1 00:00:05,720 --> 00:00:10,160 >> WELCOME TO THE 24th ANNUAL 2 00:00:10,160 --> 00:00:13,120 ASTUTE CLINICIAN LECTURE. 3 00:00:13,120 --> 00:00:16,760 I'M DR. JIM GILLMAN OF THE 4 00:00:16,760 --> 00:00:17,280 CLINICAL CENTER. 5 00:00:17,280 --> 00:00:21,360 THE SPECIAL LECTURE IS AN NIH 6 00:00:21,360 --> 00:00:24,360 DIRECTOR'S WEDNESDAY AFTERNOON 7 00:00:24,360 --> 00:00:27,480 SERIES HOSTED BY THE CLINICAL 8 00:00:27,480 --> 00:00:27,720 CENTER. 9 00:00:27,720 --> 00:00:28,920 FRANCIS COLLINS NOT ABLE TO JOIN 10 00:00:28,920 --> 00:00:30,360 US DUE TO OTHER COMMITMENTS. 11 00:00:30,360 --> 00:00:33,320 THE ASTUTE LECTURESHIP WAS 12 00:00:33,320 --> 00:00:34,640 ESTABLISHED BY THE LATE 13 00:00:34,640 --> 00:00:39,600 DR. ROBERT MILLER AND HIS WIFE, 14 00:00:39,600 --> 00:00:43,200 HARUKO AND OBSERVED A SCIENTIST 15 00:00:43,200 --> 00:00:46,240 WHO OBSERVED A NEW AVENUE OF 16 00:00:46,240 --> 00:00:47,520 RESEARCH. 17 00:00:47,520 --> 00:00:59,040 TODAY WE WELCOME DR. BRIGG ITE 18 00:00:59,040 --> 00:01:09,960 WIDEMANN ON NEUROFIBROMATOSIS 19 00:01:09,960 --> 00:01:13,240 AND THEN GRADUATED FROM THE 20 00:01:13,240 --> 00:01:14,560 NATIONAL CANCER INSTITUTE. 21 00:01:14,560 --> 00:01:17,160 SHE'S THE CHIEF OF THE PEDIATRIC 22 00:01:17,160 --> 00:01:18,320 ONCOLOGY BRANCH. 23 00:01:18,320 --> 00:01:20,040 IS THE TRAINED AS A PEDIATRIC 24 00:01:20,040 --> 00:01:21,480 ONCOLOGIST WITH EXPERTISE IN 25 00:01:21,480 --> 00:01:23,480 DRUG DEVELOPMENT AND EARLY 26 00:01:23,480 --> 00:01:24,360 CLINICAL TRIALS FOR CHILDREN 27 00:01:24,360 --> 00:01:25,720 WITH REFRACTORY CANCERS. 28 00:01:25,720 --> 00:01:28,040 SHE APPLIED HER EXPERTISE TO 29 00:01:28,040 --> 00:01:33,080 STUDY GENETIC TUMOR 30 00:01:33,080 --> 00:01:34,720 PREDISPOSITION SYNDROMES IN 31 00:01:34,720 --> 00:01:35,920 PARTICULAR NEUROFIBROMATOSIS 32 00:01:35,920 --> 00:01:37,680 TYPE 1 AND PEDIATRIC AND ADULT 33 00:01:37,680 --> 00:01:38,520 SOLID TUMORS. 34 00:01:38,520 --> 00:01:40,120 THESE EFFORTS RESULTED IN THE 35 00:01:40,120 --> 00:01:43,160 UNDERSTANDING OF THE NATURAL 36 00:01:43,160 --> 00:01:45,840 HISTORY AND BIOLOGY OF 37 00:01:45,840 --> 00:01:47,800 NEUROFIBROMATOSIS TYPE 1 RELATED 38 00:01:47,800 --> 00:01:54,080 TUMORS AND OTHER SOLID TUMORS 39 00:01:54,080 --> 00:01:55,240 AND NOVEL END POINTS AND 40 00:01:55,240 --> 00:01:56,640 MEASURES AND BASED ON HER 41 00:01:56,640 --> 00:01:58,160 CLINICAL TRIALS IN 2020 THE FDA 42 00:01:58,160 --> 00:01:59,920 APPROVED THE FIRST MEDICAL 43 00:01:59,920 --> 00:02:24,320 THERAPY THE MEK INHIBITER 44 00:02:24,320 --> 00:02:25,880 SELUMETINIB AND HAS WORKED WITH 45 00:02:25,880 --> 00:02:26,920 OTHER RESEARCHERS AND PARTNERS. 