELL AS THE FORMATIONS 188 00:06:59,137 --> 00:07:00,138 THAT DRIVE THESE ENTITIES. 189 00:07:00,138 --> 00:07:01,339 SO THESE DISCOVERIES NOW HAVE 190 00:07:01,339 --> 00:07:04,309 REALLY LED TO A COMPLETE 191 00:07:04,309 --> 00:07:06,911 RECLASSIFICATION OF KIDNEY 192 00:07:06,911 --> 00:07:09,681 CANCER IN 2022, THE W. H. O. 193 00:07:09,681 --> 00:07:10,815 RECOGNIZES, YOU KNOW A VARIETY 194 00:07:10,815 --> 00:07:12,350 OF DIFFERENT FORMS OF KIDNEY 195 00:07:12,350 --> 00:07:14,786 CANCER, SOME OF THEM STILL 196 00:07:14,786 --> 00:07:15,387 CLASSIFIED HISTOLOGICALLY BUT 197 00:07:15,387 --> 00:07:18,723 THERE IS A GREATER TENDENCY NOW 198 00:07:18,723 --> 00:07:21,059 TO RECOGNIZE GENETICALLY AND 199 00:07:21,059 --> 00:07:21,860 MOLECULARLY KIDNEY FORMS OF 200 00:07:21,860 --> 00:07:24,062 CANCER AND MANY OF THE KIDNEY 201 00:07:24,062 --> 00:07:27,932 CANCER ENTITIES, YOU SEE IN THIS 202 00:07:27,932 --> 00:07:30,201 CLASSIFICATION ACTUALLY ARE 203 00:07:30,201 --> 00:07:33,705 BASED ON MOLECULAR 204 00:07:33,705 --> 00:07:34,105 CHARACTERIZATION. 205 00:07:34,105 --> 00:07:38,610 SO WE KNOW NOW, IT'S BEEN WELL 206 00:07:38,610 --> 00:07:39,411 ESTABLISHED THAT KIDNEY CANCER 207 00:07:39,411 --> 00:07:43,381 IS NOT A SINGLE DEC BUT HOW CAN 208 00:07:43,381 --> 00:07:45,450 WE DO WITH DIAGNOSING KIDNEY 209 00:07:45,450 --> 00:07:47,452 CANCER, AND YOU DON'T TREAT ALL 210 00:07:47,452 --> 00:07:49,054 THE LEUKEMIAS, THE WAY YOU HELP 211 00:07:49,054 --> 00:07:50,922 THE 1 LEUKEMIA RIGHT, SO YOU 212 00:07:50,922 --> 00:07:52,223 WOULD ASSUME THAT WOULD 213 00:07:52,223 --> 00:07:54,659 TRANSLATE INTO KIDNEY CANCER AS 214 00:07:54,659 --> 00:07:54,993 WELL. 215 00:07:54,993 --> 00:07:56,828 UNFORTUNATELY, IT TAKES TIME FOR 216 00:07:56,828 --> 00:07:59,831 US TO TAKE WHAT WE KNOW ABOUT 217 00:07:59,831 --> 00:08:01,333 THESE TUMORS AND REALLY MAKE 218 00:08:01,333 --> 00:08:02,167 MEANINGFUL IMPACTS AND 219 00:08:02,167 --> 00:08:02,467 TREATMENTS. 220 00:08:02,467 --> 00:08:05,236 SO FOR A LONG TIME AND THAT 221 00:08:05,236 --> 00:08:07,772 TREND IS SLOWLY CHANGING NOW, 222 00:08:07,772 --> 00:08:10,842 ALL APPROACHES THAT WE HAD WERE 223 00:08:10,842 --> 00:08:12,010 REALLY DIRECTED TOWARDS THE MOST 224 00:08:12,010 --> 00:08:15,513 COMMON FORM OF KIDNEY CANCER, 225 00:08:15,513 --> 00:08:17,315 AND BECAUSE WE DIDN'T UNDERSTAND 226 00:08:17,315 --> 00:08:20,085 OTHER FORMS AS WELL AS WE DID 227 00:08:20,085 --> 00:08:22,721 CLEAR CELL KIDNEY CANCER, THE 228 00:08:22,721 --> 00:08:23,521 TREATMENTS WE DEVELOPED FOR 229 00:08:23,521 --> 00:08:24,689 CLEAR CELL WOULD BE TRY INDEED 230 00:08:24,689 --> 00:08:27,359 OTHER FORMS OF KIDNEY CANCER, 231 00:08:27,359 --> 00:08:31,062 OFTEN WITH VERY, VERY MODEST 232 00:08:31,062 --> 00:08:36,067 OUTCOMES. 233 00:08:36,067 --> 00:08:40,238 AN EXAMPLE IS THE VEGFRTKLs, 234 00:08:40,238 --> 00:08:41,973 WHICH WAS IN 2005-2006. 235 00:08:41,973 --> 00:08:43,842 AND A VARIETY OF DIFFERENT 1S, 236 00:08:43,842 --> 00:08:46,111 ALL OF WHICH WERE QUITE ACTIVE 237 00:08:46,111 --> 00:08:48,413 IN KIDNEY CLEAR CELL CANCER AND 238 00:08:48,413 --> 00:08:49,581 WERE THE MAIN STAY OF TREATMENT 239 00:08:49,581 --> 00:08:51,249 FOR THAT TYPE OF KIDNEY CANCER. 240 00:08:51,249 --> 00:08:52,851 BUT WHEN YOU LOOK AT THOSE IN 241 00:08:52,851 --> 00:08:55,086 THE ACTIVITY AND THE PATHWAY OF 242 00:08:55,086 --> 00:08:58,523 KIDNEY CANCER, THE RESPONSES 243 00:08:58,523 --> 00:08:59,524 WERE FAIRLY DISAPPOINTING. 244 00:08:59,524 --> 00:09:00,291 SO THIS REALLY HIGHLIGHTS THE 245 00:09:00,291 --> 00:09:02,761 FACT THAT YOU KNOW HAVING 246 00:09:02,761 --> 00:09:04,529 RECOGNIZED THE HETEROGENEITY OF 247 00:09:04,529 --> 00:09:07,232 KIDNEY CANCER, WE SHOULD BE 248 00:09:07,232 --> 00:09:11,136 TRYING TO DEVISE TREATMENTS THAT 249 00:09:11,136 --> 00:09:12,337 CLEARLY ACCOUNT FOR THESE 250 00:09:12,337 --> 00:09:13,171 DIFFERENCES AND THAT'S REALLY A 251 00:09:13,171 --> 00:09:17,108 LOT OF WHAT WE DO HERE AT THE 252 00:09:17,108 --> 00:09:17,809 NCI. 253 00:09:17,809 --> 00:09:19,577 WE HAVE USED INHERITED FORMS OF 254 00:09:19,577 --> 00:09:21,780 KIDNEY CANCER AS A MODEL FOR 255 00:09:21,780 --> 00:09:24,582 STUDYING NOT ONLY GENETICS AND 256 00:09:24,582 --> 00:09:25,984 THE MOLECULAR CHANGES DRIVING 257 00:09:25,984 --> 00:09:28,620 THESE TUMORS, BUT ALSO AS A 258 00:09:28,620 --> 00:09:29,888 MODEL FOR EVALUATING TREATMENTS 259 00:09:29,888 --> 00:09:32,223 THAT WE OFTEN THINK CAN THEN BE 260 00:09:32,223 --> 00:09:34,092 APPLIED TO SPORADIC FORMS OF 261 00:09:34,092 --> 00:09:38,196 KIDNEY CANCER THAT RESEMBLE SOME 262 00:09:38,196 --> 00:09:39,297 OF THESE FAILURES. 263 00:09:39,297 --> 00:09:41,499 WHY DO WE USE GENETIC FORMS OF 264 00:09:41,499 --> 00:09:44,035 KIDNEY CANCER TO STUDY 265 00:09:44,035 --> 00:09:44,369 TREATMENTS? 266 00:09:44,369 --> 00:09:46,004 THEY'RE GENETICALLY WELL 267 00:09:46,004 --> 00:09:48,206 DEFINED, MUCH MORE HOMOGENIUS 268 00:09:48,206 --> 00:09:48,940 THAN SPORADIC POPULATIONS SO 269 00:09:48,940 --> 00:09:51,075 IT'S VERY EASY TO TEST A 270 00:09:51,075 --> 00:09:51,943 SPECIFIC HYPOTHESIS AT A 271 00:09:51,943 --> 00:09:57,549 SPECIFIC TARGET IN THESE 272 00:09:57,549 --> 00:09:57,849 POPULATIONS. 273 00:09:57,849 --> 00:09:58,950 AT LEAST SCIENCE HAS MADE IT 274 00:09:58,950 --> 00:09:59,884 VERY EASY. 275 00:09:59,884 --> 00:10:01,820 GENETIC DRIVERS AND MOLECULAR 276 00:10:01,820 --> 00:10:02,887 ALTERATIONS HAVE BEEN WELL 277 00:10:02,887 --> 00:10:05,323 CHARACTERIZED IN MANY OF THESE 278 00:10:05,323 --> 00:10:07,292 INHERITED FORMS OF KIDNEY CANCER 279 00:10:07,292 --> 00:10:11,529 AND AS I POINTED OUT, THEY CAN 280 00:10:11,529 --> 00:10:16,534 REALLY SHED LIGHT ON WHAT WE CAN 281 00:10:16,534 --> 00:10:20,205 DO THEN WITH SPORADIC FORMS AND 282 00:10:20,205 --> 00:10:21,840 COUNTERPARTS OF THESE FORMS OF 283 00:10:21,840 --> 00:10:22,340 KIDNEY CANCERS. 284 00:10:22,340 --> 00:10:24,242 A VARIETY OF INHERITED FORMS OF 285 00:10:24,242 --> 00:10:27,345 KIDNEY CANCER HAVE BEEN DRIEBED 286 00:10:27,345 --> 00:10:30,548 NOW, THIS IS LITERALLY BUT NOT 287 00:10:30,548 --> 00:10:33,718 FULLY ALL ENCOMPASSING LIST OF 288 00:10:33,718 --> 00:10:35,186 INHERITED FORMS OF DISEASE. 289 00:10:35,186 --> 00:10:39,657 WHAT WE DO HERE AT THE NCI IS 290 00:10:39,657 --> 00:10:41,159 TAKE A SYSTEMATIC APPROACH TO 291 00:10:41,159 --> 00:10:44,195 CHARACTERIZATION OF THESE 292 00:10:44,195 --> 00:10:45,230 TUMORS, AND USE THE INFORMATION 293 00:10:45,230 --> 00:10:48,266 WE GET FROM THERE, TO REALLY 294 00:10:48,266 --> 00:10:49,767 DEVELOP NOVEL TREATMENT 295 00:10:49,767 --> 00:10:50,068 APPROACHES. 296 00:10:50,068 --> 00:10:55,273 SO WE START OFF BY LOOKING AT 297 00:10:55,273 --> 00:10:57,075 DISEASE CHARACTERIZATION AND 298 00:10:57,075 --> 00:10:58,476 GENE DISCOVERY, FOLLOWED BY 299 00:10:58,476 --> 00:11:00,111 MECHANISTIC STUDIES AND THEN TRY 300 00:11:00,111 --> 00:11:02,146 TO TAKE THAT INFORMATION INTO 301 00:11:02,146 --> 00:11:03,448 THE CLINIC. 302 00:11:03,448 --> 00:11:05,283 OBVIOUSLY, YOU KNOW THIS IS NOT 303 00:11:05,283 --> 00:11:07,218 A LINEAR PROCESS, THERE'S A LOT 304 00:11:07,218 --> 00:11:09,621 OF CROSS TALK BETWEEN THE 305 00:11:09,621 --> 00:11:10,989 VARIOUS GROUPS THAT ARE EXPERT 306 00:11:10,989 --> 00:11:14,025 IN EACH OF THESE APPROACHES. 307 00:11:14,025 --> 00:11:15,360 AND TODAY I'M GOING TO TRY AND 308 00:11:15,360 --> 00:11:17,328 SHOW YOU THROUGH A COUPLE OF 309 00:11:17,328 --> 00:11:19,697 EXAMPLES HOW THIS PROCESS WORKS 310 00:11:19,697 --> 00:11:22,667 AND HOW IT HAS LED TO ADVANCES 311 00:11:22,667 --> 00:11:23,868 IN HOW WE MANAGE CERTAIN GROUPS 312 00:11:23,868 --> 00:11:26,938 OF PEOPLE WITH KIDNEY CANCER. 313 00:11:26,938 --> 00:11:28,540 WE WILL START OFF WITH CLEAR 314 00:11:28,540 --> 00:11:30,642 CELL AS I SAID, A LOT IS KNOWN 315 00:11:30,642 --> 00:11:33,044 ABOUT THIS BUT I THINK IT'S VERY 316 00:11:33,044 --> 00:11:34,779 INSTRUCTIVE TO GO OVER HOW 317 00:11:34,779 --> 00:11:37,649 THISSENTITY CAME TO BE 318 00:11:37,649 --> 00:11:42,820 RECOGNIZED, HOW THE GENETIC 319 00:11:42,820 --> 00:11:43,655 UNDERPINNINGS OF THIS SUBTYPE 320 00:11:43,655 --> 00:11:47,125 CAME TO BE UNDERSTOOD AND HOW 321 00:11:47,125 --> 00:11:48,560 UNDERSTANDING THE BIOLOGY REALLY 322 00:11:48,560 --> 00:11:54,198 LED TO SPECIFIC POSITION 323 00:11:54,198 --> 00:11:55,300 TREATMENT APPROACHES. 324 00:11:55,300 --> 00:11:57,936 STORY REALLY IN TRYING TO 325 00:11:57,936 --> 00:11:59,003 UNDERSTAND CLEAR CELL KIDNEY 326 00:11:59,003 --> 00:12:00,738 CANCER AT A DEEPER LEVEL 327 00:12:00,738 --> 00:12:06,611 STARTING WITH AN INHIRITTED FORM 328 00:12:06,611 --> 00:12:08,146 OF INHERITED KIDNEY DISEASE, 329 00:12:08,146 --> 00:12:10,381 THIS IS A PREDISPOSITION FOR 330 00:12:10,381 --> 00:12:12,016 DEVELOPING TUMORS IN A VARIETY 331 00:12:12,016 --> 00:12:12,750 OF DIFFERENT ORGANS. 332 00:12:12,750 --> 00:12:14,586 IT'S RARE, THE CONDITION, 333 00:12:14,586 --> 00:12:17,188 ESTIMATED TO OCCUR IN 334 00:12:17,188 --> 00:12:19,691 APPROXIMATELY 1 IN 35-40,000 335 00:12:19,691 --> 00:12:21,492 LIVE BIRTHS IN THIS COUNTRY. 336 00:12:21,492 --> 00:12:23,461 PEN TRANCE IS VERY HIGH, ALMOST 337 00:12:23,461 --> 00:12:26,531 ALL PATIENTS BY THE AGE OF 60 338 00:12:26,531 --> 00:12:30,535 WILL LIKELY HAVE 1 OR MORE 339 00:12:30,535 --> 00:12:31,102 MANIFESTATIONS OF VHL. 340 00:12:31,102 --> 00:12:33,371 SO WHAT ARE THE MANIFESTATIONS 341 00:12:33,371 --> 00:12:34,806 OF VHL? 342 00:12:34,806 --> 00:12:36,574 OBVIOUSLY KIDNEY CANCER, CLEAR 343 00:12:36,574 --> 00:12:40,111 CELL KIDNEY CANCER, A BILATERAL 344 00:12:40,111 --> 00:12:41,045 MULTIFOCAL FASHION, THESE 345 00:12:41,045 --> 00:12:42,714 PATIENTS ALSO HAVE BILATERAL 346 00:12:42,714 --> 00:12:45,583 RENAL CYSTS, TUMORS IN THE 347 00:12:45,583 --> 00:12:48,720 PANCREAS, TUMORS OF A VERY 348 00:12:48,720 --> 00:12:51,789 SPECIFIC SUBTYPE, CALLED NEURAL 349 00:12:51,789 --> 00:12:54,726 PANCREATIC TUMORS, THEY DEVELOP 350 00:12:54,726 --> 00:12:57,295 SIGNIFY TELOMERAS AND HEME ANGIO 351 00:12:57,295 --> 00:12:58,429 BLASTOMAS, IN THE CENTRAL 352 00:12:58,429 --> 00:13:00,732 NERVOUS SYSTEM AS WELL AS OTHER 353 00:13:00,732 --> 00:13:03,835 TUMORS IN THE BROAD LIGAMENT 354 00:13:03,835 --> 00:13:06,971 MELANOMAS AS WELL AS TUMORS IN 355 00:13:06,971 --> 00:13:07,305 THE INNER EAR. 356 00:13:07,305 --> 00:13:09,440 A LITTLE BIT OF HISTORY. 357 00:13:09,440 --> 00:13:11,342 I'M A FAN OF HISTORY, SO I WILL 358 00:13:11,342 --> 00:13:12,977 SPEND A COUPLE OF MINUTES 359 00:13:12,977 --> 00:13:16,648 TALKING ABOUT A HISTORY OF VHL, 360 00:13:16,648 --> 00:13:17,682 PROBABLY THE EARLIEST 361 00:13:17,682 --> 00:13:24,055 DESCRIPTION WAS IN THE LATE 362 00:13:24,055 --> 00:13:24,789 1890S, DR. COLLINS TALKED ABOUT 363 00:13:24,789 --> 00:13:27,091 A PAIR OF SIBLING WHO IS HAD 364 00:13:27,091 --> 00:13:28,159 ABNORMAL VASCULAR GROWTHS IN 365 00:13:28,159 --> 00:13:30,228 THEIR EYES, OF COURSE AT THAT 366 00:13:30,228 --> 00:13:32,563 POINT, THERE WASN'T A LINK TO 367 00:13:32,563 --> 00:13:34,899 OTHER MANIFESTATIONS, NOR WAS 368 00:13:34,899 --> 00:13:35,767 THISSENTITY CLEARLY CHARKTIZED, 369 00:13:35,767 --> 00:13:37,201 AND AND WAS AN OBSERVATION AND 370 00:13:37,201 --> 00:13:38,302 AN IMPORTANT 1 BUT AN 371 00:13:38,302 --> 00:13:44,242 OBSERVATION AT THAT TIME. 372 00:13:44,242 --> 00:13:49,180 IN THE 1920S, HIPPEL RECREATED 373 00:13:49,180 --> 00:13:51,949 THIS FINDINGS IN PATIENTS HE WAS 374 00:13:51,949 --> 00:13:56,688 SEEING WHO HAD OFTEN BILATERAL 375 00:13:56,688 --> 00:13:59,557 HEME ANGIO BLASTOMAS THAT RAN IN 376 00:13:59,557 --> 00:14:00,024 FAMILIES. 