46 00:02:26,920 --> 00:02:30,120 SHE IS AN ELECTED MEMBER OF THE 47 00:02:30,120 --> 00:02:31,000 ASSOCIATION OF AMERICAN 48 00:02:31,000 --> 00:02:34,680 PHYSICIANS AND RECIPIENT OF THE 49 00:02:34,680 --> 00:02:39,960 2021 AACR AWARD FOR OUTSTANDING 50 00:02:39,960 --> 00:02:41,640 ACHIEVEMENT IN CLINICAL CANCER 51 00:02:41,640 --> 00:02:47,640 RESEARCH AND NOW DR. WIDEMANN. 52 00:02:47,640 --> 00:02:48,920 >> THANK YOU FOR THE 53 00:02:48,920 --> 00:02:49,240 INTRODUCTION. 54 00:02:49,240 --> 00:02:51,480 I'M VERY HUMBLED TO BE RECEIVING 55 00:02:51,480 --> 00:02:54,200 THIS AWARD AND GIVING THIS 56 00:02:54,200 --> 00:02:56,280 LECTURE TODAY IN HONOR OF 57 00:02:56,280 --> 00:02:58,040 DR. ROBERT MILLER, WHO LOOKING 58 00:02:58,040 --> 00:03:01,720 BACK AT HIS ACHIEVEMENTS, WAS 59 00:03:01,720 --> 00:03:03,760 INDEED AN EXCEPTIONAL 60 00:03:03,760 --> 00:03:06,080 PEDIATRICIAN AND SCIENTIST AND 61 00:03:06,080 --> 00:03:06,440 EPIDEMIOLOGIST. 62 00:03:06,440 --> 00:03:07,640 THANK YOU FOR GIVING ME THIS 63 00:03:07,640 --> 00:03:08,400 HONOR TODAY. 64 00:03:08,400 --> 00:03:12,520 I WILL TALK ABOUT THE JOURNEY TO 65 00:03:12,520 --> 00:03:14,800 ADVANCING THERAPIES FOR 66 00:03:14,800 --> 00:03:18,960 NEUROFIBROMATOSIS TYPE 1 OR NF1 67 00:03:18,960 --> 00:03:22,000 AND FOCUS ON LESSONS LEARNED 68 00:03:22,000 --> 00:03:22,880 FROM EVERY PATIENT. 69 00:03:22,880 --> 00:03:26,320 I HAVE NO DISCLOSURES BUT WILL 70 00:03:26,320 --> 00:03:30,560 TALK ABOUT CLINICAL TRIALS WITH 71 00:03:30,560 --> 00:03:32,640 INVESTIGATIONAL AGENTS. 72 00:03:32,640 --> 00:03:38,560 I CAME TO NIH IN 1992 UNDER THE 73 00:03:38,560 --> 00:03:48,120 LEADERSHIP OF P -- DR. PIZO TO 74 00:03:48,120 --> 00:03:55,280 GET TRAINED IN ONCOLOGY AND WHAT 75 00:03:55,280 --> 00:03:59,600 ATTRACTED ME WAS WORLD CLASS AND 76 00:03:59,600 --> 00:04:01,640 THE CLOSENESS OF THE BENCH TO 77 00:04:01,640 --> 00:04:04,160 THE BEDSIDE AND HOW THIS COULD 78 00:04:04,160 --> 00:04:06,400 LEAD TO INNOVATIVE TREATMENT FOR 79 00:04:06,400 --> 00:04:08,120 PATIENTS WITH UNMET NEED. 80 00:04:08,120 --> 00:04:11,120 AFTER COMPLETING THE FIRST YEAR 81 00:04:11,120 --> 00:04:12,400 OF CLINICAL TRAINING I JOINED 82 00:04:12,400 --> 00:04:15,400 THE PHARMACOLOGY SECTION 83 00:04:15,400 --> 00:04:18,800 DIRECTED BY DR. BAYLESS AND 84 00:04:18,800 --> 00:04:21,640 DR. PETER ADAMSON WAS MY DIRECT 85 00:04:21,640 --> 00:04:24,360 MENTOR AND AFTER LEAVING NCI 86 00:04:24,360 --> 00:04:26,280 BECAME THE CHAIR OF THE 87 00:04:26,280 --> 00:04:28,120 CHILDREN'S ONCOLOGY GROUP. 88 00:04:28,120 --> 00:04:31,000 I LEARNED A LOT THAT PREPARED ME 89 00:04:31,000 --> 00:04:35,120 FOR DOING CLINICAL TRIALS IN NF1 90 00:04:35,120 --> 00:04:36,400 DURING THIS TIME AND EARLY 91 00:04:36,400 --> 00:04:39,720 REVIEW OF CLINICAL TRIALS WE 92 00:04:39,720 --> 00:04:45,440 CONDUCTED AT NCI FOR CHILDREN 93 00:04:45,440 --> 00:04:49,280 WITH SOLID TUMORS AND REVIEWED 94 00:04:49,280 --> 00:04:51,120 BY DR. KIM A FELLOW IN THE 95 00:04:51,120 --> 00:04:52,080 BRANCH AS WELL. 96 00:04:52,080 --> 00:04:59,360 WE ENROLLED PREDOMINANTLY BRAIN 97 00:04:59,360 --> 00:05:02,640 TUMORS AND NEUROBLASTOMA AND 98 00:05:02,640 --> 00:05:08,120 OTHERS AND THE FOCUS WAS ON 99 00:05:08,120 --> 00:05:15,840 PHASE 1 TRIALS. 100 00:05:15,840 --> 00:05:18,680 90% OF THE PATIENTS HAD 101 00:05:18,680 --> 00:05:21,120 TOLERATED DOSE AND RATE OF DOSE 102 00:05:21,120 --> 00:05:23,600 LIMITING TOXICITIES WAS LOW AT 103 00:05:23,600 --> 00:05:24,480 17%. 104 00:05:24,480 --> 00:05:28,040 ONLY ONE PATIENT HAD A POSSIBLY 105 00:05:28,040 --> 00:05:30,520 DRUG RELATED ISSUE A PATIENT 106 00:05:30,520 --> 00:05:32,280 WITH A BRAIN TUMOR. 107 00:05:32,280 --> 00:05:37,720 YOU SEE THE RESPONSE RATE WAS 108 00:05:37,720 --> 00:05:39,840 VERY LOW AND A WANT TO POINT OUT 109 00:05:39,840 --> 00:05:42,520 IN PHASE 1 TRIALS IT WAS NOT THE 110 00:05:42,520 --> 00:05:47,000 OBJECTIVE BUT THE MEDIAN OVERALL 111 00:05:47,000 --> 00:05:50,000 SURVIVAL FROM ENROLLMENT WAS 112 00:05:50,000 --> 00:05:50,560 ONLY FIVE MONTHS. 113 00:05:50,560 --> 00:05:51,720 DOING THESE CLINICAL TRIALS WAS 114 00:05:51,720 --> 00:05:53,800 NOT EASY AND A WANT TO THANK 115 00:05:53,800 --> 00:05:55,560 PETER FOR TEACHING ME HOW TO BE 116 00:05:55,560 --> 00:05:57,240 HONEST WITH PATIENTS WHILE AT 117 00:05:57,240 --> 00:05:59,520 THE SAME TIME NEVER GIVING UP OR 118 00:05:59,520 --> 00:06:06,760 TAKING HOPE AWAY FROM THEM. 119 00:06:06,760 --> 00:06:08,400 IT PREPARED ME IN NOT BEING 120 00:06:08,400 --> 00:06:11,000 AFRAID OF TAKING ON A NEW 121 00:06:11,000 --> 00:06:11,240 DISEASE. 122 00:06:11,240 --> 00:06:12,400 WE WERE USED TO FAILURE IN THE 123 00:06:12,400 --> 00:06:15,160 SENSE OF DRUGS NOT WORKING AND I 124 00:06:15,160 --> 00:06:17,600 WAS NOT AFRAID THIS WOULD TAKE 125 00:06:17,600 --> 00:06:21,680 ANYTHING AWAY WHEN WE STARTED 126 00:06:21,680 --> 00:06:27,200 WORKING ON NF1 IT BECAME MY 127 00:06:27,200 --> 00:06:31,600 PROJECT AND GOT ME TENURE IN 128 00:06:31,600 --> 00:06:34,200 2009 AND THE PROTOTYPE RESULTING 129 00:06:34,200 --> 00:06:38,000 IN ACTIVATION OF THE RAS 130 00:06:38,000 --> 00:06:38,240 PATHWAY. 131 00:06:38,240 --> 00:06:42,440 BY CHARACTERIZED BY MOLECULES 132 00:06:42,440 --> 00:06:56,440 AND SKIN TUMORS AND AXILLARRY 133 00:06:56,440 --> 00:06:59,000 AND I LOOKED AT TUMORS AND VERY 134 00:06:59,000 --> 00:07:01,520 IMPORTANTLY THERE WAS NO EFFECT 135 00:07:01,520 --> 00:07:03,080 OF MEDICAL THERAPY FOR THE 136 00:07:03,080 --> 00:07:05,080 TUMORS BUT THERE WERE MANY 137 00:07:05,080 --> 00:07:13,520 AGENTS IN DEVELOPMENT FOR CANCER 138 00:07:13,520 --> 00:07:14,880 CANCERS THAT EMBARK ON THE 139 00:07:14,880 --> 00:07:21,160 PATHWAY AND WHY WE STUDY THE 140 00:07:21,160 --> 00:07:23,120 NEUROFIBROMATOSIS TYPE 1 AND THE 141 00:07:23,120 --> 00:07:26,000 GENE PRODUCT FUNCTIONS AS AN 142 00:07:26,000 --> 00:07:31,080 ACTIVATOR PROTEIN AND TURNS ATP 143 00:07:31,080 --> 00:07:37,000 RAS TO INACTIVE ATP BOUND RAS. 144 00:07:37,000 --> 00:07:43,000 WHEN NEUROFIBE ROMIN IS 145 00:07:43,000 --> 00:07:48,200 DEFICIENT THERE'S THE RAF 146 00:07:48,200 --> 00:07:51,440 PATHWAY AND OTHER PATHWAYS. 