377 00:14:00,024 --> 00:14:00,725 THIS OBSERVATION WAS 378 00:14:00,725 --> 00:14:06,297 COMPLEMENTED A FEW YEARS LATER 379 00:14:06,297 --> 00:14:09,667 BY ALBERT LINDAU WHO DESCRIBED 380 00:14:09,667 --> 00:14:10,301 CNS BLASTOMA TUMORS. 381 00:14:10,301 --> 00:14:13,304 OVER THE NEXT FEW YEARS, THE 382 00:14:13,304 --> 00:14:15,206 ENTITY VHL CAME TO BE RECOGNIZED 383 00:14:15,206 --> 00:14:21,312 AND IT WAS NAMED AFTER HIPPEL 384 00:14:21,312 --> 00:14:21,646 AND LINDAU. 385 00:14:21,646 --> 00:14:24,649 WE DON'T SEE A LOT IN THE 386 00:14:24,649 --> 00:14:26,384 LITERATURE ABOUT VHL FOR THE 387 00:14:26,384 --> 00:14:27,051 NEXT SEVERAL DECADES. 388 00:14:27,051 --> 00:14:32,356 WHAT WE DO KNOW AND AS A GEANIAL 389 00:14:32,356 --> 00:14:34,058 ONCOLOGIST, MY FOCUS IS ON 390 00:14:34,058 --> 00:14:34,459 KIDNEY CANCER. 391 00:14:34,459 --> 00:14:35,860 SO WHAT WE KNOW IS FOR THE 392 00:14:35,860 --> 00:14:37,595 LONGEST PERIOD THESE PATIENTS 393 00:14:37,595 --> 00:14:41,165 WERE MANAGED BECAUSE THEY HAVE 394 00:14:41,165 --> 00:14:41,966 BILATERAL MULTIFOCAL TUMORS, 395 00:14:41,966 --> 00:14:44,368 THEY COULD WITHOUT LIFE, IF YOU 396 00:14:44,368 --> 00:14:47,705 TOOK TUMORS BACK, WITH NEW 397 00:14:47,705 --> 00:14:49,774 TUMORS, WOULD FORM, SO TO COMBAT 398 00:14:49,774 --> 00:14:52,076 THAT ISSUE, WHAT UROLOGISTS WERE 399 00:14:52,076 --> 00:14:54,278 DOING UNTIL 1970S AND EARLY 80S 400 00:14:54,278 --> 00:14:55,813 WAS DOING STAGED BILATERAL NEFF 401 00:14:55,813 --> 00:14:56,347 RECTIFIED ME. 402 00:14:56,347 --> 00:14:58,149 SO THEY WOULD TAKE A KIDNEY OUT. 403 00:14:58,149 --> 00:15:00,418 GO BACK AND TAKE ANOTHER KIDNEY 404 00:15:00,418 --> 00:15:03,287 OUT AND YOU KNOW LET THE PATIENT 405 00:15:03,287 --> 00:15:04,856 SURVIVAL DIALYSIS THE REST OF 406 00:15:04,856 --> 00:15:05,356 THEIR LIVES. 407 00:15:05,356 --> 00:15:07,125 WHY WERE THEY DOING THIS WHY 408 00:15:07,125 --> 00:15:09,393 WOULD THEY NEED TO REMOVE THIS? 409 00:15:09,393 --> 00:15:11,262 BECAUSE THEY HAD MET STATIC 410 00:15:11,262 --> 00:15:11,529 POTENTIAL. 411 00:15:11,529 --> 00:15:14,465 IF YOU DID NOTHING, THEY WOULD 412 00:15:14,465 --> 00:15:15,433 GROW, BECOME METASTATIC AND WE 413 00:15:15,433 --> 00:15:20,905 HAD NO CURE FOR THE PATIENTS. 414 00:15:20,905 --> 00:15:23,341 SO THIS WAS MEANT TO SAVE THE 415 00:15:23,341 --> 00:15:24,375 PATIENTS BUT UNFORTUNATELY IT 416 00:15:24,375 --> 00:15:26,244 LED TO REMOVAL OF BOTH KIDNEYS. 417 00:15:26,244 --> 00:15:28,012 A PROGRAM TO STUDY THE VHL WAS 418 00:15:28,012 --> 00:15:33,284 TEABED IN THE EARLY 1980S OF THE 419 00:15:33,284 --> 00:15:35,086 NCI LED DOCTOR AND HIS 420 00:15:35,086 --> 00:15:35,386 COLLEAGUES. 421 00:15:35,386 --> 00:15:36,454 ONE OF THE THINGS THAT THE 422 00:15:36,454 --> 00:15:37,955 PROGRAM ACHIEVED AND THERE ARE 423 00:15:37,955 --> 00:15:38,956 SEVERAL OVER THE ACCOMPLISHMENTS 424 00:15:38,956 --> 00:15:41,793 IN THE NEXT FEW MINUTES WAS TO 425 00:15:41,793 --> 00:15:44,529 CHANGE THIS APPROACH AND THE 426 00:15:44,529 --> 00:15:45,930 APPROACH THEY TOOK WAS TO ASK 427 00:15:45,930 --> 00:15:47,698 THEMSELVES DO WE REALLY NEED TO 428 00:15:47,698 --> 00:15:48,599 TAKE BOTH KIDNEYS OUT. 429 00:15:48,599 --> 00:15:52,069 YES, WE UNDERSTAND THAT A 430 00:15:52,069 --> 00:15:53,771 BILATERAL MULTIFOCAL TUMORS BUT 431 00:15:53,771 --> 00:15:56,007 HOW CAN WE TRY AND SPARE THE 432 00:15:56,007 --> 00:15:57,542 KIDNEYS WITHOUT ALLOWING THESE 433 00:15:57,542 --> 00:15:58,743 TUMORS TO BECOME METASTATIC. 434 00:15:58,743 --> 00:16:01,546 OVER THE YEARS THEY DEVELOPED A 435 00:16:01,546 --> 00:16:03,281 SYSTEM WHEREBY THEY WOULD TAKE 436 00:16:03,281 --> 00:16:06,918 TUMORS THAT WERE LARGE ENOUGH TO 437 00:16:06,918 --> 00:16:08,953 CAUSE PROBLEMS, AND THAT SIZE 438 00:16:08,953 --> 00:16:11,856 CAME TO BE DETERMINED TO BE 439 00:16:11,856 --> 00:16:13,791 AROUND 3-CENTIMETERS OR SO, 440 00:16:13,791 --> 00:16:14,992 THAT'S THE THRESHOLD BEYOND 441 00:16:14,992 --> 00:16:17,161 WHICH THE RISK OF METASTASIS 442 00:16:17,161 --> 00:16:17,728 CONTINUES TO BUILD. 443 00:16:17,728 --> 00:16:20,765 SO THEY WOULD TAKE OUT TUMORS 444 00:16:20,765 --> 00:16:22,033 THAT WERE APPROACHES 445 00:16:22,033 --> 00:16:23,067 3-CENTIMETERS, AND THEY WOULD 446 00:16:23,067 --> 00:16:25,469 TAKE OUT ONLY THE TUMORS. 447 00:16:25,469 --> 00:16:27,438 NOT THE WHOLE KIDNEY. 448 00:16:27,438 --> 00:16:30,208 SO THEY WERE ABLE TO GO IN VERY 449 00:16:30,208 --> 00:16:32,410 SELECTIVELY, REMOVE THE TUMORS, 450 00:16:32,410 --> 00:16:39,250 WITH A LOT OF NORMAL NEPHRONS, 451 00:16:39,250 --> 00:16:41,752 AND THIS GAME STUDIED AND HAS 452 00:16:41,752 --> 00:16:42,687 BOTTOM AN ACCEPTED PRACTICE IN 453 00:16:42,687 --> 00:16:49,193 THE MANAGEMENT OF THESE 454 00:16:49,193 --> 00:16:49,760 PATIENTS. 455 00:16:49,760 --> 00:16:51,596 UNTIL RECENTLY, VHL WAS 456 00:16:51,596 --> 00:16:53,464 ESSENTIALLY A DISEASE MANAGED BY 457 00:16:53,464 --> 00:16:56,067 SURMINGICAL AND LOCAL THERAPIES. 458 00:16:56,067 --> 00:16:58,269 -- SURGICAL AND LOCAL THERAPIES. 459 00:16:58,269 --> 00:17:00,137 WHAT WAS THE GOAL IN KIDNEY 460 00:17:00,137 --> 00:17:00,571 CANCER? 461 00:17:00,571 --> 00:17:02,340 THE GOAL IS TO PREVENT 462 00:17:02,340 --> 00:17:03,841 METASTATIC DISEASE AND AS I ALSO 463 00:17:03,841 --> 00:17:05,843 POINTED OUT TO MINIMIZE THE RISK 464 00:17:05,843 --> 00:17:07,144 OF METASTATIC DISEASE, TUMORS 465 00:17:07,144 --> 00:17:09,881 WOULD GET TAKEN OUT BEFORE THEY 466 00:17:09,881 --> 00:17:12,483 REACHED 3-CENTIMETERS OR AS THEY 467 00:17:12,483 --> 00:17:13,384 WERE REACHING 3-CENTIMETERS. 468 00:17:13,384 --> 00:17:16,754 NOT ALL TUMORS ASSOCIATED WITH 469 00:17:16,754 --> 00:17:19,457 VHL HAVE METASTATIC POTENTIAL. 470 00:17:19,457 --> 00:17:21,325 NONETHELESS, THEY ALL CAN CAUSE 471 00:17:21,325 --> 00:17:22,159 PROBLEMS. 472 00:17:22,159 --> 00:17:24,929 FOR INSTANCE CNS, AND THE 473 00:17:24,929 --> 00:17:26,397 BLASTOMAS, DON'T METASTASIZE, 474 00:17:26,397 --> 00:17:28,132 BUT BECAUSE OF THEIR LOCATION 475 00:17:28,132 --> 00:17:30,201 THEY CAN CAUSE SIGNIFICANT 476 00:17:30,201 --> 00:17:31,335 FUNCTIONAL IMPAIRMENT AND THE 477 00:17:31,335 --> 00:17:35,172 GOAL IN THOSE TUMORS IS TO TRY 478 00:17:35,172 --> 00:17:38,910 AND REGAIN FUNCTION AND AGAIN, 479 00:17:38,910 --> 00:17:39,644 LOCAL APPROACHES WERE REALLY ALL 480 00:17:39,644 --> 00:17:42,246 THAT WERE AVAILABLE TO US UNTIL 481 00:17:42,246 --> 00:17:42,713 RECENTLY. 482 00:17:42,713 --> 00:17:44,048 SO WHILE THESE PROTESTS WERE 483 00:17:44,048 --> 00:17:46,684 EFFECTIVE IN MANAGING THESE 484 00:17:46,684 --> 00:17:48,519 PATIENTS, THEY CAME AT A COST, 485 00:17:48,519 --> 00:17:51,055 LIKE MANY OF THESE PATIENTS 486 00:17:51,055 --> 00:17:52,957 NEEDED SURGERIES IN MULTIPLE 487 00:17:52,957 --> 00:17:53,691 ORGANS, SOMETIMES REPEATED 488 00:17:53,691 --> 00:17:54,959 SEVERAL TIMES DURING THEIR 489 00:17:54,959 --> 00:17:57,495 LIFETIME AND THIS REALLY BECAME 490 00:17:57,495 --> 00:18:00,798 A VERY BURDENSOME AFFAIR. 491 00:18:00,798 --> 00:18:01,432 SURE, WITH CAREFUL SURVEILLANCE 492 00:18:01,432 --> 00:18:03,901 AND ALL OF THESE TUMORS YOU 493 00:18:03,901 --> 00:18:05,336 COULD REGAIN FUNCTION TO A 494 00:18:05,336 --> 00:18:06,737 SIGNIFICANT DEGREE IN SOME OF 495 00:18:06,737 --> 00:18:07,672 THESE PATIENTS, YOU COULD 496 00:18:07,672 --> 00:18:09,307 MINIMIZE THE RISK OF METASTATIC 497 00:18:09,307 --> 00:18:12,510 DEC BUT IT CAME AT A -- THE 498 00:18:12,510 --> 00:18:14,211 PATIENT'S PAID A PRICE FOR IT. 499 00:18:14,211 --> 00:18:16,280 WHEN I CAME INTO THE NCI, 1 OF 500 00:18:16,280 --> 00:18:18,015 THE GOALS HIWAS TO TRY AND FIND 501 00:18:18,015 --> 00:18:20,985 -- I HAD WAS TO TRY AND FIND A 502 00:18:20,985 --> 00:18:22,586 SYSTEMIC OPTION THAT COULD WORK 503 00:18:22,586 --> 00:18:25,556 IN CONJUNCTION WITH ESTABLISHED 504 00:18:25,556 --> 00:18:26,691 PRACTICES, OBVIOUSLY THE NEED 505 00:18:26,691 --> 00:18:30,428 FOR SURGERY OR MINIMIZE THE NEED 506 00:18:30,428 --> 00:18:30,795 FOR SURGERY. 507 00:18:30,795 --> 00:18:33,664 SO HOW DO YOU EVEN GO ABOUT 508 00:18:33,664 --> 00:18:34,765 DEVISING SYSTEM AND TREATMENT. 509 00:18:34,765 --> 00:18:36,434 THERE WERE NO SYSTEM AND 510 00:18:36,434 --> 00:18:37,401 TREATMENTS OTHER THAN CYTOKINE 511 00:18:37,401 --> 00:18:40,905 THERAPY WHICH IS EFFECTIVE IN 512 00:18:40,905 --> 00:18:42,540 PROPULSION OF METASTATIC CANCER 513 00:18:42,540 --> 00:18:46,811 UNTIL THE EARLY 2000S. 514 00:18:46,811 --> 00:18:49,447 BUT THE INITIAL STEPS REALLY 515 00:18:49,447 --> 00:18:51,148 THAT REALLY BROUGHT US TO A 516 00:18:51,148 --> 00:18:54,518 POINT WHERE WE COULD DEVISE 517 00:18:54,518 --> 00:18:55,252 THESE TREATMENTS, TOOK SHAPE 518 00:18:55,252 --> 00:19:01,492 AGAIN IN THE EARLY 80S AND 519 00:19:01,492 --> 00:19:02,560 MARSTON LINEHAN JOINED STEVE'S 520 00:19:02,560 --> 00:19:07,465 GROUP HERE AT THE NCI, HE TOOK 521 00:19:07,465 --> 00:19:09,800 IT UPON HIMSELF TO STUDY VHL AND 522 00:19:09,800 --> 00:19:12,036 WAS CONVINCED BY STUDYING THESE 523 00:19:12,036 --> 00:19:13,671 PATIENTS WITH VHL, THESE 524 00:19:13,671 --> 00:19:17,108 FAMILIES WITH VHL, HE WOULD BE 525 00:19:17,108 --> 00:19:18,909 ABLE TO IDENTIFY THE GENETIC 526 00:19:18,909 --> 00:19:19,810 CAUSE OF THE DISEASE. 527 00:19:19,810 --> 00:19:25,016 SO THAT WAS A GENETIC DEFECT 528 00:19:25,016 --> 00:19:26,317 THAT LED TO THESE TUMORS. 529 00:19:26,317 --> 00:19:28,386 AND ALSO BY UNDERSTANDING VHL, 530 00:19:28,386 --> 00:19:33,157 HE COULD ALSO SHED LIGHT ON HOW 531 00:19:33,157 --> 00:19:35,426 PATIENTS WITH SPORADIC KIDNEY 532 00:19:35,426 --> 00:19:37,328 CANCERS AND GUARD AGAINST THOSE 533 00:19:37,328 --> 00:19:38,095 CANCERS. 534 00:19:38,095 --> 00:19:39,130 LONG STORY SHORT. 535 00:19:39,130 --> 00:19:46,137 TOOK AROUND 10 YEARS, LINEHAN 536 00:19:46,137 --> 00:19:49,140 AND ZBAR, ALONG WITH OTHER 537 00:19:49,140 --> 00:19:50,408 INVESTIGATORS WERE ABLE TO 538 00:19:50,408 --> 00:19:52,209 IDENTIFY THE JEERN THAT CAUSED 539 00:19:52,209 --> 00:19:52,543 VHL. 540 00:19:52,543 --> 00:19:56,247 AND WERE ABLE TO IDENTIFY ON 541 00:19:56,247 --> 00:19:58,883 CHROMOSOME 3, THE ABLE TO DEFECT 542 00:19:58,883 --> 00:20:00,284 AND FURTHER LOCALIZE THE GENE, 543 00:20:00,284 --> 00:20:02,486 NOW WHICH WE CALL THE VHL YEEN 544 00:20:02,486 --> 00:20:03,721 THAT WAS ACTIVATING MUTATIONS IN 545 00:20:03,721 --> 00:20:06,690 THE GERM LINE. 546 00:20:06,690 --> 00:20:08,959 AND THIS WAS THEN SHOWN TO BE 547 00:20:08,959 --> 00:20:14,065 THE CAUSE FOR VHL DISEASE. 548 00:20:14,065 --> 00:20:16,567 THE VERY SAME GENE AND VERY 549 00:20:16,567 --> 00:20:19,637 SIMILAR MUTATIONS ALSO OCCUR IN 550 00:20:19,637 --> 00:20:21,405 THE SPORADIC VARIANT OF KIDNEY 551 00:20:21,405 --> 00:20:22,273 CELL CANCER. 552 00:20:22,273 --> 00:20:24,575 MUCH MORE THAN THE GENETIC FORM, 553 00:20:24,575 --> 00:20:26,110 THE DIFFERENCE BEING IN VHL 554 00:20:26,110 --> 00:20:28,312 DISEASE, 1 IS THE PRESENT GERM 555 00:20:28,312 --> 00:20:30,681 LINE AND THE SECOND IN THE 556 00:20:30,681 --> 00:20:32,650 SOMATIC TISSUE WHILE BOTH ARE 557 00:20:32,650 --> 00:20:36,921 SOMATIC IN THE SPORADIC VERSION 558 00:20:36,921 --> 00:20:39,223 OF CLEAR CELL RCC. 559 00:20:39,223 --> 00:20:40,724 VHL DOES HAVE A CLASSIC GENE 560 00:20:40,724 --> 00:20:44,829 THAT REQUIRES TO HITS FOR FULL 561 00:20:44,829 --> 00:20:45,162 MANIFESTATION. 