147 00:07:51,440 --> 00:08:03,400 AT THE END OF AROUND 1998, 148 00:08:03,400 --> 00:08:05,240 TRANSFERRASE WERE STUDIED AND 149 00:08:05,240 --> 00:08:06,680 THIS WAS THE FIRST CLINICAL 150 00:08:06,680 --> 00:08:12,480 TRIAL I TOOK FORWARD FOR 151 00:08:12,480 --> 00:08:14,480 PATIENTS WITH NF1. 152 00:08:14,480 --> 00:08:16,760 IT WAS NOT SUCCESSFUL BECAUSE 153 00:08:16,760 --> 00:08:19,600 SUBSEQUENTLY I AND OTHERS 154 00:08:19,600 --> 00:08:23,280 EVALUATED A NUMBER OF ADDITIONAL 155 00:08:23,280 --> 00:08:26,160 AGENTS WITHOUT CLINICAL SUCCESS 156 00:08:26,160 --> 00:08:30,960 UNTIL WE STUDIED MEK INHIBITOR. 157 00:08:30,960 --> 00:08:34,760 WHEN WE BEGAN STUDYING NF1 WE 158 00:08:34,760 --> 00:08:39,800 KNEW PATIENTS DEVELOP SKIN 159 00:08:39,800 --> 00:08:45,360 TUMORS IN EARLY ADOLESCENTS OR 160 00:08:45,360 --> 00:08:48,400 EARLY ADULTHOOD AND THE TUMOR I 161 00:08:48,400 --> 00:08:52,880 WAS FOCUSSED ON WAS FLEXIFORM 162 00:08:52,880 --> 00:08:57,720 FIBROMA WE BELIEVE ARE 163 00:08:57,720 --> 00:09:06,120 CONGENITAL AND WHILE 164 00:09:06,120 --> 00:09:11,560 HISTOLOGICALLY COMBINED AND CAN 165 00:09:11,560 --> 00:09:13,920 TURN INTO AGGRESSIVE CANCERS 166 00:09:13,920 --> 00:09:15,360 WITH SURGERY AND THROUGH 167 00:09:15,360 --> 00:09:19,080 STUDYING THESE TUMORS WE BEGAN 168 00:09:19,080 --> 00:09:21,880 TO LEARN MORE ABOUT A TYPE OF 169 00:09:21,880 --> 00:09:27,000 TUMOR WHICH IS A PRECURSOR TO 170 00:09:27,000 --> 00:09:27,880 MALIGNANT TUMORS AND I'LL TALK 171 00:09:27,880 --> 00:09:29,840 ABOUT IT DURING THE TALK AND THE 172 00:09:29,840 --> 00:09:31,280 GENOMIC CHARACTERISTICS OF THE 173 00:09:31,280 --> 00:09:33,120 TUMORS THAT HELP US UNDERSTAND 174 00:09:33,120 --> 00:09:33,960 THE MALIGNANT TRANSFORMATION 175 00:09:33,960 --> 00:09:42,080 BETTER. 176 00:09:42,080 --> 00:09:46,320 WHEN WE MEASURED THEM THIS WAS 177 00:09:46,320 --> 00:09:48,440 USED FOR EVERY PATIENT AS METRIC 178 00:09:48,440 --> 00:09:49,880 MEASUREMENTS AND WHEN WE START 179 00:09:49,880 --> 00:09:51,600 THE WORK WE HAD NO IDEA ABOUT 180 00:09:51,600 --> 00:09:53,280 THE NATURAL HISTORY OF THE 181 00:09:53,280 --> 00:09:53,520 TUMORS. 182 00:09:53,520 --> 00:09:57,240 MANY OF US THOUGHT THEY WERE 183 00:09:57,240 --> 00:09:58,840 ERRATICALLY GROWING AND WE HAVE 184 00:09:58,840 --> 00:09:59,760 NOW CHARACTERIZED THE NATURAL 185 00:09:59,760 --> 00:10:00,000 HISTORY. 186 00:10:00,000 --> 00:10:03,240 WHEN WE STARTED THERE WERE FEW 187 00:10:03,240 --> 00:10:04,920 CLINICAL TRIALS AND NO 188 00:10:04,920 --> 00:10:06,200 MEANINGFUL OUTCOME MEASURES AND 189 00:10:06,200 --> 00:10:11,200 NOW WE HAVE MEANINGFUL OUTCOME 190 00:10:11,200 --> 00:10:13,440 MEASURES AND PATIENT-REPORTED 191 00:10:13,440 --> 00:10:14,880 OUTCOMES AND A MEDICAL THERAPY 192 00:10:14,880 --> 00:10:17,760 APPROVED FOR THE TUMORS FOR THE 193 00:10:17,760 --> 00:10:23,400 FIRST TIME. 194 00:10:23,400 --> 00:10:24,400 NEUROFIBROMAS WERE CHARACTERIZED 195 00:10:24,400 --> 00:10:29,560 BY PATHOLOGIC CHANGES AND NOW 196 00:10:29,560 --> 00:10:31,520 CHARACTERIZED THEM AS MALIGNANT 197 00:10:31,520 --> 00:10:33,200 TUMORS AND WE HAVE INITIATE THE 198 00:10:33,200 --> 00:10:34,240 FIRST CLINICAL TRIAL TARGETING 199 00:10:34,240 --> 00:10:40,320 THESE TUMORS AND AS IT RELATES 200 00:10:40,320 --> 00:10:42,560 TO OTHER TUMORS WHILE THERE'S NO 201 00:10:42,560 --> 00:10:43,760 EFFECTIVE THERAPY TODAY WE ARE 202 00:10:43,760 --> 00:10:49,240 WORKING ON A STRATEGY TO PREVENT 203 00:10:49,240 --> 00:10:58,000 THESE TUMORS AND OVER THE YEARS 204 00:10:58,000 --> 00:10:59,400 PRECLINICAL MODELS HAVE BEEN 205 00:10:59,400 --> 00:11:02,120 DEVELOPED FOR THE THREE TUMORS 206 00:11:02,120 --> 00:11:07,320 AND IT'S VALIDATED. 207 00:11:07,320 --> 00:11:14,200 STARTING WITH THE PLEXIFORM 208 00:11:14,200 --> 00:11:15,920 FIBROMAS, WE KNEW THEY WERE 209 00:11:15,920 --> 00:11:17,480 DEVELOPING IN VERY YOUNG 210 00:11:17,480 --> 00:11:21,160 PATIENTS AND KNEW THEY CAN CAUSE 211 00:11:21,160 --> 00:11:22,600 DISFIGUREMENT AND CAN GROW 212 00:11:22,600 --> 00:11:24,400 QUICKLY IN YOUNG PATIENTS AND 213 00:11:24,400 --> 00:11:27,360 THE TUMORS ARE BRIGHT ON MRI 214 00:11:27,360 --> 00:11:27,920 COMPARED TO THE SURROUNDING 215 00:11:27,920 --> 00:11:38,320 TISSUE. 216 00:11:38,320 --> 00:11:41,040 ONE ASPECT WAS DIFFICULT TO 217 00:11:41,040 --> 00:11:44,360 MEASURE THE TUMORS AND I'M 218 00:11:44,360 --> 00:11:49,320 SHOWING THIS IN A PLEXIFORM 219 00:11:49,320 --> 00:11:50,520 NEUROFIBROMA THIS IS A TUMOR OF 220 00:11:50,520 --> 00:11:53,320 A PATIENT IN 2007 AND YOU SEE IT 221 00:11:53,320 --> 00:11:56,280 IN 2008 AND 2009 AND IN 2012 AND 222 00:11:56,280 --> 00:11:57,880 WHILE I DO THINK YOU CAN SEE 223 00:11:57,880 --> 00:11:59,760 THERE HAS BEEN SOME INCREASE 224 00:11:59,760 --> 00:12:02,600 OVER TIME, MOST OF THE RADIOLOGY 225 00:12:02,600 --> 00:12:03,960 REPORTS WOULD TELL US THERE'S NO 226 00:12:03,960 --> 00:12:07,680 CHANGE BECAUSE WE USUALLY LOOK A 227 00:12:07,680 --> 00:12:09,240 MAXIMUM OF FEW MONTHS BUT NOT 228 00:12:09,240 --> 00:12:10,640 FOR A YEAR. 229 00:12:10,640 --> 00:12:12,600 THESE TUMORS GROW MORE SLOWLY 230 00:12:12,600 --> 00:12:15,920 OVER TIME COMPARED TO CANCER 231 00:12:15,920 --> 00:12:22,280 TUMORS. 232 00:12:22,280 --> 00:12:25,560 SO DR. SOLMAN CAPTURED THE IMAGE 233 00:12:25,560 --> 00:12:27,280 WITH THE AREA AND WE CAN 234 00:12:27,280 --> 00:12:30,240 CALCULATE THE TUMOR VOLUME. 