562 00:20:45,162 --> 00:20:46,931 SO NOW WE KNOW THERE'S A GENE 563 00:20:46,931 --> 00:20:48,065 THAT CAUSES THIS DISEASE EMPLOY 564 00:20:48,065 --> 00:20:50,801 THE NEXT QUESTION OF COURSE THAT 565 00:20:50,801 --> 00:20:54,038 FACED IN A SCIENTISTS IN THE 566 00:20:54,038 --> 00:20:57,141 1990S WAS HOW DOES LOSING VHL 567 00:20:57,141 --> 00:20:58,776 FUNCTION LEAD TO KIDNEY CANCER. 568 00:20:58,776 --> 00:21:01,779 ONE OF THE EARLIEST CLUES REALLY 569 00:21:01,779 --> 00:21:04,248 CAME FROM STUDIES THAT WERE BONE 570 00:21:04,248 --> 00:21:09,186 BY FORMER NCI DIRECTOR CLAUSEN, 571 00:21:09,186 --> 00:21:12,923 AS WELL AS A LAB IN HARBOR, 572 00:21:12,923 --> 00:21:14,558 THERE'S LOTS OF STORIES THAT I 573 00:21:14,558 --> 00:21:16,927 DON'T HAVE TIME TO GO INTO 574 00:21:16,927 --> 00:21:19,163 TODAY, BUT WHAT BOTH GROUPS 575 00:21:19,163 --> 00:21:21,899 IDENTIFIED WAS THAT VHL WAS 576 00:21:21,899 --> 00:21:25,069 ASSOCIATED WITH B& C WHICH IS 577 00:21:25,069 --> 00:21:26,670 WHERE TRANSCRIPTION OF FACTORS 578 00:21:26,670 --> 00:21:28,172 BUT ALSO HAD LONG FUNCTION. 579 00:21:28,172 --> 00:21:30,674 THIS VERY, VERY CRITICAL FINDING 580 00:21:30,674 --> 00:21:35,112 WAS THEN FOLLOWED BY OBSERVATION 581 00:21:35,112 --> 00:21:40,284 THAT ELONGINS IN TURN COMPLEXED 582 00:21:40,284 --> 00:21:41,819 WITH RBX 1 WAS -- THIS REALLY 583 00:21:41,819 --> 00:21:43,587 PAVED THE WAY FOR US TO 584 00:21:43,587 --> 00:21:45,789 UNDERSTAND 1 OF THE MANY 585 00:21:45,789 --> 00:21:48,192 FUNCTIONS OF VHL WAS THAT IT 586 00:21:48,192 --> 00:21:50,461 ACTS AS A COMPLEMENT OF E-3 587 00:21:50,461 --> 00:21:52,463 LIAISON GAS WHICH REGULATES 588 00:21:52,463 --> 00:21:53,264 MULTIPLE CELLULAR PROTEINS. 589 00:21:53,264 --> 00:21:55,232 OVER THE NEXT SEVERAL YEARS, IT 590 00:21:55,232 --> 00:21:57,768 BECAME A PATTERN THAT 1 OF THE 591 00:21:57,768 --> 00:21:59,103 KEY PROTEINS THAT WAS REGULATED 592 00:21:59,103 --> 00:22:01,839 WAS A GROUP OF TRANSCRIPTION 593 00:22:01,839 --> 00:22:03,007 FACTORS CALLED HYPOXIA AND 594 00:22:03,007 --> 00:22:05,576 FACTORS 1 AND 2 BEING THE 2, IN 595 00:22:05,576 --> 00:22:07,411 THE MOST WELL RECOGNIZED 596 00:22:07,411 --> 00:22:08,913 VERSIONS OF THIS, YOU HAVE THIS 597 00:22:08,913 --> 00:22:13,751 GROUP OF TRANSCRIPTION FACTORS. 598 00:22:13,751 --> 00:22:16,487 AND IT BECAME A MODEL IS 599 00:22:16,487 --> 00:22:19,056 PROPOSED WHEREBY IN NORMAL CELLS 600 00:22:19,056 --> 00:22:20,624 WITH INTACT VHL, THE LEVEL OF 601 00:22:20,624 --> 00:22:22,493 THESE LEVELS WILL BE TIGHTLY 602 00:22:22,493 --> 00:22:24,695 REGULATED BASED ON THE LEVELS OF 603 00:22:24,695 --> 00:22:26,263 AMBIENT OXYGEN. 604 00:22:26,263 --> 00:22:30,601 IF THERE WAS ENOUGH AMBIENT 605 00:22:30,601 --> 00:22:33,470 OXYGEN, VHL WOULD BIND TO AND 606 00:22:33,470 --> 00:22:34,972 LEAD TO DEGRADATION OF THESE 607 00:22:34,972 --> 00:22:35,206 FACTORS. 608 00:22:35,206 --> 00:22:37,541 ON THE OTHER HAND, POST 609 00:22:37,541 --> 00:22:38,042 TRANSLATIONAL CLINICAL 610 00:22:38,042 --> 00:22:41,845 MODIFICATION OF THESE FACT FACS 611 00:22:41,845 --> 00:22:44,114 WHICH WAS NECESSARY BY THE VHL 612 00:22:44,114 --> 00:22:45,983 WOULD NOT THERE, AND THEREFORE 613 00:22:45,983 --> 00:22:46,650 THESE FACTORS WOULD ACCUMULATE 614 00:22:46,650 --> 00:22:48,852 IN A BIT OF REVERSE, THE 615 00:22:48,852 --> 00:22:50,854 CONSEQUENCES OF HYPOXIA. 616 00:22:50,854 --> 00:22:53,857 IN PATIENTS IN INACTIVE VHL, THE 617 00:22:53,857 --> 00:22:55,893 SYSTEMS ON ALL THE TIME. 618 00:22:55,893 --> 00:23:01,932 VHL IS UNABLE TO RECOGNIZE HIF, 619 00:23:01,932 --> 00:23:03,901 REGARDLESS OF AMBIENT OXYGEN 620 00:23:03,901 --> 00:23:04,735 RETENTION AND THEREFORE 621 00:23:04,735 --> 00:23:07,504 UPREGULATION OF THE SYSTEM AND 622 00:23:07,504 --> 00:23:08,339 DOWN STREAM CONQUENCES. 623 00:23:08,339 --> 00:23:09,873 IN FACT, IT WAS UNDERSTANDING 624 00:23:09,873 --> 00:23:15,679 THIS PATHWAY WHICH BY THE WAY 625 00:23:15,679 --> 00:23:20,584 WAS CRITICAL IN TRIBUTING IN 626 00:23:20,584 --> 00:23:24,588 2019 THAT 3 INVESTIGATORS 627 00:23:24,588 --> 00:23:27,024 RECEIVED, ALLEN, AND RATLIFF AND 628 00:23:27,024 --> 00:23:27,658 COLLEAGUES, IT'S UNDERSTANDING 629 00:23:27,658 --> 00:23:28,826 THAT A LOT OF THE TREATMENTS WE 630 00:23:28,826 --> 00:23:30,728 HAD, AT LEAST THE TARGETED 631 00:23:30,728 --> 00:23:32,263 TREATMENTS WE'VE HAD FOR 632 00:23:32,263 --> 00:23:34,632 PATIENTS WITH CLEAR CELL KIDNEY 633 00:23:34,632 --> 00:23:35,299 CANCER WERE DEVISED. 634 00:23:35,299 --> 00:23:37,268 MOST OF THESE TREATMENTS AS 635 00:23:37,268 --> 00:23:39,670 SHOWN HERE, TARGETED DOWN STREAM 636 00:23:39,670 --> 00:23:44,675 CONSEQUENCES OF HIF REGULATION, 637 00:23:44,675 --> 00:23:48,779 SUCH AS VEG-F, PDFR AND 638 00:23:48,779 --> 00:23:49,513 PROLIFERATION. 639 00:23:49,513 --> 00:23:52,116 THE FIELD HAS LONG THIRSTED 640 00:23:52,116 --> 00:23:54,251 HOWEVER TO TRY AND TARGET THIS 641 00:23:54,251 --> 00:23:58,656 PATHWAY APPROXIMATELY 3 AS A 642 00:23:58,656 --> 00:24:01,659 LEVEL OF HIH, THIS PROVED TO BE 643 00:24:01,659 --> 00:24:03,060 A BIGGER CHALLENGE THAN WE WOULD 644 00:24:03,060 --> 00:24:04,695 HAVE LIKED. 645 00:24:04,695 --> 00:24:06,530 THESE TRANSCRIPTION FACTORS AND 646 00:24:06,530 --> 00:24:07,364 THORSITORIOUSLY DIFFICULT TO 647 00:24:07,364 --> 00:24:10,000 TARGET, BUT WE THOUGHT IN THE 648 00:24:10,000 --> 00:24:11,602 EARLY 2000S THAT WE MAY BE ABLE 649 00:24:11,602 --> 00:24:20,511 TO DO JUST THAT. 650 00:24:20,511 --> 00:24:23,380 LYNN NECKERS AND POST DOC AT THE 651 00:24:23,380 --> 00:24:26,684 TIME WERE STUDYING A GROUP OF 652 00:24:26,684 --> 00:24:28,185 MOLECULES AND LYNN'S AN EXPERT 653 00:24:28,185 --> 00:24:30,721 ON P90 AND THEY STARTED A GROUP 654 00:24:30,721 --> 00:24:37,695 OF P90 AND SHOWED THAT THESE 655 00:24:37,695 --> 00:24:39,496 MOLECULES IN PROTOTYPIC TRIALS 656 00:24:39,496 --> 00:24:42,933 WERE ABLE TO DOWN REGULATE HIF. 657 00:24:42,933 --> 00:24:44,601 THIS WAS VERY EXCITING FINDING 658 00:24:44,601 --> 00:24:45,269 FOR US. 659 00:24:45,269 --> 00:24:51,342 AT THAT TIME, WE KNEW THAT THESE 660 00:24:51,342 --> 00:24:52,976 DRUGS DOWN REGULATED HIF 1, 661 00:24:52,976 --> 00:24:54,945 BECAUSE IT'S A CLIENT PROTEIN 662 00:24:54,945 --> 00:24:55,679 FOR THE HSP90 SYSTEM. 663 00:24:55,679 --> 00:24:57,981 WE WERE NOT ABLE TO STUDY HIF2 664 00:24:57,981 --> 00:24:59,883 AS WELL AS WE WOULD LIKE BECAUSE 665 00:24:59,883 --> 00:25:01,385 WE DIDN'T HAVE AN ANTIBODIES 666 00:25:01,385 --> 00:25:03,153 THAT WERE GOOD ENOUGH BUT THERE 667 00:25:03,153 --> 00:25:05,456 WERE INDICATIONS FROM OTHER 668 00:25:05,456 --> 00:25:06,857 GROUPS INCLUDING BILL'S GROUP 669 00:25:06,857 --> 00:25:09,727 THAT HIF2 MIGHT ALSO BE A CLIENT 670 00:25:09,727 --> 00:25:11,795 FOR HSP90 AND MIGHT BE DOWN 671 00:25:11,795 --> 00:25:13,831 REGULATED SO WE HAD SOME 672 00:25:13,831 --> 00:25:14,765 INFORMATION ABOUT WHAT THESE 673 00:25:14,765 --> 00:25:17,468 DRUGS DID FOR THE HIF AXIS BUT 674 00:25:17,468 --> 00:25:18,535 THERE WAS CLEARLY SOME 675 00:25:18,535 --> 00:25:19,236 INFORMATION MISSING BUT WE 676 00:25:19,236 --> 00:25:22,172 THOUGHT THIS WAS EXCITING ENOUGH 677 00:25:22,172 --> 00:25:24,274 THAT THIS WAS AN APPROACH THAT 678 00:25:24,274 --> 00:25:27,845 COULD POTENTIALLY BE TESTED IN 679 00:25:27,845 --> 00:25:28,946 THE CLINIC. 680 00:25:28,946 --> 00:25:30,280 AND SO WE UNDERTOOK THE FIRST 681 00:25:30,280 --> 00:25:31,982 EVER CLINICAL TRIAL OF A 682 00:25:31,982 --> 00:25:33,417 SYSTEMIC AGENT IN THE PATIENTS 683 00:25:33,417 --> 00:25:36,019 WITH VHL, THIS WAS AS I SAID A 684 00:25:36,019 --> 00:25:37,621 AGENT AND INTRANSLATIONAL 685 00:25:37,621 --> 00:25:38,856 RESEARCH VENOUS AGENT AND WE 686 00:25:38,856 --> 00:25:43,060 ALSO ASKED VERY SIMPLE 687 00:25:43,060 --> 00:25:50,100 QUESTIONS, FIRST , THE SPECIFIC 688 00:25:50,100 --> 00:25:51,935 ISSUES KEEPING IN MIND WHEN 689 00:25:51,935 --> 00:25:53,804 TREATING THESE PATIENTS. 690 00:25:53,804 --> 00:25:57,474 THE DESIGN WE HAD TO TAKE 691 00:25:57,474 --> 00:25:59,543 PATIENTS THAT WERE GOING TO 692 00:25:59,543 --> 00:26:01,779 SURGERY, THEY HAD TUMORS THAT 693 00:26:01,779 --> 00:26:03,680 WERE APPROACHING 3-CENTIMETERS 694 00:26:03,680 --> 00:26:04,748 AND THE PHYSICIANS THOUGHT THEY 695 00:26:04,748 --> 00:26:06,750 SHOULD HAVE THESE TUMORS REMOVED 696 00:26:06,750 --> 00:26:07,584 AND ADMINISTERED THIS DRULG FOR 697 00:26:07,584 --> 00:26:10,220 A PERIOD OF TIME, IF THE 698 00:26:10,220 --> 00:26:11,088 PATIENTS RESPONDED WE WOULD 699 00:26:11,088 --> 00:26:12,122 CONTINUE TREATMENT, IF THEY 700 00:26:12,122 --> 00:26:13,857 DIDN'T RESPOND WE WOULD TAKE 701 00:26:13,857 --> 00:26:15,692 THEM TO SURGERY, COLLECT THE 702 00:26:15,692 --> 00:26:17,227 TISSUE TO SEE IF THE PATHWAY WE 703 00:26:17,227 --> 00:26:20,097 THOUGHT WOULD BE IMPACTED WAS 704 00:26:20,097 --> 00:26:21,899 IMPACTED BY THIS DRUG. 705 00:26:21,899 --> 00:26:25,202 THIS IS AN EXCEEDINGLY DIFFICULT 706 00:26:25,202 --> 00:26:27,237 STUDY TO CONDUCT BECAUSE OF THE 707 00:26:27,237 --> 00:26:28,505 DRUG PARTLY BUT ALSO BECAUSE AT 708 00:26:28,505 --> 00:26:30,140 THAT POINT WE FAILED TO 709 00:26:30,140 --> 00:26:33,744 RECOGNIZE HOW DIFFICULT IT WAS 710 00:26:33,744 --> 00:26:37,481 TO BRING THESE PATIENTS IN AND 711 00:26:37,481 --> 00:26:41,251 HAVE THEM UNDERGO A STUDY THAT 712 00:26:41,251 --> 00:26:41,718 WAS FAIRLY COMPLEX. 713 00:26:41,718 --> 00:26:43,253 BUT A LOT OF LESSONS TO LEARN 714 00:26:43,253 --> 00:26:44,688 FROM THIS AND 1 OF THOSE THAT 715 00:26:44,688 --> 00:26:46,557 WAS THAT YES, WE COULD DO THE 716 00:26:46,557 --> 00:26:48,659 STUDIES IN VHL PATIENTS AND IT 717 00:26:48,659 --> 00:26:49,760 ALSO IDENTIFIED FOR SEVERAL 718 00:26:49,760 --> 00:26:53,697 FACTORS, WE NEEDED TO TAKE INTO 719 00:26:53,697 --> 00:26:55,032 ACCOUNT, TO IMPROVE STRATEGIES 720 00:26:55,032 --> 00:26:55,833 WITH FUTURE TRIALS. 721 00:26:55,833 --> 00:26:58,168 THE TRIAL ITSELF WAS NOT 722 00:26:58,168 --> 00:26:59,036 CLINICALLY VERY PROMISING. 723 00:26:59,036 --> 00:27:01,472 WE SAW NO RESPONSES, WE DID SEE 724 00:27:01,472 --> 00:27:04,308 A LOT OF STABLE DISEASE BUT OVER 725 00:27:04,308 --> 00:27:05,375 4 MONTHS, STABLE DISEASE IS THE 726 00:27:05,375 --> 00:27:07,578 NORM IN PATIENTS WITH VHL, EVEN 727 00:27:07,578 --> 00:27:11,648 IF YOU DIDN'T TREAT THEM. 728 00:27:11,648 --> 00:27:12,683 OVER THE SUCCEEDING YEARS AND 729 00:27:12,683 --> 00:27:15,085 THIS WAS AROUND THE TIME WHEN 730 00:27:15,085 --> 00:27:16,253 VEG F TARGETS BECAME AVAILABLE 731 00:27:16,253 --> 00:27:17,688 FOR CLINICAL USE AND WAS SHOWN 732 00:27:17,688 --> 00:27:20,057 TO BE EFFECTIVE IN THE SPORADIC 733 00:27:20,057 --> 00:27:22,759 FORM OF CLEAR CELL RCC, AND WE 734 00:27:22,759 --> 00:27:24,461 AND OTHER INVESTIGATORS ASKED IF 735 00:27:24,461 --> 00:27:29,833 THESE VEG F TARGETED 18thS 736 00:27:29,833 --> 00:27:31,235 TYROSEEN INHIBITORS WOULD HAVE 737 00:27:31,235 --> 00:27:34,137 CLINICAL UTILITY IN PATIENTS 738 00:27:34,137 --> 00:27:35,005 WITH VHL. 739 00:27:35,005 --> 00:27:36,173 I'LL SUMMARIZE THE DATA FROM 740 00:27:36,173 --> 00:27:38,609 THOSE STUDIES IN A COUPLE OF 741 00:27:38,609 --> 00:27:39,076 SLIDES. 742 00:27:39,076 --> 00:27:42,045 WHAT WE LEARNED THEN WAS THAT 743 00:27:42,045 --> 00:27:43,146 YES, THERE'S SOME ACTIVITY 744 00:27:43,146 --> 00:27:44,748 ASSOCIATED WITH THESE AGENTS, 745 00:27:44,748 --> 00:27:52,956 I'M SHOWING 2 STUDIES WITH 1 746 00:27:52,956 --> 00:27:56,426 CALLED VANDETANIB, AND ALSO 747 00:27:56,426 --> 00:27:58,862 SUNITINIKB SIN, STUDIED AT MD 748 00:27:58,862 --> 00:27:59,129 ANDERSON. 749 00:27:59,129 --> 00:28:01,932 WE DID SEE A LOT OF ACTIVITY IN 750 00:28:01,932 --> 00:28:03,166 THE OTHER MANIFESTATIONS, 751 00:28:03,166 --> 00:28:04,468 CERTAINLY NOT THE OTHER 752 00:28:04,468 --> 00:28:06,703 BLASTOMAS THAT ARE ASSOCIATE 753 00:28:06,703 --> 00:28:07,471 WIDE VHL. 754 00:28:07,471 --> 00:28:09,740 BUT KIDNEY CANCERS DID SEEM TO 755 00:28:09,740 --> 00:28:11,174 REGRESS AT LEAST IN THE 756 00:28:11,174 --> 00:28:12,342 PROPORTION OF PATIENTS. 757 00:28:12,342 --> 00:28:14,578 THE MAJOR PROBLEM AND THE SECOND 758 00:28:14,578 --> 00:28:17,214 LESSON WE LEARNED IN TREATING 759 00:28:17,214 --> 00:28:18,282 THESE VHL PATIENTS WAS THAT A 760 00:28:18,282 --> 00:28:19,850 LOT OF THESE PATIENTS DIDN'T 761 00:28:19,850 --> 00:28:21,585 LIKE THESE DRUGS. 762 00:28:21,585 --> 00:28:22,252 PATIENTS WITH METASTATIC KIDNEY 763 00:28:22,252 --> 00:28:23,554 CANCER WHO HAVE NO OTHER 764 00:28:23,554 --> 00:28:24,288 TREATMENT OPTIONS AND ARE GOING 765 00:28:24,288 --> 00:28:26,323 TO DIE IF THEY DON'T GET THIS 766 00:28:26,323 --> 00:28:27,758 TREATMENT ARE WILLING TO ACCEPT 767 00:28:27,758 --> 00:28:29,493 A LOT OF TOXICITY THAT WHAT USED 768 00:28:29,493 --> 00:28:32,663 TO BE CHARACTERIZED AS WELL 769 00:28:32,663 --> 00:28:33,230 TOLERATED KINASE INHIBITORS. 770 00:28:33,230 --> 00:28:34,798 THESE PATIENT WHO IS HAD 771 00:28:34,798 --> 00:28:36,133 LOCALIZED DISEASE WHO HAD 772 00:28:36,133 --> 00:28:38,068 SURGICAL OPTIONS, NOT A WALK IN 773 00:28:38,068 --> 00:28:39,469 THE PARK THEMSELVES BUT THEY HAD 774 00:28:39,469 --> 00:28:44,341 OTHER OPTIONS AND THEY WERE NOT 775 00:28:44,341 --> 00:28:45,142 STARING IMMINENT DEATH IN THE 776 00:28:45,142 --> 00:28:46,543 FACE IF THEY DIDN'T TAKE THIS 777 00:28:46,543 --> 00:28:47,077 DRUG. 778 00:28:47,077 --> 00:28:48,412 THEY HAD A VERY LEVEL OF 779 00:28:48,412 --> 00:28:49,780 ACCEPTANCE FOR THESE SIDE CENTER 780 00:28:49,780 --> 00:28:51,014 FOR EXCELLENCE ON AGINGS, MEDIAN 781 00:28:51,014 --> 00:28:52,783 TIME WITH THESE STUDIES WAS ON 782 00:28:52,783 --> 00:28:54,418 DRUG IN NEEZ STUDIES WAS LESS 783 00:28:54,418 --> 00:28:56,053 THAN 6 MONTHS WITH THE VAST 784 00:28:56,053 --> 00:29:00,457 MAIORITY OF PATIENTS CONTINUING 785 00:29:00,457 --> 00:29:01,925 -- CONTINUING TREATMENT FOR 786 00:29:01,925 --> 00:29:02,225 TOXICITY. 787 00:29:02,225 --> 00:29:02,960 SO SECOND IMPORTANT LESSON 788 00:29:02,960 --> 00:29:06,663 LEARNED IF YOU WANT TO DEVICE 789 00:29:06,663 --> 00:29:07,497 EFFECTIVE TREATMENT STRATEGY FOR 790 00:29:07,497 --> 00:29:08,999 THESE PATIENTS ISSUES THE TARGET 791 00:29:08,999 --> 00:29:11,401 ON THE VHL TUMORS, WE NEED TO 792 00:29:11,401 --> 00:29:13,203 DEVISE DRUGS THAT ARE WELL 793 00:29:13,203 --> 00:29:19,943 TOLERATED AND REALLY WELL 794 00:29:19,943 --> 00:29:20,644 TOLERATED. 795 00:29:20,644 --> 00:29:23,847 I UNDERSTAND EARLY 2000S WORK IN 796 00:29:23,847 --> 00:29:28,485 LINEHAN'S LAB AT NCI AND ANOTHER 797 00:29:28,485 --> 00:29:29,820 COLLEAGUE'S LAB AT HARVARD, 798 00:29:29,820 --> 00:29:32,022 DEMONSTRATE THAD HIF1 AND 2, HIF 799 00:29:32,022 --> 00:29:33,991 2 SEEMED TO BE THE MORE 800 00:29:33,991 --> 00:29:37,527 ONCOGENIC DRIVER OF THESE 801 00:29:37,527 --> 00:29:37,995 TUMORS. 802 00:29:37,995 --> 00:29:40,297 HIF1 IN THIS CONTEXT CONFERS AT 803 00:29:40,297 --> 00:29:47,070 LEAST TO SOME EXTENT A TUMOR 804 00:29:47,070 --> 00:29:47,604 EFFECT. 805 00:29:47,604 --> 00:29:48,805 SO, EFFORTS THEN WERE DIRECTED 806 00:29:48,805 --> 00:29:51,108 AT TRYING TO FIND AN AGENT OR 807 00:29:51,108 --> 00:29:52,843 AGENTS THAT SPECIFICALLY TARGET 808 00:29:52,843 --> 00:29:54,878 HIF2 BECAUSE IT COULD BE ARGUED 809 00:29:54,878 --> 00:29:58,181 THAT TARGETING HIF1 MIGHT BE 810 00:29:58,181 --> 00:29:58,515 DELETERIOUS. 811 00:29:58,515 --> 00:30:01,818 AS I SAID, TARGETS TRANSCRIPTION 812 00:30:01,818 --> 00:30:03,553 FACTORS IS NOT EASY AND IT 813 00:30:03,553 --> 00:30:05,756 WASN'T IN THIS CASE, SO IT TOOK 814 00:30:05,756 --> 00:30:06,990 SEVERAL YEARS BEFORE A BREAK 815 00:30:06,990 --> 00:30:12,562 THROUGH CAME AND THE BREAK 816 00:30:12,562 --> 00:30:16,299 THROUGH CAME FROM DR. BRUIC AND 817 00:30:16,299 --> 00:30:17,467 GARDENER'S LAB AT UT 818 00:30:17,467 --> 00:30:18,301 SOUTHWESTERN EMPLOY TO 819 00:30:18,301 --> 00:30:19,936 UNDERSTAND HOW THEY DEVELOPED 820 00:30:19,936 --> 00:30:22,305 THIS DRUG, IT'S IMPORTANT TO 821 00:30:22,305 --> 00:30:27,077 SPEND A MINUTEOT HIF FUNCTION, 822 00:30:27,077 --> 00:30:30,414 BOTH HIF1 AND 2 FUNCTION AS A 823 00:30:30,414 --> 00:30:30,981 HETERODIMER. 824 00:30:30,981 --> 00:30:34,851 SO HIF1 AND 2 ARE 2 DISTINCT 825 00:30:34,851 --> 00:30:39,056 ALPHA SUBUNITS BUT THEY'RE A 826 00:30:39,056 --> 00:30:40,223 HETERODIMIC PARTNER, IS COMMON. 827 00:30:40,223 --> 00:30:43,660 SO THEY HAD TO DEVISE A METHOD 828 00:30:43,660 --> 00:30:45,595 THAT WOULD SELECTIVELY KNOCK 829 00:30:45,595 --> 00:30:48,131 DOWN HIF2 BUT NOT HIF1. 830 00:30:48,131 --> 00:30:49,099 AND IN EVALUATING THESE 831 00:30:49,099 --> 00:30:51,501 MOLECULES THEY WERE ABLE TO 832 00:30:51,501 --> 00:30:54,571 IDENTIFY A PAST B DOMAINOIN IN 833 00:30:54,571 --> 00:30:58,308 HIF-2 FROM WHAT WAS EXISTED IN 834 00:30:58,308 --> 00:31:00,677 FIH1, AND DEVELOP A GROUP OF 835 00:31:00,677 --> 00:31:02,212 DRUGS THAT SPECIFICALLY FIT IN 836 00:31:02,212 --> 00:31:05,982 THIS DOMAIN AND AS 837 00:31:05,982 --> 00:31:07,117 HETERODIMMERAISATION, IF YOU 838 00:31:07,117 --> 00:31:09,886 DON'T HAVE THE FACTORS, THESE 839 00:31:09,886 --> 00:31:13,323 TRANSCRIPTIONS ARE NOT 840 00:31:13,323 --> 00:31:13,657 ACTIVATING. 841 00:31:13,657 --> 00:31:15,525 THEY SYNTHESIZED AND RELATED 842 00:31:15,525 --> 00:31:17,461 CHEMICALLY TO 1 ANOTHER, AND 843 00:31:17,461 --> 00:31:19,830 EARLY COMPOUNDS WERE SHOWN TO BE 844 00:31:19,830 --> 00:31:21,631 VERY EFFECTIVE. 845 00:31:21,631 --> 00:31:24,501 INHIBITORS OF HIF2 ALPHA AS WELL 846 00:31:24,501 --> 00:31:27,938 AS INDUCING REGRESSION IN VHL 847 00:31:27,938 --> 00:31:29,673 HIF TUMORS BY THE EVANS GROUP AT 848 00:31:29,673 --> 00:31:34,778 HARVARD AS WELL AS JIM'S GROUP 849 00:31:34,778 --> 00:31:35,779 AT UT SOUTHWESTERN. 850 00:31:35,779 --> 00:31:37,981 SO AT LONG LOST, WE HAD DRUGGED 851 00:31:37,981 --> 00:31:41,618 THAT WE COULD TARGET, WE COULD 852 00:31:41,618 --> 00:31:45,355 USE TO TARGET HIF2 ALPHA. 853 00:31:45,355 --> 00:31:48,592 SO HOW DO WE REALLY THEN 854 00:31:48,592 --> 00:31:49,359 EVALUATE THESE DRUGS. 855 00:31:49,359 --> 00:31:51,061 IN CANCER MOST DRUGS ARE 856 00:31:51,061 --> 00:31:52,696 EVALUATED FIRST IN PATIENTS WHO 857 00:31:52,696 --> 00:31:55,532 HAVE NO OTHER OPTIONS, TYPICALLY 858 00:31:55,532 --> 00:31:57,033 IN THE METASTATIC SETTING WHERE 859 00:31:57,033 --> 00:31:58,235 OTHER OPTIONS HAVE BEEN 860 00:31:58,235 --> 00:32:00,103 EXHAUSTED OR THERE ARE NO OTHER 861 00:32:00,103 --> 00:32:04,808 TREATMENTS FOR GIVEN SETTING. 862 00:32:04,808 --> 00:32:06,977 HOWEVER, I THINK PEOPLE WHO MADE 863 00:32:06,977 --> 00:32:14,885 THIS DRUG COMPANY, CALLED 864 00:32:14,885 --> 00:32:16,553 PELATTA AT THE TIME, RECOGNIZED 865 00:32:16,553 --> 00:32:18,421 THAT THE MODEL, BUT NOT A 866 00:32:18,421 --> 00:32:19,456 TYPICAL APPROACH MIGHT ACTUALLY 867 00:32:19,456 --> 00:32:22,092 PROVIDE A GOOD ANSWER TO AS TO 868 00:32:22,092 --> 00:32:24,528 WHETHER OR NOT A DRUG AS 869 00:32:24,528 --> 00:32:28,165 SPECIFIC AS THIS TARGETS HIF2, 870 00:32:28,165 --> 00:32:30,066 HAS ACTIVITY IN HIF2 AND TUMORS, 871 00:32:30,066 --> 00:32:31,401 SO THEY CAME TO US AND APPROACH 872 00:32:31,401 --> 00:32:34,504 US AND SAY, DO YOU THINK A STUDY 873 00:32:34,504 --> 00:32:35,772 IN VHL PATIENT SYSTEM FEASIBLE 874 00:32:35,772 --> 00:32:36,840 EMPLOY THEY HAD GONE THROUGH THE 875 00:32:36,840 --> 00:32:38,942 PHASE 1 STUDY AT THE TIME AND 1 876 00:32:38,942 --> 00:32:40,644 OF THE FIRST QUESTIONS I HAD FOR 877 00:32:40,644 --> 00:32:43,747 THEM WAS HOW WELL TOLERATED IS 878 00:32:43,747 --> 00:32:48,051 THIS DRUG IN AND IT DID SEEM TO 879 00:32:48,051 --> 00:32:49,219 HAVE AN EXCELLENT TOLERANCE. 880 00:32:49,219 --> 00:32:51,688 THERE WAS NO DOUBT IN OUR MINDS 881 00:32:51,688 --> 00:32:53,190 THAT TO EVALUATE A POSITION DRUG 882 00:32:53,190 --> 00:32:59,963 SUCH AS THE 1S THAT DEVELOP, 883 00:32:59,963 --> 00:33:01,231 CLEAN LITERALLY HOMOGENOUS MODEL 884 00:33:01,231 --> 00:33:03,300 THAT WAS CLEARLY DRIVEN BY THE 885 00:33:03,300 --> 00:33:05,569 TARGET OF THEIR DRUG WOULD 886 00:33:05,569 --> 00:33:07,838 PROBABLY BE THE BEST MODEL FOR 887 00:33:07,838 --> 00:33:10,140 LOOKING AT PROOF OF PRINCIPLE 888 00:33:10,140 --> 00:33:13,777 THAT THIS PATHWAY CAN BE 889 00:33:13,777 --> 00:33:15,378 SUCCESSFULLY INTERDICTED TO 890 00:33:15,378 --> 00:33:19,115 REALLY DEVELOP -- TO DELIVER 891 00:33:19,115 --> 00:33:19,516 CLINICAL EFFICACY. 892 00:33:19,516 --> 00:33:21,952 SO WE UNDERTOOK A STUDY AT THE 893 00:33:21,952 --> 00:33:24,187 NCI IN 2017 OF THE FIRST AGENT 894 00:33:24,187 --> 00:33:26,356 IN THIS GROUP TO GET TO THE 895 00:33:26,356 --> 00:33:30,827 CLINIC WAS A DRUG CALLED PD2085. 896 00:33:30,827 --> 00:33:32,429 IT WAS A SINGLE SET STUDY AND 897 00:33:32,429 --> 00:33:33,597 VERY SOON AFTER THE FIRST 898 00:33:33,597 --> 00:33:34,564 PATIENT WAS TREATED WE KNEW THIS 899 00:33:34,564 --> 00:33:36,066 WAS ANYTHING TO BE A VERY 900 00:33:36,066 --> 00:33:37,901 EFFECTIVE CLASS OF DRUGS. 901 00:33:37,901 --> 00:33:39,402 WE SAW A CLEAR REDUCTION IN THE 902 00:33:39,402 --> 00:33:45,542 SIZE OF THE RENAL TUMORS. 903 00:33:45,542 --> 00:33:50,180 DR. CHU AND DR. WILEY, THEY HAD 904 00:33:50,180 --> 00:33:51,815 THE FIRST EVALUATION OF THE 905 00:33:51,815 --> 00:33:52,515 PATIENTOT DRUG, CAME RUNNING 906 00:33:52,515 --> 00:33:54,150 DOWN TO THE CLINIC AND SAID YOU 907 00:33:54,150 --> 00:33:56,553 HAVE TO SEE THESE TUMORS AND THE 908 00:33:56,553 --> 00:33:57,821 SIZE AND THE PROGRESS. 909 00:33:57,821 --> 00:34:00,257 WE TRIED TO FOR YEARS TO DO ALL 910 00:34:00,257 --> 00:34:04,261 KINDS OF THING BUSINESS SYSTEMIC 911 00:34:04,261 --> 00:34:05,195 THERAPY, NOTHING AFFECTED THESE 912 00:34:05,195 --> 00:34:07,631 TUMORS SO FAR BUT THIS DRUG HAS. 913 00:34:07,631 --> 00:34:09,165 WE UNFORTUNATELY WERE ABLE TO 914 00:34:09,165 --> 00:34:11,401 TREAT ONLY 4 PATIENTS ON THIS 915 00:34:11,401 --> 00:34:12,903 STUDY AND THIS WAS LARGELY 916 00:34:12,903 --> 00:34:14,504 BECAUSE EVEN THOUGH THIS DRUG 917 00:34:14,504 --> 00:34:17,440 WAS EFFECTIVE, THERE WAS SOME 918 00:34:17,440 --> 00:34:19,476 FORMULATION ISSUES, THERE WERE 919 00:34:19,476 --> 00:34:21,845 PK VARIABLES BETWEEN PATIENTS 920 00:34:21,845 --> 00:34:24,381 AND SO WE ACTUALLY DISCONTINUED 921 00:34:24,381 --> 00:34:25,682 THE STUDY IN FAVOR OF A SECOND 922 00:34:25,682 --> 00:34:28,985 STUDY WITH A DRUG THAT TRIED TO 923 00:34:28,985 --> 00:34:30,720 OVERCOME THESE ISSUES, A DRUG 924 00:34:30,720 --> 00:34:34,724 THAT WAS CALLED PD2977 OR 925 00:34:34,724 --> 00:34:38,161 MK6482, NOW KNOWN AS 926 00:34:38,161 --> 00:34:38,862 BELZIDIFIDE. 