235 00:12:30,240 --> 00:12:32,720 AND SUBSEQUENTLY WE USED THIS 236 00:12:32,720 --> 00:12:33,720 METHOD IN THE NATURAL HISTORY 237 00:12:33,720 --> 00:12:36,120 STUDIES WE CONDUCTED AND IN 238 00:12:36,120 --> 00:12:37,560 CLINICAL TRIALS AND IT WAS A 239 00:12:37,560 --> 00:12:40,640 VERY CRITICAL STEP TO MAKING 240 00:12:40,640 --> 00:12:42,000 PROGRESS IN NF1 TUMORS. 241 00:12:42,000 --> 00:12:44,800 YOU CAN NOW SEE WITHIN A YEAR, 242 00:12:44,800 --> 00:12:46,640 THE TUMOR HAD INCREASE IN VOLUME 243 00:12:46,640 --> 00:12:49,480 OF 28% AND THAT BY THE TIME 244 00:12:49,480 --> 00:12:51,360 THERE WERE FIVE OR SIX YEARS THE 245 00:12:51,360 --> 00:12:52,160 TUMOR VOLUME HAD MORE THAN 246 00:12:52,160 --> 00:12:54,920 DOUBLED. 247 00:12:54,920 --> 00:12:57,320 OUR APPROACH WAS TO USE THE MORE 248 00:12:57,320 --> 00:12:59,520 SENSITIVE AND REPRODUCIBLE 249 00:12:59,520 --> 00:13:02,320 METHOD IN PARALLEL IN NATURAL 250 00:13:02,320 --> 00:13:04,400 HISTORY STUDY BUT AT THE SAME 251 00:13:04,400 --> 00:13:06,840 TIME WE DIDN'T WANT TO WAIT WITH 252 00:13:06,840 --> 00:13:07,720 CLINICAL TRIALS EVALUATING THE 253 00:13:07,720 --> 00:13:11,000 POTENTIAL BENEFIT OF AGENTS AND 254 00:13:11,000 --> 00:13:15,360 THE PROGRESSION WAS DEFINED BY A 255 00:13:15,360 --> 00:13:19,520 20% INCREASE IN VOLUME AND 256 00:13:19,520 --> 00:13:22,760 DR. DOUMI HAD RESPONSE 257 00:13:22,760 --> 00:13:23,720 EVALUATIONS ON MANY NATIONAL 258 00:13:23,720 --> 00:13:25,000 CLINICAL TRIALS. 259 00:13:25,000 --> 00:13:26,840 THIS IS ANOTHER QUICK EXAMPLE TO 260 00:13:26,840 --> 00:13:31,560 SHOW YOU HOW MUCH FURTHER THE 261 00:13:31,560 --> 00:13:33,000 VOLUMETRIC METHOD IS AND SEE A 262 00:13:33,000 --> 00:13:43,800 PATIENT WITH A NECK PLEXIFORM 263 00:13:43,800 --> 00:13:52,680 NEUROOWE -- NEU FIBROMA AND WE 264 00:13:52,680 --> 00:13:54,520 STARTED EMBARKING ON NATURAL 265 00:13:54,520 --> 00:13:59,760 HISTORY STUDIES AND THE NIH 266 00:13:59,760 --> 00:14:03,320 CENTER IS THE PLACE TO CONDUCT 267 00:14:03,320 --> 00:14:05,320 THESE STUDIES. 268 00:14:05,320 --> 00:14:10,200 A GENETICISTS AND NEUROLOGIST 269 00:14:10,200 --> 00:14:10,800 STARTED THE FIRST NATURAL 270 00:14:10,800 --> 00:14:12,400 HISTORY STUDY IN 2001 AND WE 271 00:14:12,400 --> 00:14:13,520 PARTICIPATED IN IT. 272 00:14:13,520 --> 00:14:20,640 THE STUDY USED OVER THREE YEARS 273 00:14:20,640 --> 00:14:26,320 VOLUMETRIC ANALYSIS AND AND WE 274 00:14:26,320 --> 00:14:28,720 HAVE VOLUMETRIC MEASURES OVER 20 275 00:14:28,720 --> 00:14:35,560 YEARS AND OUR STUDY FOCUSSED ON 276 00:14:35,560 --> 00:14:41,280 UNDERSTANDING THE PLEXI FORM 277 00:14:41,280 --> 00:14:43,160 NEUROFIBROMA AND WERE FORTUNATE 278 00:14:43,160 --> 00:14:45,880 TO HAVE MANY INVESTIGATORS 279 00:14:45,880 --> 00:14:48,280 HELPING US UNDERSTAND OTHER 280 00:14:48,280 --> 00:14:51,120 ASPECTS OF NF1 SUCH AS 281 00:14:51,120 --> 00:14:52,000 SOCIAL/EMOTIONAL FUNCTION AND 282 00:14:52,000 --> 00:14:54,000 MOTOR FUNCTION AND HEARING AND 283 00:14:54,000 --> 00:14:57,640 ENDOCRINE MANIFESTATIONS. 