927 00:34:38,862 --> 00:34:41,364 THIS STUDY WAS AN INTERNATIONAL 928 00:34:41,364 --> 00:34:44,000 MULTICENTER STUDY THAT WE HELPED 929 00:34:44,000 --> 00:34:48,939 LEAD THAT LOOKED AT BELZIDIFIAN 930 00:34:48,939 --> 00:34:50,974 THAT LOOKED AT TAKING IT ONCE A 931 00:34:50,974 --> 00:34:53,376 DAY IN PEASHTS WHO HAD VHL 932 00:34:53,376 --> 00:34:54,911 DISEASE, DID NOT RECEIVE PRIOR 933 00:34:54,911 --> 00:34:57,280 TREATMENT AND DID NOT HAVE MATTA 934 00:34:57,280 --> 00:34:58,581 STATIC DISEASE, SO WE WERE 935 00:34:58,581 --> 00:35:00,216 TREATING PATIENTS WITH LOCALIZED 936 00:35:00,216 --> 00:35:01,084 DISEASE, THE PRIMARY END POINT 937 00:35:01,084 --> 00:35:03,753 WAS TO LOOK AT RESPONSE IN VHL 938 00:35:03,753 --> 00:35:05,155 ASSOCIATED KIDNEY TUMORS BUT 939 00:35:05,155 --> 00:35:06,589 ALSO LOOKING AT TUMORS IN ALL 940 00:35:06,589 --> 00:35:11,494 THE OTHER ORGANS AS WELL AS 941 00:35:11,494 --> 00:35:12,996 STARTING THERAPY. 942 00:35:12,996 --> 00:35:15,298 THE DATA WAS PUBLISHED IN 2021, 943 00:35:15,298 --> 00:35:16,933 I'M SURE YOU RECOGNIZE 1 PERSON 944 00:35:16,933 --> 00:35:19,336 IN THIS COLLAGE OF PHOTOGRAPHS, 945 00:35:19,336 --> 00:35:21,304 THE DOCTOR AT VANDERBILT AT THE 946 00:35:21,304 --> 00:35:22,806 TIME AND PRESENTED WITH THE 947 00:35:22,806 --> 00:35:23,273 STUDY. 948 00:35:23,273 --> 00:35:26,476 DATA WERE FURTHER UPDATED AND 949 00:35:26,476 --> 00:35:28,011 ACL LAST YEAR, SO I WILL PROVIDE 950 00:35:28,011 --> 00:35:32,816 A SUMMARY OF THE DATA FROM A 951 00:35:32,816 --> 00:35:35,485 YEAR OR SO AGO OF THE 61 952 00:35:35,485 --> 00:35:36,886 PATIENTS TREATED, AT THE TIME OF 953 00:35:36,886 --> 00:35:38,822 THIS ANALYSIS WHICH WAS 954 00:35:38,822 --> 00:35:41,658 APPROXIMATELY A MEDIAN FOLLOW UP 955 00:35:41,658 --> 00:35:43,326 OF 4 YEARS, 36 REMAINED ON 956 00:35:43,326 --> 00:35:43,526 STUDY. 957 00:35:43,526 --> 00:35:44,861 PATIENTS WENT OFF STUDY FOR A 958 00:35:44,861 --> 00:35:47,564 VARIETY OF REASONS, MOST OF THEM 959 00:35:47,564 --> 00:35:51,134 BECAUSE THEY CHOSE TO GO OFF 960 00:35:51,134 --> 00:35:52,802 STUDY OR BECAUSE AFTER FDA 961 00:35:52,802 --> 00:35:54,170 APPROVED THIS DRUG, THEY COULD 962 00:35:54,170 --> 00:35:56,206 GET THIS DRUG LOCALLY AND THEY 963 00:35:56,206 --> 00:35:58,608 SAW NO REASON TO REMAIN ON THE 964 00:35:58,608 --> 00:35:58,808 STUDY. 965 00:35:58,808 --> 00:36:01,211 BUT THE PATIENTS THAT PROGRESSED 966 00:36:01,211 --> 00:36:03,747 IN THE STUDY, WENT OFF FOR THOSE 967 00:36:03,747 --> 00:36:04,114 REASONS. 968 00:36:04,114 --> 00:36:08,518 THE HIGHLY EFFECTIVE DRUG, 969 00:36:08,518 --> 00:36:10,120 ALMOST 90 + PATIENTS HAD SOME 970 00:36:10,120 --> 00:36:11,888 LEVEL OF TUMOR REGRESSION, WITH 971 00:36:11,888 --> 00:36:13,289 AFTER OVERALL RESPONSE RATE OF 972 00:36:13,289 --> 00:36:18,628 67% AND A COMPLETE RESPONSE RATE 973 00:36:18,628 --> 00:36:19,295 OF AROUND 11%. 974 00:36:19,295 --> 00:36:21,131 WHAT KIND OF RESPONSES ARE WE 975 00:36:21,131 --> 00:36:22,132 SEEING IN THESE PATIENTS IN I 976 00:36:22,132 --> 00:36:24,000 WILL SHOW YOU EXAMPLES OF TUMOR 977 00:36:24,000 --> 00:36:25,502 REGRESSIONS IN VARIOUS ORGANS. 978 00:36:25,502 --> 00:36:27,270 THIS FIRST CASE IS A 45 YEAR-OLD 979 00:36:27,270 --> 00:36:31,107 WOMAN WHO CAME TO US HAVING 980 00:36:31,107 --> 00:36:34,310 PREVIOUSLY BEEN DIAGNOSE TD 981 00:36:34,310 --> 00:36:36,079 EARLIER WITH VHL. 982 00:36:36,079 --> 00:36:42,018 HAD UNDER GONE A PARTIAL NEFF 983 00:36:42,018 --> 00:36:44,354 RECTIFIED ME, AND SOME CNS 984 00:36:44,354 --> 00:36:46,156 BLASTIO ANG I DON'T MEANAS, SHE 985 00:36:46,156 --> 00:36:49,092 WAS VERY MUCH DESIRING MORE 986 00:36:49,092 --> 00:36:51,728 SURGERY IF SHE COULD AND WE HAD 987 00:36:51,728 --> 00:36:53,463 AN OPENING AND WE PUT HER ON THE 988 00:36:53,463 --> 00:36:53,696 STUDY. 989 00:36:53,696 --> 00:36:56,099 ON THE LEFT YOU SEE THE PATIENT 990 00:36:56,099 --> 00:36:58,435 HAS BILATERAL FAIRLY LARGE 991 00:36:58,435 --> 00:36:59,169 TUMORS, APPROACHING SURGICAL 992 00:36:59,169 --> 00:37:03,173 SIZE, SO SHE WOULD HAVE GONE TO 993 00:37:03,173 --> 00:37:04,374 SURGERY NOT SOON AFTER BUT THE 994 00:37:04,374 --> 00:37:06,876 DRUG WAS REALLY ABLE TO INDUCE 995 00:37:06,876 --> 00:37:07,944 REGRESSION OF THESE TUMORS. 996 00:37:07,944 --> 00:37:09,746 YOU CAN SEE THE RIGHT SIDE OF 997 00:37:09,746 --> 00:37:11,381 TUMORS IS BADLY VISIBLE AND YOU 998 00:37:11,381 --> 00:37:17,353 CAN SEE A BIT OF THE LEFT SIDE 999 00:37:17,353 --> 00:37:18,555 OF THE TUMORS. 1000 00:37:18,555 --> 00:37:19,856 WE KNOW THIS DRUG CAUSES 1001 00:37:19,856 --> 00:37:21,357 REGRESSION OF RENAL TUMORS, I 1002 00:37:21,357 --> 00:37:23,593 ALSO TOLD YOU THAT SOME OF THE 1003 00:37:23,593 --> 00:37:25,462 VEG F TARGETED AGENTS WERE 1004 00:37:25,462 --> 00:37:26,596 EFFECTIVE IN KIDNEY CANCER AND 1005 00:37:26,596 --> 00:37:28,031 NOT EFFECTIVE IN OTHER AGENTS SO 1006 00:37:28,031 --> 00:37:29,365 WE WERE VERY, VERY INTERESTED IN 1007 00:37:29,365 --> 00:37:30,733 SEEING WHAT HAPPENS IN OTHER 1008 00:37:30,733 --> 00:37:33,236 TUMORS HERE AND WE SAW THAT 1009 00:37:33,236 --> 00:37:35,305 THERE WAS ACTIVITY ACROSS THE 1010 00:37:35,305 --> 00:37:39,442 SPECTRUM OF VHL MANIFESTATIONS. 1011 00:37:39,442 --> 00:37:40,243 PANCREATIC NEUROENDOCRINE 1012 00:37:40,243 --> 00:37:41,277 TUMORS, ALTHOUGH LIMITED IN 1013 00:37:41,277 --> 00:37:42,612 NUMBER, ONLY 22 OF THESE PATE 1014 00:37:42,612 --> 00:37:45,615 WHO IS HAD KIDNEY TUMORS ALSO 1015 00:37:45,615 --> 00:37:46,950 HAD A PANCREATIC ENDOCRINE 1016 00:37:46,950 --> 00:37:47,150 TUMOR. 1017 00:37:47,150 --> 00:37:52,188 POST OF THEM HAD A RESPONSE TO 1018 00:37:52,188 --> 00:37:55,558 THIS DRUG AAS DID PATIENTS WITH 1019 00:37:55,558 --> 00:37:57,260 THE CNS HEME ANGIO BLASTOMAS. 1020 00:37:57,260 --> 00:38:00,330 THIS IS A CASE I WILL SHOW YOU 1021 00:38:00,330 --> 00:38:03,600 OF A 30 YEAR-OLD MAN DIAGNOSED 1022 00:38:03,600 --> 00:38:04,567 WITH VHL AT 12. 1023 00:38:04,567 --> 00:38:10,640 BETWEEN 12 AND 30 HE HAD 1024 00:38:10,640 --> 00:38:13,076 MULTIPLE SURGERIES, HE HAD AN A, 1025 00:38:13,076 --> 00:38:15,278 QUIRED PHENOTYPE WITH MULTIPLE 1026 00:38:15,278 --> 00:38:15,979 SURGERIES LEAVING HIM WITH 1027 00:38:15,979 --> 00:38:24,721 DEFINITES FROM THE SURGERY BUT 1028 00:38:24,721 --> 00:38:26,689 SOME OF THE PREVIOUS TUMORS THAT 1029 00:38:26,689 --> 00:38:27,957 HADN'T BEEN REMOVED WERE 1030 00:38:27,957 --> 00:38:28,625 STARTING TO GO. 1031 00:38:28,625 --> 00:38:31,060 WE ALSO HAD OTHER MANIFESTATIONS 1032 00:38:31,060 --> 00:38:32,795 OF KIDNEY CANCER OF RCC. 1033 00:38:32,795 --> 00:38:36,366 THIS IS THE SPINAL HEME ANCHLIO 1034 00:38:36,366 --> 00:38:39,969 BLASTOMA THAT I SHOW YOU ON THE 1035 00:38:39,969 --> 00:38:44,207 RIGHT, AND THE LEFT HEME ANGIO 1036 00:38:44,207 --> 00:38:47,510 BLASTOMA, AND THE STAGE AFTER 1037 00:38:47,510 --> 00:38:50,180 THERAPY, AS YOU KNOW, 1038 00:38:50,180 --> 00:38:50,847 NEUROSURGEONS WERE CLOSELY 1039 00:38:50,847 --> 00:38:55,752 INVOLVED WITH THESE STUDIES AND 1040 00:38:55,752 --> 00:38:58,254 ALL THE DECISIONS MADE ON THESE 1041 00:38:58,254 --> 00:39:00,123 THERAPIES, WHO TO TAKE TO 1042 00:39:00,123 --> 00:39:03,293 SURGERY, WHO TO TAKE FOR THE 1043 00:39:03,293 --> 00:39:03,660 STUDIES. 1044 00:39:03,660 --> 00:39:05,495 THESE WERE PUBLISHED EARLIER IN 1045 00:39:05,495 --> 00:39:06,162 2024. 1046 00:39:06,162 --> 00:39:07,230 I TOLD YOU ANN ECTOMYOSIN 1047 00:39:07,230 --> 00:39:09,699 DETOMORROW NATION ABOUT A 1048 00:39:09,699 --> 00:39:12,235 PATIENT WITH RETINAL HEME ANGIO 1049 00:39:12,235 --> 00:39:13,736 BLASTOMAS WHO EXPERIENCED TUMOR 1050 00:39:13,736 --> 00:39:16,206 REGRESSION, WE HAD A TOTAL OF 12 1051 00:39:16,206 --> 00:39:18,241 PATIENTS WITH 16 AFFECTED ON THE 1052 00:39:18,241 --> 00:39:19,475 STUDY, AND THEN CLOSELY LOOKING 1053 00:39:19,475 --> 00:39:23,213 AT THESE PATIENTS WITH OUR 1054 00:39:23,213 --> 00:39:24,681 OPHTHALMOLOGIST, WE WERE ABLE TO 1055 00:39:24,681 --> 00:39:27,083 FIND THAT IN EVERY SINGLE 1056 00:39:27,083 --> 00:39:28,451 PATIENT, WE EITHER ARRESTED THE 1057 00:39:28,451 --> 00:39:31,354 GROWTH OF THE TUMORS OR INDUCED 1058 00:39:31,354 --> 00:39:31,888 REGRESSION. 1059 00:39:31,888 --> 00:39:33,990 AND THESE DATA BEEN DETAIL 1060 00:39:33,990 --> 00:39:35,058 INDEED A RECENT PUBLICATION FROM 1061 00:39:35,058 --> 00:39:35,959 OUR GROUP. 1062 00:39:35,959 --> 00:39:37,360 I SPENT A LITTLE TIME TALKING 1063 00:39:37,360 --> 00:39:38,661 ABOUT THE IMPORTANCE OF SIDE 1064 00:39:38,661 --> 00:39:38,895 EFFECTS. 1065 00:39:38,895 --> 00:39:40,663 THIS IS AS I SAID A WELL 1066 00:39:40,663 --> 00:39:41,798 TOLERATED DRUG EMPLOY THE MAJOR 1067 00:39:41,798 --> 00:39:43,900 SIDE EFFECT OF THIS DRUG IS 1068 00:39:43,900 --> 00:39:46,936 ANEMIA WHICH IS AN ON-TARGET 1069 00:39:46,936 --> 00:39:50,006 SIDE EFFECT EMPLOY THE POINT IN 1070 00:39:50,006 --> 00:39:50,640 THIS TRANSCRIPTIONALLY REGULATED 1071 00:39:50,640 --> 00:39:52,575 SO IF YOU ADD IT SHOULD GO DOWN 1072 00:39:52,575 --> 00:39:54,777 AND THEN IT TELLS US THE DRUG IS 1073 00:39:54,777 --> 00:39:56,379 HITTING THE TARGET AT LEAST TO 1074 00:39:56,379 --> 00:39:57,981 SOME EXTENT. 1075 00:39:57,981 --> 00:39:59,949 THIS IS SO FAIRLY EASILY MANAGED 1076 00:39:59,949 --> 00:40:01,251 SIDE EFFECT ALTHOUGH IN A FEW 1077 00:40:01,251 --> 00:40:03,419 PATIENTS IT CAN BE CHALLENGING 1078 00:40:03,419 --> 00:40:04,621 TO MANAGE. 1079 00:40:04,621 --> 00:40:05,321 FATIGUE, HEADACHES, DIZZINESS 1080 00:40:05,321 --> 00:40:07,490 AND A HOST OF OTHER SYMPTOMS 1081 00:40:07,490 --> 00:40:09,459 WERE SEEN IN A PROPORTION OF 1082 00:40:09,459 --> 00:40:10,159 PATIENTS TREATED. 1083 00:40:10,159 --> 00:40:12,061 I WILL FOCUS ON 2 SIDE EFFECTS 1084 00:40:12,061 --> 00:40:13,997 WHICH I THINK ARE THE MOST 1085 00:40:13,997 --> 00:40:15,331 CLINICALLY RELEVANT IN THESE 1086 00:40:15,331 --> 00:40:17,133 PATIENTS, ANEMIA AS I SAID, ON 1087 00:40:17,133 --> 00:40:17,767 TARGET SIDE CENTER FOR 1088 00:40:17,767 --> 00:40:20,169 EXCELLENCE ON AGINGS SEEN IN 90% 1089 00:40:20,169 --> 00:40:22,605 BUT LOW GRADE IN MOST PATIENTS. 1090 00:40:22,605 --> 00:40:24,574 MOST PATIENTS ARE MANAGED WITH 1091 00:40:24,574 --> 00:40:25,341 DOSE REDUCTIONS AND TRANSFUSIONS 1092 00:40:25,341 --> 00:40:26,709 IN A FEW PATIENTS. 1093 00:40:26,709 --> 00:40:28,444 WE HAVE SUCCESSFULLY USED ESAs 1094 00:40:28,444 --> 00:40:31,981 IN THESE PATIENTS TO RESCUE 1095 00:40:31,981 --> 00:40:32,782 THEIR ANEMIA. 1096 00:40:32,782 --> 00:40:35,118 A MORE CONCERNING SIDE EFFECT IS 1097 00:40:35,118 --> 00:40:36,519 HYPOXIA, A MECHANISM FOR THIS 1098 00:40:36,519 --> 00:40:38,187 REMAINS UNCLEAR ALTHOUGH WE HAVE 1099 00:40:38,187 --> 00:40:39,289 THEORIES. 1100 00:40:39,289 --> 00:40:42,392 ON OUR STUDY, ONLY 1 PATIENT HAD 1101 00:40:42,392 --> 00:40:45,395 HYPOXIA, OUT OF THE 61, 1102 00:40:45,395 --> 00:40:47,697 ALTHOUGH, IN A PARALLEL STUDY, 1103 00:40:47,697 --> 00:40:55,872 PHASE 2 STUDY ACTUALLY OF 1104 00:40:55,872 --> 00:40:57,507 BLEZIDIFAN, THE PATIENTS' 1105 00:40:57,507 --> 00:40:58,875 INCIDENCE WAS MUCH HIGHER. 