284 00:14:57,640 --> 00:14:59,400 A VERY ESTEEMED COLLEAGUE OF 285 00:14:59,400 --> 00:15:01,080 MINE AFTER A FEW YEARS IN THE 286 00:15:01,080 --> 00:15:03,040 NATURAL HISTORY STUDY SAID WHEN 287 00:15:03,040 --> 00:15:04,200 ARE YOU GOING TO STOP. 288 00:15:04,200 --> 00:15:05,480 THIS IS A VERY RESEARCH 289 00:15:05,480 --> 00:15:07,160 INTENSIVE STUDY AND I THINK IT'S 290 00:15:07,160 --> 00:15:09,360 A RELEVANT QUESTION BECAUSE WE 291 00:15:09,360 --> 00:15:12,400 WANT TO ALWAYS THINK ABOUT WHEN 292 00:15:12,400 --> 00:15:16,120 CAN WE STOP AND START AND EMBARK 293 00:15:16,120 --> 00:15:17,960 ON SOMETHING NEW. 294 00:15:17,960 --> 00:15:19,560 WE DIDN'T STOP THE NATURAL 295 00:15:19,560 --> 00:15:21,200 HISTORY STUDY AND I THINK IT WAS 296 00:15:21,200 --> 00:15:23,440 A GOOD DECISION. 297 00:15:23,440 --> 00:15:25,200 MORE THAN 25 MANUSCRIPTS HAVE 298 00:15:25,200 --> 00:15:26,480 COME FROM THIS AND SOME ARE VERY 299 00:15:26,480 --> 00:15:27,200 IMPORTANT AND I WANT TO 300 00:15:27,200 --> 00:15:29,320 HIGHLIGHT A FEW OF THEM. 301 00:15:29,320 --> 00:15:39,720 THE CHARACTERIZATION OF THE 302 00:15:39,720 --> 00:15:43,240 PLEXIFORM NEUROFIBROMA SERVED AS 303 00:15:43,240 --> 00:15:46,200 CRITICAL TO FDA APPROVAL AND 304 00:15:46,200 --> 00:15:50,720 CHARACTERIZING THE TUMORS 305 00:15:50,720 --> 00:15:55,640 CAREFULLY LED TO THE 306 00:15:55,640 --> 00:15:59,920 IDENTIFICATION OF THE TUMORS. 307 00:15:59,920 --> 00:16:01,960 IT'S BEEN USED FOR THE PAIN 308 00:16:01,960 --> 00:16:06,320 SCALE AS A PRIMARY END POINT AND 309 00:16:06,320 --> 00:16:08,360 THE NATURAL HISTORY STUDY HAS 310 00:16:08,360 --> 00:16:09,720 CHARACTERIZATION OF THE TUMORS. 311 00:16:09,720 --> 00:16:12,040 SHOWN HERE ARE THE KEY FINDINGS 312 00:16:12,040 --> 00:16:15,440 FROM THE NATURAL HISTORY STUDY 313 00:16:15,440 --> 00:16:20,840 FOR THE GROWTH OF PLEXIFORM 314 00:16:20,840 --> 00:16:22,400 NEUROFIBROMAS AND YOUNG CHILDREN 315 00:16:22,400 --> 00:16:24,080 HAVE THE MOST RAPIDLY GROWING 316 00:16:24,080 --> 00:16:26,520 TUMORS WHICH IS WHY WE WERE SO 317 00:16:26,520 --> 00:16:28,520 INTERESTED IN FOCUSSING ON DRUG 318 00:16:28,520 --> 00:16:31,360 DEVELOPMENT EFFORTS ON YOUNG 319 00:16:31,360 --> 00:16:33,880 CHILDREN AND NOT ADULTS WHERE WE 320 00:16:33,880 --> 00:16:36,720 DON'T SEE TUMORS GROWING. 321 00:16:36,720 --> 00:16:38,160 THERE GROSS DID AN ANALYSIS OF 322 00:16:38,160 --> 00:16:39,600 THE COMORBIDITY THAT COMES FROM 323 00:16:39,600 --> 00:16:40,880 THE TUMORS AND COULD SHOW MOST 324 00:16:40,880 --> 00:16:42,880 OF THE PATIENTS FROM THE FIRST 325 00:16:42,880 --> 00:16:47,600 TIME THEY CAME TO THE NIH 326 00:16:47,600 --> 00:16:50,480 CLINICAL CENTER ALREADY HAD 327 00:16:50,480 --> 00:16:52,600 SUBSTANTIAL MORBIDITY AND ONCE 328 00:16:52,600 --> 00:16:55,880 PRESENT IT DIDN'T RESERVE. 