1106 00:40:58,875 --> 00:41:02,545 THERE ARE SERL REASONS FOR THIS, 1107 00:41:02,545 --> 00:41:04,547 1 PATIENT MIGHT BE THE PATIENTS 1108 00:41:04,547 --> 00:41:07,850 ARE YOUNGER, AND WITH THE 1109 00:41:07,850 --> 00:41:08,785 METASTATIC OCCURRENCES, THE 1110 00:41:08,785 --> 00:41:10,853 PATIENTS WERE OLDER AND THEY MAY 1111 00:41:10,853 --> 00:41:12,155 HAVE HAD MORE CO-MORBIDITIES 1112 00:41:12,155 --> 00:41:13,389 THAT MAY HAVE CONTRIBUTED TO 1113 00:41:13,389 --> 00:41:13,656 THIS. 1114 00:41:13,656 --> 00:41:16,259 THE WAY WE MANAGE THIS IS TO 1115 00:41:16,259 --> 00:41:19,462 RECOGNIZE IT AS AN EVENT. 1116 00:41:19,462 --> 00:41:21,064 USE CERTAINTIED MEASURES, DOSING 1117 00:41:21,064 --> 00:41:23,733 AND DISRUPTION IF NEEDED. 1118 00:41:23,733 --> 00:41:26,736 SO NOW WE HAD THE DATA AND NEXT 1119 00:41:26,736 --> 00:41:29,072 QUESTION WE HAD TO ASK OURSELVES 1120 00:41:29,072 --> 00:41:30,940 WAS CAN WE USE THIS DATA TO 1121 00:41:30,940 --> 00:41:32,241 BENEFIT PATIENTS AT LARGE WITH 1122 00:41:32,241 --> 00:41:34,010 VHL AND IN OTHER WORDS IS THERE 1123 00:41:34,010 --> 00:41:36,779 A PATH FOR REGULATORY APPROVAL. 1124 00:41:36,779 --> 00:41:38,481 WE ALREADY KNOW, AND KNEW AT 1125 00:41:38,481 --> 00:41:40,116 THAT POINT THAT A RANDOMIZED 1126 00:41:40,116 --> 00:41:41,617 STUDY COULD BE DONE WITH THE 1127 00:41:41,617 --> 00:41:42,819 DISEASE, WITH DIFFICULT END 1128 00:41:42,819 --> 00:41:44,754 POINTS, WE COULDN'T USE THE 1129 00:41:44,754 --> 00:41:46,022 USUAL SURVIVAL END POINTS THAT 1 1130 00:41:46,022 --> 00:41:48,458 USES IN PATIENTS AND METASTATIC 1131 00:41:48,458 --> 00:41:48,691 CANCER. 1132 00:41:48,691 --> 00:41:52,795 SO THEN WE ASKED OURSELVES HOW 1133 00:41:52,795 --> 00:41:59,802 CAN WE UTILIZE STUDIES FROM A 1134 00:41:59,802 --> 00:42:01,637 NONRANDOMMIZED NONCONTROLLED 1135 00:42:01,637 --> 00:42:03,072 SINGLE ARM INTERVENTION? 1136 00:42:03,072 --> 00:42:05,241 THE FDA PREVIOUSLY PROVIDED 1137 00:42:05,241 --> 00:42:10,580 AROUND THAT TIME GUIDANCE THAT 1138 00:42:10,580 --> 00:42:12,148 SUGGESTED THAT IN THESE KINDS OF 1139 00:42:12,148 --> 00:42:13,983 CIRCUMSTANCES, NATURAL HISTORY 1140 00:42:13,983 --> 00:42:14,784 STUDIES, WELL CHARACTERIZED 1141 00:42:14,784 --> 00:42:19,422 NATURAL HISTORY STUDIES COULD BE 1142 00:42:19,422 --> 00:42:21,157 USED AS AN EXTERNAL OPERATOR TO 1143 00:42:21,157 --> 00:42:23,893 TRY TO DETERMINE THE BENEFIT OF 1144 00:42:23,893 --> 00:42:29,532 AN INTERVENTION IN THE STUDY OF 1145 00:42:29,532 --> 00:42:30,099 THIS KIND. 1146 00:42:30,099 --> 00:42:31,834 SINCE THE EARLY 80S ON A NATURAL 1147 00:42:31,834 --> 00:42:34,437 HISTORY STUDY OF VHL, THE 1148 00:42:34,437 --> 00:42:35,638 ONCOLOGY BRANCH HAD BEEN 1149 00:42:35,638 --> 00:42:37,940 COLLECTING DATA ON THE GROWTH 1150 00:42:37,940 --> 00:42:39,675 CHARACTERISTICS OF TUMORS IN 1151 00:42:39,675 --> 00:42:42,779 VHL, AND IN THIS PUBLICATION, 1152 00:42:42,779 --> 00:42:47,116 AND IN THE MAYBE NOT 5 OR 6 1153 00:42:47,116 --> 00:42:50,386 YEARS AGO, CAREFULLY 1154 00:42:50,386 --> 00:42:51,788 CHARACTERIZED THE GROWTH 1155 00:42:51,788 --> 00:42:52,989 CHARACTERISTICS OF VHL 1156 00:42:52,989 --> 00:42:54,724 ASSOCIATED RENAL TUMORS AND A 1157 00:42:54,724 --> 00:42:58,194 SIMILAR PATTERN ACTUALLY OBTAINS 1158 00:42:58,194 --> 00:43:00,062 FOR OTHER MEN FESTATIONS AS WELL 1159 00:43:00,062 --> 00:43:02,999 AND WHAT THEY WERE FINDING IS 1160 00:43:02,999 --> 00:43:04,033 THEY WERE STUDYING 400 FAMILIES 1161 00:43:04,033 --> 00:43:09,038 OVER 30 YEARS WAS AN ABSENCE OF 1162 00:43:09,038 --> 00:43:09,439 INTERVENTION OF 1163 00:43:09,439 --> 00:43:11,140 INEXPECTATIONSONNABLE GROWTH OF 1164 00:43:11,140 --> 00:43:12,275 RENAL TUMORS RENAL AND 1165 00:43:12,275 --> 00:43:13,509 OTHERWISE. 1166 00:43:13,509 --> 00:43:18,281 AND THE AVERAGE GROWTH WAS 1167 00:43:18,281 --> 00:43:19,215 AROUND 3.5-MILLIMETERS IN THE 1168 00:43:19,215 --> 00:43:19,482 STUDY. 1169 00:43:19,482 --> 00:43:20,550 SO WE LOOKED TO SEE WHAT 1170 00:43:20,550 --> 00:43:22,752 HAPPENED IN OUR STUDY BECAUSE WE 1171 00:43:22,752 --> 00:43:24,153 HAD CAREFULLY COLLECTED DATA 1172 00:43:24,153 --> 00:43:28,491 FROM ALL ENTRANCE AS PART OF THE 1173 00:43:28,491 --> 00:43:30,359 STUDY AND POINT, WE KNEW WHAT 1174 00:43:30,359 --> 00:43:33,663 THE GROWTH TRAJECTORY WAS BEFORE 1175 00:43:33,663 --> 00:43:34,363 THEY STARTED TREATMENT. 1176 00:43:34,363 --> 00:43:35,598 AND IT SORT OF PARALLELLED WHAT 1177 00:43:35,598 --> 00:43:36,933 WE SAW IN THE NATURAL HISTORY 1178 00:43:36,933 --> 00:43:40,002 STUDY. 1179 00:43:40,002 --> 00:43:42,305 ALL THESE TUMORS GREW BUT A 1180 00:43:42,305 --> 00:43:44,440 SIGNIFICANT CHANGE IN THE 1181 00:43:44,440 --> 00:43:54,050 TRAJECTORY WAS SEWN ONCE THE 1182 00:43:54,050 --> 00:43:54,917 INTERVENTION BELZUTIFAN WAS 1183 00:43:54,917 --> 00:43:55,151 APPLIED. 1184 00:43:55,151 --> 00:43:57,820 WE WANTED TO SEE IF IF THERE WAS 1185 00:43:57,820 --> 00:43:58,888 A MORE QUANTIFIABLE BENEFIT TO 1186 00:43:58,888 --> 00:43:59,455 THIS DRUG. 1187 00:43:59,455 --> 00:44:01,090 ONE WAY TO WAS TO SEE IF THE 1188 00:44:01,090 --> 00:44:03,459 NUMBER OF THE ISHT VENTIONS, 1189 00:44:03,459 --> 00:44:04,627 SURGICAL INTERVENTIONS CHANGE 1190 00:44:04,627 --> 00:44:05,328 WIDE THE DRUG. 1191 00:44:05,328 --> 00:44:08,364 AND INDEED WE FOUND THERE WAS A 1192 00:44:08,364 --> 00:44:10,333 SIGNIFICANT DROP IN THE SURGICAL 1193 00:44:10,333 --> 00:44:11,167 INTERVENTIONS, 1 PATIENT SPENT 1194 00:44:11,167 --> 00:44:13,903 ON THE STUDY, USING THEIR OWN 1195 00:44:13,903 --> 00:44:15,538 PREVIOUS HISTORY AS AN INTERNAL 1196 00:44:15,538 --> 00:44:15,805 CONTROL. 1197 00:44:15,805 --> 00:44:19,242 SO BASED ON THESE DATA, THE FDA 1198 00:44:19,242 --> 00:44:26,048 APPROVED THE USE OF BELZUTIFAN, 1199 00:44:26,048 --> 00:44:28,150 FOR THE USE OF COMBATING TUMORS. 1200 00:44:28,150 --> 00:44:30,119 I WANT TO EMPHASIZE, THAT IT IS 1201 00:44:30,119 --> 00:44:33,389 AND CAN BE USED AS AN ADJUNCT, 1202 00:44:33,389 --> 00:44:34,957 NOT AS A SUBSTITUTE FOR SURGERY 1203 00:44:34,957 --> 00:44:36,526 BECAUSE I THINK THERE'S STILL A 1204 00:44:36,526 --> 00:44:40,663 LOT WE DON'T UNDERSTAND ABOUT 1205 00:44:40,663 --> 00:44:42,298 BELZUTIFAN, AND WE DON'T KNOW IF 1206 00:44:42,298 --> 00:44:44,834 -- I'M NOT CONFIDENT WE CAN 1207 00:44:44,834 --> 00:44:45,801 COMPLETELY DO AWAY WITH SURGERY 1208 00:44:45,801 --> 00:44:48,571 BUT I THINK WE CAN SIGNIFICANTLY 1209 00:44:48,571 --> 00:44:49,972 IN WELL SELECTED PATIENTS REDUCE 1210 00:44:49,972 --> 00:44:51,007 THE NEED FOR SURGERY. 1211 00:44:51,007 --> 00:44:54,644 I WILL SKIP A COUPLE SLIDES AND 1212 00:44:54,644 --> 00:44:57,480 POINT OUT THAT FOLLOWING THIS 1213 00:44:57,480 --> 00:44:59,782 STUDY, THIS DRUG HAS ALSO BEEN 1214 00:44:59,782 --> 00:45:01,617 APPROVED BASED ON THIS 1215 00:45:01,617 --> 00:45:02,184 RANDOMIZED PHASE 3 STUDY FOR 1216 00:45:02,184 --> 00:45:04,654 PATIENT WHO IS ARE PREVIOUSLY 1217 00:45:04,654 --> 00:45:06,389 PROGRESSED AND STANDARD 1218 00:45:06,389 --> 00:45:07,523 TREATMENT OPTIONS WITH 1219 00:45:07,523 --> 00:45:08,791 METASTATIC CLEAR CELL KIDNEY 1220 00:45:08,791 --> 00:45:09,158 CANCER. 1221 00:45:09,158 --> 00:45:10,793 THIS IS A LARGE PHASE 3 STUDY 1222 00:45:10,793 --> 00:45:12,762 THAT WE DIDN'T PARTICIPATE IN 1223 00:45:12,762 --> 00:45:18,801 WHERE, THE INVESTIGATOR SHOWED 1224 00:45:18,801 --> 00:45:29,278 THAT COMPARED TO EVEROLIMUS, 1225 00:45:29,712 --> 00:45:34,517 BETZUTIFAN WAS IMPROVED MUCH 1226 00:45:34,517 --> 00:45:35,518 MORE. 1227 00:45:35,518 --> 00:45:39,322 FDA APPROVED IT FOR USING IT IN 1228 00:45:39,322 --> 00:45:39,555 PEASHS. 1229 00:45:39,555 --> 00:45:44,160 I WANT TO SUMMARIZE THIS PART F 1230 00:45:44,160 --> 00:45:47,463 THE TALK BY WORKING ON THE VHL, 1231 00:45:47,463 --> 00:45:51,233 WE WERE ABLE TO DEVISE TARGETED 1232 00:45:51,233 --> 00:45:53,002 EFFECTIVE STRATEGIES THAT WERE 1233 00:45:53,002 --> 00:45:55,104 SPORADIC AND INHERITED FORMS OF 1234 00:45:55,104 --> 00:45:55,771 CLEAR CELL RCC. 1235 00:45:55,771 --> 00:45:59,108 I WILL SPEND THE NEXT FEW MINUES 1236 00:45:59,108 --> 00:46:05,481 TALKING ABOUT 1 FORM OF KIDNEY 1237 00:46:05,481 --> 00:46:06,382 CANCER, HLRCC. 1238 00:46:06,382 --> 00:46:11,554 WE'VE DONE SINCE THE 1990S THAT 1239 00:46:11,554 --> 00:46:14,857 THERE IS A GROUP OF TUMORS WHICH 1240 00:46:14,857 --> 00:46:17,426 HAVE PATHWAY FEATURES AND 1 1241 00:46:17,426 --> 00:46:18,995 HISTOLOGIC EVALUATION AND OVER 1242 00:46:18,995 --> 00:46:21,063 THE YEARS AS A SAD PATHOLOGIST 1243 00:46:21,063 --> 00:46:23,633 TRIED TO CLASSIFY IT INTO TYPE 1 1244 00:46:23,633 --> 00:46:26,202 OR TYPE 2 AND NONTYPE 1. 1245 00:46:26,202 --> 00:46:28,838 DR. MARINO IN THE AUDIENCE TODAY 1246 00:46:28,838 --> 00:46:31,440 WAS INSTRUMENTAL IN HELPING NOT 1247 00:46:31,440 --> 00:46:35,344 ONLY RECOGNIZE MANY OF THESE 1248 00:46:35,344 --> 00:46:38,547 ENTITIES THAT ALSO POINTING 1249 00:46:38,547 --> 00:46:38,981 THERE'S SIGNIFICANT 1250 00:46:38,981 --> 00:46:44,687 HETEROGENEITY WITHIN THE TUMORS 1251 00:46:44,687 --> 00:46:55,197 WE CALL PAPILLARY, WITHIN THE 1252 00:46:56,866 --> 00:46:59,602 PAPILLARY GROUP. 1253 00:46:59,602 --> 00:47:02,405 THE HETEROGENEITY WAS MADE EVEN 1254 00:47:02,405 --> 00:47:04,006 MORE APPARENT AND CONFIRMED WHEN 1255 00:47:04,006 --> 00:47:07,677 WE DID A BROAD BASED MOLECULAR 1256 00:47:07,677 --> 00:47:10,613 ANALYSIS UNDER THE AUSPICES OF 1257 00:47:10,613 --> 00:47:12,214 STGA, WHICH SHOWED AT A IN 1258 00:47:12,214 --> 00:47:14,717 LECULAR LEVEL AT LEAST 4 1259 00:47:14,717 --> 00:47:16,052 DISTINCT FORMS OF PAPILLARY 1260 00:47:16,052 --> 00:47:18,387 TUMORS, I THINK THE STORY'S MORE 1261 00:47:18,387 --> 00:47:19,755 COMPLICATED BUT WE WERE ABLE TO 1262 00:47:19,755 --> 00:47:20,823 SHOW UNDER STUDY THAT THERE WERE 1263 00:47:20,823 --> 00:47:22,024 AT LEAST MORE THAN 2. 1264 00:47:22,024 --> 00:47:28,164 I WILL FOCUS TODAY ON HLRCC, 1265 00:47:28,164 --> 00:47:29,965 FAMILIARIAL SYNDROME, IT'S A 1266 00:47:29,965 --> 00:47:32,568 VERY AGGRESSIVE OF KIDNEY CANCER 1267 00:47:32,568 --> 00:47:34,236 WITH PAPILLARY FEATURES. 1268 00:47:34,236 --> 00:47:37,006 PATIENTS ALSO DEVELOP SKIN AND 1269 00:47:37,006 --> 00:47:39,275 MYELOMAS AS PART OF THE 1270 00:47:39,275 --> 00:47:39,709 MANIFESTATION. 1271 00:47:39,709 --> 00:47:40,976 UNTIL RECENTLY AGAIN THERE WERE 1272 00:47:40,976 --> 00:47:43,846 NO EFFECTIVE TREATMENT OPTIONS 1273 00:47:43,846 --> 00:47:44,513 FOR THESE PATIENTS. 1274 00:47:44,513 --> 00:47:45,781 TREATMENT OPTIONS THAT WORK WELL 1275 00:47:45,781 --> 00:47:49,118 IN CLEAR CELL KIDNEY CANCER WERE 1276 00:47:49,118 --> 00:47:50,186 MODEST USE IN THESE PATIENTS. 1277 00:47:50,186 --> 00:47:52,388 THEY DID WORK IN SOME PATIENTS 1278 00:47:52,388 --> 00:47:57,526 BUT THE RESPONSES WERE FEW. 1279 00:47:57,526 --> 00:47:58,861 SO THE FIRST QUESTION WE ASKED 1280 00:47:58,861 --> 00:48:01,597 OURSELVES IS WHAT CAUSED THIS 1281 00:48:01,597 --> 00:48:01,831 CANCER? 1282 00:48:01,831 --> 00:48:03,332 THAL INSTANCE IT IS GERM LINE 1283 00:48:03,332 --> 00:48:06,502 ALTERATION AND A KREBS CYCLE 1284 00:48:06,502 --> 00:48:07,503 DESIGN. 1285 00:48:07,503 --> 00:48:08,904 THE NEXT QUESTION OF COURSE, 1286 00:48:08,904 --> 00:48:12,575 LOGICAL QUESTION TO ASK WAS HOW 1287 00:48:12,575 --> 00:48:14,577 DOES LOSS OF KREBS CYCLE ENZYME 1288 00:48:14,577 --> 00:48:15,411 LEAD TO KIDNEY CANCER? 1289 00:48:15,411 --> 00:48:17,613 I DON'T THINK WE HAVE ALL THE 1290 00:48:17,613 --> 00:48:21,150 ANSWERS YET BUT I THINK WE HAVE 1291 00:48:21,150 --> 00:48:26,756 AN UNDERSTANDING SEVERAL 1292 00:48:26,756 --> 00:48:28,224 MECHANISMS THAT COULD GO BIG 1293 00:48:28,224 --> 00:48:32,495 CELL WHICH WAS DEFECTIVE HIDE 1294 00:48:32,495 --> 00:48:35,898 RATAISS--SYNTH AND MAKE A CELL 1295 00:48:35,898 --> 00:48:36,432 WITH KIDNEY CANCER. 1296 00:48:36,432 --> 00:48:45,207 ONE OF THE CONSEQUENCES OF 1297 00:48:45,207 --> 00:48:47,643 FUMARATE HYDRATASE, AND THAT HAS 1298 00:48:47,643 --> 00:48:48,477 MULTIPLE CONSEQUENCES IN THE 1299 00:48:48,477 --> 00:48:50,012 CELL. 1300 00:48:50,012 --> 00:48:52,281 ONE OF THESE IS -- SEE THOSE 1301 00:48:52,281 --> 00:48:53,949 POST TRANSLATION MODIIVESS AND 1302 00:48:53,949 --> 00:48:55,918 VARIETY OF INTRACELLULAR 1303 00:48:55,918 --> 00:48:57,753 PROTEINS PROCESSED ON SUCK 1304 00:48:57,753 --> 00:48:59,155 SINNATION, IT ENDS UP ACTIVATING 1305 00:48:59,155 --> 00:49:01,390 THE PROTEINS THAT ARE THUS 1306 00:49:01,390 --> 00:49:02,858 MODIFIED IN A STUDY THAT CAME 1307 00:49:02,858 --> 00:49:08,097 OUT OF THE ULB, AND NICHD LED BY 1308 00:49:08,097 --> 00:49:10,533 2 GROUPS, IT WAS SHOWN THAT 1 OF 1309 00:49:10,533 --> 00:49:16,839 THE PROTEINS THAT IS ENACTIVATED 1310 00:49:16,839 --> 00:49:21,010 BY SUCKINNATION, WHICH IS 1311 00:49:21,010 --> 00:49:23,045 CRITICAL IN MAINTAINING 1312 00:49:23,045 --> 00:49:25,781 MITOCHONDRIA AND DNA 1313 00:49:25,781 --> 00:49:28,684 REPRECATION. REP RE-- 1314 00:49:28,684 --> 00:49:29,451 REPLICATION. 1315 00:49:29,451 --> 00:49:30,786 ON THE PATIENTS WITH TUMORS 1316 00:49:30,786 --> 00:49:33,222 LOSS, THERE WAS LESS DNA AND THE 1317 00:49:33,222 --> 00:49:36,292 MITOCHONDRIA DNA THAT DID EXIST 1318 00:49:36,292 --> 00:49:37,893 WAS SEVERELY DAMAGED. 1319 00:49:37,893 --> 00:49:41,130 THESE CELLS CONSEQUENTLY HAVE NO 1320 00:49:41,130 --> 00:49:42,498 ABILITY TO PERFORM 1321 00:49:42,498 --> 00:49:45,768 MITOCHONDRIA ASPECTS OF 1322 00:49:45,768 --> 00:49:46,936 RESPIRATION, SO NO 1323 00:49:46,936 --> 00:49:49,305 PHOSPHORYLATION, FORCING THEM TO 1324 00:49:49,305 --> 00:49:52,541 RELY ON A MORE PRIMITIVE FORM OF 1325 00:49:52,541 --> 00:50:03,085 ENERGY GENERATION, GLYCOLYSIS, 1326 00:50:07,723 --> 00:50:12,628 EVEN UNDER AEROBIC PROCESS. 1327 00:50:12,628 --> 00:50:16,465 TO TRY AND TARGET THIS GROUP OF 1328 00:50:16,465 --> 00:50:22,905 TUMORS, WE CHOSE TO EVALUATE VEG 1329 00:50:22,905 --> 00:50:26,675 F TARGETED AGENT BETUZAM, AND IN 1330 00:50:26,675 --> 00:50:29,945 PATIENTS WITH METASTATIC HLRCC. 1331 00:50:29,945 --> 00:50:31,847 THE STUDY DESIGN WE UNDERTOOK 1332 00:50:31,847 --> 00:50:33,215 WAS FAIRLY SIMPLE. 1333 00:50:33,215 --> 00:50:35,718 WE HAD 2 COHORTS OF PATIENTS, 1334 00:50:35,718 --> 00:50:37,419 INDEPENDENT COHORTS, 1 WAS A 1335 00:50:37,419 --> 00:50:38,520 PATIENT OF METASTATIC HLRCC, AND 1336 00:50:38,520 --> 00:50:43,559 THERE WAS A GROUP OF SPORADIC 1337 00:50:43,559 --> 00:50:44,526 HLRCC TUMORS, SOME OF WHOM WE 1338 00:50:44,526 --> 00:50:46,629 KNEW AT THE TIME HAD SOME 1339 00:50:46,629 --> 00:50:48,631 OVERLAPPING CHARACTERISTICS WITH 1340 00:50:48,631 --> 00:50:49,398 PATIENTS WITH HLRCC. 1341 00:50:49,398 --> 00:50:51,133 AND WE HAVE A MUCH BEATER 1342 00:50:51,133 --> 00:50:52,201 UNDERSTANDING OF THESE TUMORS 1343 00:50:52,201 --> 00:50:53,869 NOW THAN WE DID AT THAT POINT. 1344 00:50:53,869 --> 00:50:59,541 PATIENTS RECEIVE A STANDARD DOSE 1345 00:50:59,541 --> 00:51:02,344 OF BETAZUMAB, PLUS ERLOTINIB, 1346 00:51:02,344 --> 00:51:03,646 AND SHOWING HERE, IT'S IMPORTANT 1347 00:51:03,646 --> 00:51:05,281 TO NOTE, THAT MANY OF THESE 1348 00:51:05,281 --> 00:51:06,582 PATIENTS HAD PREVIOUSLY RECEIVED 1349 00:51:06,582 --> 00:51:06,815 THERAPY. 1350 00:51:06,815 --> 00:51:09,818 THIS IS NOT A TREATMENT NAIVE 1351 00:51:09,818 --> 00:51:10,753 GROUP OF PATIENTS. 1352 00:51:10,753 --> 00:51:11,887 OVERALL RESPONSE RETINAL 1353 00:51:11,887 --> 00:51:14,957 LOCATION IN THE HLRCC GROUP WAS 1354 00:51:14,957 --> 00:51:16,959 72% FOR A DISEASE WHERE NOTHING 1355 00:51:16,959 --> 00:51:17,393 REALLY WORKED. 1356 00:51:17,393 --> 00:51:21,697 THIS WAS A VERY, VERY YOU KNOW 1357 00:51:21,697 --> 00:51:22,164 SATISFYING EXPERIENCE. 1358 00:51:22,164 --> 00:51:28,704 A LOT OF THESE PATIENTS DID 1359 00:51:28,704 --> 00:51:30,439 EXTREMELY WELL AND I WILL SHOW 1360 00:51:30,439 --> 00:51:31,974 MORE ABOUT THE DURATION OF THESE 1361 00:51:31,974 --> 00:51:33,275 AND RESPONSES IN A SECOND. 1362 00:51:33,275 --> 00:51:36,111 MOST OF THESE RESPONSES ARE 1363 00:51:36,111 --> 00:51:38,213 PARTIAL RESPONSES BUT NOT 1364 00:51:38,213 --> 00:51:41,550 SUSTAINED COMPLETE RESPONSES. 1365 00:51:41,550 --> 00:51:42,818 THE MEDIAN PFS WAS ALMOST 2 1366 00:51:42,818 --> 00:51:45,254 YEARS SO THE RESPONSES WERE VERY 1367 00:51:45,254 --> 00:51:45,554 DURABLE. 1368 00:51:45,554 --> 00:51:46,689 WE ALSO LOOKED TO SEE WHAT 1369 00:51:46,689 --> 00:51:49,458 HAPPENED IN THE SPORADIC 1370 00:51:49,458 --> 00:51:50,859 POPULATION, SURPRISINGLY THE 1371 00:51:50,859 --> 00:51:51,660 SPORADIC POPULATIONS, THERE WAS 1372 00:51:51,660 --> 00:51:55,531 NOT A LOT WITH THESE GROUP OF 1373 00:51:55,531 --> 00:51:57,299 PATIENTS, SOME OF THEM SEEMED TO 1374 00:51:57,299 --> 00:51:57,900 RESPOND. 1375 00:51:57,900 --> 00:51:58,567 THIS WAS LOWER. 1376 00:51:58,567 --> 00:52:01,270 THIS WAS AN UNSELECTED GROUP OF 1377 00:52:01,270 --> 00:52:03,772 PATES UNLIKE THE 1S WITH HLRCC, 1378 00:52:03,772 --> 00:52:05,574 BUT WE SAW A LEVEL OF RESPONSE 1379 00:52:05,574 --> 00:52:08,944 OF 35% OR SO. 1380 00:52:08,944 --> 00:52:11,981 THE MEDIAN PF WAS NOT AS GOOD AT 1381 00:52:11,981 --> 00:52:16,018 8 MONTHS, NOT AS GOOD AS HLRCC, 1382 00:52:16,018 --> 00:52:17,519 BUT BETTER OR COMPARABLE THAT 1383 00:52:17,519 --> 00:52:19,388 EXISTED FOR TREATING PATIENTS 1384 00:52:19,388 --> 00:52:22,091 WITH THE PAPILLARY RCC. 1385 00:52:22,091 --> 00:52:26,328 SO WE HAD THEN A GROUP, AN 1386 00:52:26,328 --> 00:52:27,496 INTERVENTION THAT RESULTED IN 1387 00:52:27,496 --> 00:52:29,164 HIGH RESPONSE RATES PARTICULARLY 1388 00:52:29,164 --> 00:52:31,400 IN PATIENTS WITH THE DEFICIENT 1389 00:52:31,400 --> 00:52:31,700 RCC. 1390 00:52:31,700 --> 00:52:34,169 BUT WAWE ALSO KNEW WAS THAT MOST 1391 00:52:34,169 --> 00:52:34,837 PATIENTS EVENTUALLY PROGRESSED 1392 00:52:34,837 --> 00:52:38,674 AND DIE FRIDAY THEIR DISEASE. 1393 00:52:38,674 --> 00:52:40,976 OUR NEXT EFFORTS THEN WERE 1394 00:52:40,976 --> 00:52:42,811 FOCUSED ON CAN WE IMPROVE ON 1395 00:52:42,811 --> 00:52:45,781 THIS, CAN WE TAKE SOME OF THESE 1396 00:52:45,781 --> 00:52:47,516 PATIENTS FOR HAVING PARTIAL 1397 00:52:47,516 --> 00:52:49,685 RESPONSES AND EVENTUALLY DYING 1398 00:52:49,685 --> 00:52:50,853 FROM THE CANCER, CAN TAKE SOME 1399 00:52:50,853 --> 00:52:52,154 OF THEM AT LEAST PROPORTION OF 1400 00:52:52,154 --> 00:52:55,924 THEM AND TURN THEM INTO MORE 1401 00:52:55,924 --> 00:52:57,026 DURABLE SPONSORS BUT WE ALSO 1402 00:52:57,026 --> 00:52:59,328 RECOGNIZE THERE'S A NEED TO FIND 1403 00:52:59,328 --> 00:53:00,929 ADDITIONAL STRATEGIES FOR 1404 00:53:00,929 --> 00:53:03,098 PATIENTS WHO ACTUALLY PROGRESS 1405 00:53:03,098 --> 00:53:04,166 ON THIS APPROACH. 1406 00:53:04,166 --> 00:53:05,701 I SPENT A COUPLE OF MINUTES 1407 00:53:05,701 --> 00:53:08,504 TALKING ABOUT HOW WE ARE 1408 00:53:08,504 --> 00:53:10,305 TACKLING THE FIRST ISSUE. 1409 00:53:10,305 --> 00:53:15,677 AS YOU KNOW IN THE MITSD OF THE 1410 00:53:15,677 --> 00:53:18,113 LAST DECADE, IMMUNE CHECK POINT 1411 00:53:18,113 --> 00:53:21,750 WAS TARGETED CTLA-4 AND THE PD1 1412 00:53:21,750 --> 00:53:22,951 AXIS AND BECAME WIDELY USE 1413 00:53:22,951 --> 00:53:24,019 INDEED CANCER AND WE WERE 1414 00:53:24,019 --> 00:53:25,521 INTERESTED IN SEEING IF THEY 1415 00:53:25,521 --> 00:53:28,090 HAVE ACTIVITY IN THIS GROUP OF 1416 00:53:28,090 --> 00:53:28,323 TUMORS. 1417 00:53:28,323 --> 00:53:33,062 THAT DR. MARINO LOOKEDDA LOOKEA 1418 00:53:33,062 --> 00:53:34,797 LARGE NUMBER OF PATIENTS THAT 1419 00:53:34,797 --> 00:53:39,134 HAD TUMORS THAT INCLUDED VHL, 1420 00:53:39,134 --> 00:53:42,871 AND RCC, AND FOUND THAT UNLIKE 1421 00:53:42,871 --> 00:53:46,041 MANY FORMS OF RCC, THERE WERE A 1422 00:53:46,041 --> 00:53:48,544 LOT OF PATIENTS, ALMOST 60% OF 1423 00:53:48,544 --> 00:53:50,746 THE PATIENTS WITH FH-DEFICIENT 1424 00:53:50,746 --> 00:53:55,350 TUMORS WHO HAD HIGH LEVELS OF 1425 00:53:55,350 --> 00:53:58,253 PDL1, AND DENSE INFILTRATES. 1426 00:53:58,253 --> 00:54:00,956 IN KIDNEY CANCER, EXPRESSION OF 1427 00:54:00,956 --> 00:54:02,524 PD1 OR PDL1 DOESN'T NECESSARILY 1428 00:54:02,524 --> 00:54:03,559 CORRELATE THE RESPONSE, BUT WE 1429 00:54:03,559 --> 00:54:06,228 HAVE A COUPLE OF ANECDOTES OF 1430 00:54:06,228 --> 00:54:08,330 THIS KIND THAT ACTUALLY 1431 00:54:08,330 --> 00:54:09,731 ENCOURAGE US TO LOOK INTO THIS 1432 00:54:09,731 --> 00:54:12,167 GROUP OF AGENTS A BIT MORE IN 1433 00:54:12,167 --> 00:54:16,638 THESE TUMORS, THIS IS A PATIENT 1434 00:54:16,638 --> 00:54:27,182 WHO HAD RECEIVED, RESPONDED WELL 1435 00:54:29,651 --> 00:54:31,820 TO ZELATINIB, AND WE PUT THIS 1436 00:54:31,820 --> 00:54:35,557 PATIENT ON NIVOLUMAB, AND SAW 1437 00:54:35,557 --> 00:54:36,525 GRATIFYINGLY COMPLETE RESPONSE 1438 00:54:36,525 --> 00:54:37,526 DEVELOPING WITHIN A FEW MONTHS 1439 00:54:37,526 --> 00:54:40,062 THAT WAS SUSTAINED FOR MANY, 1440 00:54:40,062 --> 00:54:40,863 MANY YEARS. 1441 00:54:40,863 --> 00:54:43,532 ON WITH THE PRECLINICAL DATA AND 1442 00:54:43,532 --> 00:54:44,700 WITH ANECDOTA CLINICAL DATA WE 1443 00:54:44,700 --> 00:54:46,568 THEN TOOK THE STEP TO DEVISE A 1444 00:54:46,568 --> 00:54:49,171 NEXT CLINICAL TODAY WHICH WAS A 1445 00:54:49,171 --> 00:54:54,076 COMBINATION OF A CHECK POINT 1446 00:54:54,076 --> 00:54:58,480 INHIBITOR TARGETS PDL, AND 1447 00:54:58,480 --> 00:55:00,215 TARGETING NIVOLUMAB, AND THIS IS 1448 00:55:00,215 --> 00:55:01,850 A STUDY THAT'S ONGOING IN THE 1449 00:55:01,850 --> 00:55:07,489 NEXT YEAR OR 2 TO DISCUSS DATA 1450 00:55:07,489 --> 00:55:09,691 FROM THE STUDY. 1451 00:55:09,691 --> 00:55:11,426 I CANNOT END THIS TALK WITHOUT 1452 00:55:11,426 --> 00:55:15,597 REALLY TELLING THE AUDIENCE 1453 00:55:15,597 --> 00:55:18,600 ABOUT THE STRONG AND LONG 1454 00:55:18,600 --> 00:55:19,101 ASSOCIATION BETWEEN 1455 00:55:19,101 --> 00:55:20,269 INVESTIGATORS OF THE NIH AND KID 1456 00:55:20,269 --> 00:55:20,536 NO CANCER. 1457 00:55:20,536 --> 00:55:22,871 I THINK WE HAVE A VERY, VERY 1458 00:55:22,871 --> 00:55:24,406 RICH LEGACY STARTING WITH 1459 00:55:24,406 --> 00:55:25,974 DEVELOPMENT OF CYTOKINE 1460 00:55:25,974 --> 00:55:28,043 THERAPIES BY STEVE ROSENBERG AND 1461 00:55:28,043 --> 00:55:29,144 HIS COLLEAGUES IN PATIENTS WITH 1462 00:55:29,144 --> 00:55:30,512 KIDNEY CANCER WHICH I SAID FOR 1463 00:55:30,512 --> 00:55:32,181 MORE THAN A COUPLE OF DECADES 1464 00:55:32,181 --> 00:55:34,016 WAS THE ONLY ACTIVE GROUP OF 1465 00:55:34,016 --> 00:55:37,486 AGENTS IN THESE TUMORS. 1466 00:55:37,486 --> 00:55:39,588 FIRST IDENTIFICATION OF A KIDNEY 1467 00:55:39,588 --> 00:55:41,657 CANCER GENE, DETAILED DEFINITION 1468 00:55:41,657 --> 00:55:43,959 OF GENETIC HISTOLOGIC AND 1469 00:55:43,959 --> 00:55:45,894 CLINICAL HETEROGENEITY OF KIDNEY 1470 00:55:45,894 --> 00:55:46,261 CANCER. 1471 00:55:46,261 --> 00:55:48,497 THE FIRST VEG F TARGETED AGENT, 1472 00:55:48,497 --> 00:55:50,933 CELLULAR THERAPIES AND ON TO THE 1473 00:55:50,933 --> 00:55:52,701 CURRENT ERA WHERE WE ARE IN THE 1474 00:55:52,701 --> 00:55:57,372 PROCESS OF IDENTIFYING AND 1475 00:55:57,372 --> 00:55:58,307 EVALUATING THE EFFICACY OF 1476 00:55:58,307 --> 00:56:00,342 TARGET AS WELL AS IMMUNO 1477 00:56:00,342 --> 00:56:01,577 THERAPEUTIC APPROACHES. 1478 00:56:01,577 --> 00:56:04,112 WE HAVE A LONG WAY TO GO BUT I'M 1479 00:56:04,112 --> 00:56:08,116 VERY OPTIMISTIC THAT WE'RE WELL 1480 00:56:08,116 --> 00:56:10,986 ON OUR WAY TO EVENTUALLY 1481 00:56:10,986 --> 00:56:13,021 INSURING THAT EVERY SINGLE 1482 00:56:13,021 --> 00:56:15,090 PATIENT WITH KIDNEY CANCER HAS A 1483 00:56:15,090 --> 00:56:17,659 VIABLE TREATMENT OPTION AND 1484 00:56:17,659 --> 00:56:20,562 HOPEFULLY 1 THAT WILL LEAD 1485 00:56:20,562 --> 00:56:21,196 EEIVETTUALLY TO ERADICATION AND 1486 00:56:21,196 --> 00:56:23,565 CURE OF THIS DISEASE. 1487 00:56:23,565 --> 00:56:25,067 I WILL STOP THERE, TAKE A MEMORY 1488 00:56:25,067 --> 00:56:26,001 CLONE TONIGHT ACKNOWLEDGE ALL 1489 00:56:26,001 --> 00:56:29,605 THE PATIENTS AND THE FAMILIES 1490 00:56:29,605 --> 00:56:31,840 WHO HAVE BEEN WILLING 1491 00:56:31,840 --> 00:56:32,874 PARTICIPANTS AND PARTNERS IN THE 1492 00:56:32,874 --> 00:56:34,243 ALL RESEARCH WE'VE DONE HERE 1493 00:56:34,243 --> 00:56:36,645 WITHOUT THEM NONE OF THIS WORK 1494 00:56:36,645 --> 00:56:37,145 WOULD BE POSSIBLE. 1495 00:56:37,145 --> 00:56:39,548 I ALSO WANT TO TAKE A MOMENT TO 1496 00:56:39,548 --> 00:56:40,482 ACKNOWLEDGE THE WONDERFUL GROUP 1497 00:56:40,482 --> 00:56:42,884 OF PEOPLE THAT WE HAVE HERE AT 1498 00:56:42,884 --> 00:56:45,120 THE NIH AND THIS IS NOT JUST CCR 1499 00:56:45,120 --> 00:56:50,592 OR NCI, AS YOU CAN SEE, THE 1500 00:56:50,592 --> 00:56:53,729 EFFORT IS TRANS-NIH AND OFTEN 1501 00:56:53,729 --> 00:56:54,596 INVOLVES COLLABORATORS OUTSIDE 1502 00:56:54,596 --> 00:56:58,267 THE NIESH H AS WELL AS FAR MORE 1503 00:56:58,267 --> 00:56:58,634 COLLABORATORS. 1504 00:56:58,634 --> 00:56:59,801 WITHOUT THIS INCREDIBLY 1505 00:56:59,801 --> 00:57:00,969 COMMITTED AND DEDICATED SMART 1506 00:57:00,969 --> 00:57:02,638 GROUP OF WORK WITH THESE PEOPLE 1507 00:57:02,638 --> 00:57:04,273 NONE OF THIS WORK WOULD BE 1508 00:57:04,273 --> 00:57:04,539 POSSIBLE. 1509 00:57:04,539 --> 00:57:06,942 I WILL STOP THERE AND TAKE ANY 1510 00:57:06,942 --> 00:57:10,545 QUESTIONS YOU MAY HAVE. 1511 00:57:10,545 --> 00:57:14,082 KD--SALLY ARK PLAWZ 1512 00:57:14,082 --> 00:57:14,449 [ APPLAUSE ] 1513 00:57:14,449 --> 00:57:16,184 >> THANK YOU THAT WAS A 1514 00:57:16,184 --> 00:57:16,952 WONDERFUL PRESENTATION, 1515 00:57:16,952 --> 00:57:18,353 APPRECIATE YOU CLARIFYING A VERY 1516 00:57:18,353 --> 00:57:19,521 RICH FIELD AND THANK YOU FOR 1517 00:57:19,521 --> 00:57:23,492 YOUR CONTRIBUTIONS FOR A VERY 1518 00:57:23,492 --> 00:57:23,759 IMPORTANT. 1519 00:57:23,759 --> 00:57:24,793 ARE THERE ANY QUESTIONS, WE 1520 00:57:24,793 --> 00:57:27,162 PROBABLY HAVE TIME FOR 1 1521 00:57:27,162 --> 00:57:27,529 QUESTION. 1522 00:57:27,529 --> 00:57:29,698 ONE QUESTION, I DO HAVE AND IT'S 1523 00:57:29,698 --> 00:57:31,533 NOT REALLY TREATMENT, IT'S MORE 1524 00:57:31,533 --> 00:57:32,401 ABOUT THE TREATMENT EVALUATION, 1525 00:57:32,401 --> 00:57:34,603 SO IF YOU HAVE A PATIENT WITH 1526 00:57:34,603 --> 00:57:37,205 RENAL CELL CARCINOMA, VHL, IF I 1527 00:57:37,205 --> 00:57:39,741 RECALL THE VHL, INHERITANCE IS 1528 00:57:39,741 --> 00:57:43,478 LIKE 50%, IT'S LIKE AUTOSOMAL 1529 00:57:43,478 --> 00:57:44,646 DOMINANT. 1530 00:57:44,646 --> 00:57:45,447 >> IT'S AUTOSOMAL DOMINANT, YES. 1531 00:57:45,447 --> 00:57:47,249 >> SO IF YOU HAVE THE INDEX CASE 1532 00:57:47,249 --> 00:57:49,551 HOW DO YOU EVALUATE AND MANAGE 1533 00:57:49,551 --> 00:57:50,552 THE FAMILIES? 1534 00:57:50,552 --> 00:57:50,886 >> RIGHT. 1535 00:57:50,886 --> 00:57:52,187 SO ONCE WE KNOW WHICH SIDE OF 1536 00:57:52,187 --> 00:57:54,890 THE FAMILY IS EFFECTED, WE 1537 00:57:54,890 --> 00:57:56,892 RECOMMEND ALL OF THEM GET 1538 00:57:56,892 --> 00:57:57,893 GENETICALLY SCREENED, ANYBODY 1539 00:57:57,893 --> 00:58:00,228 WHO HAS THE GENE UNDERGOES 1540 00:58:00,228 --> 00:58:01,296 CAREFUL SURVEILLANCE, THERE'S A 1541 00:58:01,296 --> 00:58:05,100 SCHEME OF SURVEILLANCE THAT WE 1542 00:58:05,100 --> 00:58:05,767 PRACTICE, THERE'S VHL LINES THAT 1543 00:58:05,767 --> 00:58:07,002 AM CAN UP WITH RECOMMENDATIONS 1544 00:58:07,002 --> 00:58:08,670 ON HOW TO SCREEN PATIENTS AS YOU 1545 00:58:08,670 --> 00:58:10,605 CAN IMAGINE, THE SCREENING FOR 1546 00:58:10,605 --> 00:58:11,340 DIFFERENT MANNESTATION WILL BE 1547 00:58:11,340 --> 00:58:11,606 DIFFERENT. 1548 00:58:11,606 --> 00:58:15,277 SOME OF THESE MANIFESTATIONS 1549 00:58:15,277 --> 00:58:16,712 LIKE RETINAL HEME ANGIO BLASTOMA 1550 00:58:16,712 --> 00:58:18,613 WILL BE DONE VERY, VERY EARLY. 1551 00:58:18,613 --> 00:58:20,182 YOU HAVE 1 YEAR-OLD CHILDREN 1552 00:58:20,182 --> 00:58:20,849 WITH THESE MANIFESTATIONS. 1553 00:58:20,849 --> 00:58:22,451 SO THE SCREENING FOR THAT WILL 1554 00:58:22,451 --> 00:58:24,653 BE DIFFERENT FOR KIDNEY CANCER 1555 00:58:24,653 --> 00:58:27,723 WHICH CAN AFFECT SLIGHTLY OLDER 1556 00:58:27,723 --> 00:58:28,023 INDIVIDUALS. 1557 00:58:28,023 --> 00:58:30,058 BUT FOR EACH OF THESE 1558 00:58:30,058 --> 00:58:30,892 MANIFESTATIONS, THERE'S A 1559 00:58:30,892 --> 00:58:33,829 PRESCRIBED SCREENING OF 1560 00:58:33,829 --> 00:58:36,331 SURVEILLANCE IN A SCHEMATIC THAT 1561 00:58:36,331 --> 00:58:38,533 WE FOLLOW AND USING THIS 1562 00:58:38,533 --> 00:58:40,669 APPROACH, I THINK IF THE IDEA TO 1563 00:58:40,669 --> 00:58:41,837 THIS APPROACH, WE ARE ABLE TO 1564 00:58:41,837 --> 00:58:44,806 HEAD OFF A LOT OF THE BAD 1565 00:58:44,806 --> 00:58:49,811 CONSEQUENCES BUT AS A -- THAT'S 1566 00:58:49,811 --> 00:58:51,880 WHY I THINK THESE NEW TREATMENT 1567 00:58:51,880 --> 00:58:53,215 OPTIONS ARE GOING TO PLAY A 1568 00:58:53,215 --> 00:58:54,916 SIGNIFICANT ROLE IN THE 1569 00:58:54,916 --> 00:58:55,817 MANAGEMENT OF THESE VHL PATIENTS 1570 00:58:55,817 --> 00:58:59,388 NWHEN YOU HAVE -- 1571 00:58:59,388 --> 00:59:01,356 >> WHEN YOU HAVE A PATIENT WITH 1572 00:59:01,356 --> 00:59:05,394 RENAL CELL VHL POSITIVE, DO YOU 1573 00:59:05,394 --> 00:59:07,596 SEE IT IN THE CHILDREN AS WELL, 1574 00:59:07,596 --> 00:59:09,598 SAME TYPE OF TUMOR OR ANY TYPE 1575 00:59:09,598 --> 00:59:10,298 OF TUMOR? 1576 00:59:10,298 --> 00:59:12,267 >> SO PATIENT FIST VHL, THE 1577 00:59:12,267 --> 00:59:13,769 RENAL TUMORS ARE ALWAYS CLEAR 1578 00:59:13,769 --> 00:59:15,270 CELL, THEY'RE ALWAYS CLEAR CELL, 1579 00:59:15,270 --> 00:59:17,439 BUT I DON'T KNOW IF I GOT YOUR 1580 00:59:17,439 --> 00:59:17,939 QUESTION CORRECT. 1581 00:59:17,939 --> 00:59:20,542 >> LIKE DO THEY GET PNET OR 1582 00:59:20,542 --> 00:59:22,677 RETINAL TUMORS? 1583 00:59:22,677 --> 00:59:24,780 >> YES, ANYBODY WITH VHL CAN GET 1584 00:59:24,780 --> 00:59:26,748 ANY OF THESE TUMORS AND MANY OF 1585 00:59:26,748 --> 00:59:28,216 THEM GET MULTIPLE FORMS OF 1586 00:59:28,216 --> 00:59:28,683 TUMORS. 1587 00:59:28,683 --> 00:59:31,653 THERE ARE SOME GENETIC PHENOTYPE 1588 00:59:31,653 --> 00:59:34,923 CORRELATIONS WHICH THERE ARE 1589 00:59:34,923 --> 00:59:36,324 GROUPS THAT WON'T GET OR HAVE A 1590 00:59:36,324 --> 00:59:41,997 LOW RISK OF GETTING SITELOMERAS, 1591 00:59:41,997 --> 00:59:46,568 AND THERE ARE GROUPS THAT HAVE 1592 00:59:46,568 --> 00:59:48,737 MORE, BUT THOSE EXCEPTIONS 1593 00:59:48,737 --> 00:59:51,039 APART, MOST OF THESE PEOPLE WILL 1594 00:59:51,039 --> 00:59:59,548 GET FORMS OF V, -- VHL TUMORS. 1595 00:59:59,548 --> 01:00:01,583 THE KIDNEY CANCER MAY BE PRENT 1596 01:00:01,583 --> 01:00:02,784 IN THE 3 OR 4 GROUPS? 1597 01:00:02,784 --> 01:00:05,320 , WE HAVE A QUESTION THERE. 1598 01:00:05,320 --> 01:00:08,089 >> HI, REALLY COOL TALK, I HAD A 1599 01:00:08,089 --> 01:00:09,291 QUESTION REGARDING, I GUESS AT 1600 01:00:09,291 --> 01:00:10,859 THE END OF THE TALK WHERE YOU'RE 1601 01:00:10,859 --> 01:00:13,728 GOING OVER DRUG TREATMENT FOR 1602 01:00:13,728 --> 01:00:16,031 HLRCC, I WAS CURIOUS DO WE HAVE 1603 01:00:16,031 --> 01:00:17,532 ANY INKLING TO KNOW WHY THE 1604 01:00:17,532 --> 01:00:19,935 TREATMENT SEEMS TO WORK SO MUCH 1605 01:00:19,935 --> 01:00:21,570 BETTER IN THE HEREDITARY CASE 1606 01:00:21,570 --> 01:00:25,106 RATHER THAN IN THE SPORADIC 1607 01:00:25,106 --> 01:00:25,307 CASE? 1608 01:00:25,307 --> 01:00:26,475 >> YEAH, FIRST OF ALL I THINK 1609 01:00:26,475 --> 01:00:28,376 THERE ARE A FEW FACTORS TO 1610 01:00:28,376 --> 01:00:28,643 CONSIDER. 1611 01:00:28,643 --> 01:00:30,912 WE DESIGN THIS TREATMENT TO BE 1612 01:00:30,912 --> 01:00:31,947 EFFECTIVE, BASED ON OUR 1613 01:00:31,947 --> 01:00:35,016 UNDERSTANDING OF THE BIOLOGY OF 1614 01:00:35,016 --> 01:00:36,551 THE HEREDITY FORM OF DEC TO BE 1615 01:00:36,551 --> 01:00:39,821 EFFECTIVE IN THAT PARTICULAR 1616 01:00:39,821 --> 01:00:40,121 POPULATION. 1617 01:00:40,121 --> 01:00:43,124 IT'S ALSO A MUCH MORE HOMOGENOUS 1618 01:00:43,124 --> 01:00:43,492 POPULATION. 1619 01:00:43,492 --> 01:00:45,894 IN THE SPORADIC POPULATION WE 1620 01:00:45,894 --> 01:00:47,529 HAVE NO IDEA A PRIORI WHO THOSE 1621 01:00:47,529 --> 01:00:48,530 PATES ARE. 1622 01:00:48,530 --> 01:00:50,198 WE KNOW NOW AFTER HAVING TREATED 1623 01:00:50,198 --> 01:00:54,703 THEM AND STUDIED THEM, DONE SOME 1624 01:00:54,703 --> 01:00:56,304 BACKGROUND GENETIC AND OTHER 1625 01:00:56,304 --> 01:00:58,907 ANALYSIS WHO EACH OF THOSE 1626 01:00:58,907 --> 01:01:03,144 PATIENTS IS, BUT IT IS A VERY 1627 01:01:03,144 --> 01:01:03,712 DESPERATE GROUP OF PEOPLE. 1628 01:01:03,712 --> 01:01:06,014 SOME OF THOSE PATIENT ANDS THEIR 1629 01:01:06,014 --> 01:01:09,651 TUMORS WERE NOT DRIVEN BY THE 1630 01:01:09,651 --> 01:01:13,555 SAME FACTORS THAT DROVE HLRCCOR 1631 01:01:13,555 --> 01:01:15,223 THAT DRIVE HLRCC TUMORS SO IT'S 1632 01:01:15,223 --> 01:01:16,958 NOT SURPRISING THOSE PATIENTS 1633 01:01:16,958 --> 01:01:17,325 DIDN'T RESPOND. 1634 01:01:17,325 --> 01:01:18,894 THOSE ARE THE REASONS FOR THE 1635 01:01:18,894 --> 01:01:19,995 DISPARITY IN RESPONSES. 1636 01:01:19,995 --> 01:01:21,897 AGAIN, WE WERE NOT SURPRISED, WE 1637 01:01:21,897 --> 01:01:23,298 WERE ACTUALLY HAPPY THAT WE GOT 1638 01:01:23,298 --> 01:01:25,267 SOME RESPONSES ON THIS, AND WE 1639 01:01:25,267 --> 01:01:29,137 ARE TRYING TO NAIL DOWN WHO 1640 01:01:29,137 --> 01:01:33,008 THOSE PATIENTS WITH HRLCCR, DO 1641 01:01:33,008 --> 01:01:34,776 RESPOND, THOSE PATIENTS THATY 1642 01:01:34,776 --> 01:01:37,012 BEHAVE AND RESPOND JUST LIKE 1643 01:01:37,012 --> 01:01:40,749 HLRCC PATIENTS, IF THEY DO, IT'S 1644 01:01:40,749 --> 01:01:42,250 DOABLE, AND IT'S PFS WILL BE 1645 01:01:42,250 --> 01:01:45,053 SIMILAR TO WHAT WE SEE IN 1646 01:01:45,053 --> 01:01:46,388 HLRCC PATIENTS SO IT'S MORE A 1647 01:01:46,388 --> 01:01:47,522 QUESTION OF IDENTIFYING THE 1648 01:01:47,522 --> 01:01:48,723 RIGHT TUMORRINGS THAN ANYTHING 1649 01:01:48,723 --> 01:01:49,558 ELSE. 1650 01:01:49,558 --> 01:01:50,425 >> THANK YOU. 1651 01:01:50,425 --> 01:01:52,527 >> THANK YOU AGAIN AND THANK YOU 1652 01:01:52,527 --> 01:01:53,728 FOR JOINING -- IF YOU HAVE ANY 1653 01:01:53,728 --> 01:01:58,366 QUESTIONS CAN YOU COME ON DOWN. 1654 01:01:58,366 --> 01:02:01,970 >> YEAH, WE CAN CATCH UP LATER. 1655 01:02:01,970 --> 01:02:12,247 >> THANK YOU.