329 00:16:55,880 --> 00:16:59,800 AND WE DID A PHASE 2 TRIAL AND 330 00:16:59,800 --> 00:17:04,080 AN IT WAS ONE OF THE MOST 331 00:17:04,080 --> 00:17:08,640 STUDIES DONE TO DATE ON NF1. 332 00:17:08,640 --> 00:17:12,760 IT HAPPENED AT A TIME WHEN THERE 333 00:17:12,760 --> 00:17:17,320 WAS A PLACEBO CROSSOVER DESIGN 334 00:17:17,320 --> 00:17:20,600 AND THE STUDY TAUGHT US A LOT. 335 00:17:20,600 --> 00:17:23,120 DPN A VERY ESTEEMED COLLEAGUE 336 00:17:23,120 --> 00:17:25,520 I'M VERY FRIEND HI WITH EVEN 337 00:17:25,520 --> 00:17:27,280 TODAY SAID IS THERE A STOPPING 338 00:17:27,280 --> 00:17:30,640 ROUTE TO YOUR TRIAL BECAUSE THIS 339 00:17:30,640 --> 00:17:34,120 INVESTIGATOR DID ANTICIPATE THE 340 00:17:34,120 --> 00:17:39,720 TRANSFERASE INFIBT 341 00:17:41,440 --> 00:17:42,520 INHIBITOR WAS NOT GOING TO WORK 342 00:17:42,520 --> 00:17:47,200 AND YOU SEE HERE FOR THE PLACEBO 343 00:17:47,200 --> 00:17:48,200 INDEPENDENT IF THE PATIENT 344 00:17:48,200 --> 00:17:50,200 STARTED ON THE FIRST OR SECOND 345 00:17:50,200 --> 00:17:52,320 PHASE THERE'S AN OVERLAY 346 00:17:52,320 --> 00:17:53,880 HOWEVER, WHAT THIS STUDY TAUGHT 347 00:17:53,880 --> 00:17:57,440 US FOR THE FIRST TIME WE HAD 348 00:17:57,440 --> 00:17:59,160 NATURAL HISTORY DATA ON THE 349 00:17:59,160 --> 00:18:03,560 FORMATION OF PLEXIFORM 350 00:18:03,560 --> 00:18:06,800 NEUROFIBROMATOSISES USING AS THE 351 00:18:06,800 --> 00:18:11,800 BENCHMARK FOR CLINICAL TRIAL AND 352 00:18:11,800 --> 00:18:13,520 THE USE OF MRI ANALYSIS WAS THE 353 00:18:13,520 --> 00:18:16,480 ONLY METHOD HOW WE COULD WITHIN 354 00:18:16,480 --> 00:18:18,120 A REASONABLE TIME PERIOD 355 00:18:18,120 --> 00:18:24,720 COMPLETE THESE STUDIES. 356 00:18:24,720 --> 00:18:29,560 THE REASON TIPIFARNIB DID NOT 357 00:18:29,560 --> 00:18:36,400 WORK IS THE RAS CAN INSERT IN 358 00:18:36,400 --> 00:18:39,920 THE PLASMA MEMBRANE. 359 00:18:39,920 --> 00:18:42,000 CLEARLY IT WAS NOT EFFECTIVE FOR 360 00:18:42,000 --> 00:18:42,360 THE TUMORS. 361 00:18:42,360 --> 00:18:44,640 ANOTHER THING WE OBSERVED IN THE 362 00:18:44,640 --> 00:18:48,760 PATIENTS ON THE TIPIFARNIB STUDY 363 00:18:48,760 --> 00:18:51,800 WAS TUMORS GROW FASTER IN KIDS. 364 00:18:51,800 --> 00:19:05,320 YOU SEE THE 3-YEAR-OLD AND IF 365 00:19:05,320 --> 00:19:07,080 YOU LOOK AT THE LOWER PANEL WE 366 00:19:07,080 --> 00:19:08,640 ENROLLED A PATIENT A 14-YEAR-OLD 367 00:19:08,640 --> 00:19:13,520 AND THEY HAD A NODULE LESION 368 00:19:13,520 --> 00:19:15,200 THAT GREW AND AFTER SIX MONTHS 369 00:19:15,200 --> 00:19:17,280 ON STUDY HE CAME OFF THE 370 00:19:17,280 --> 00:19:18,200 TREATMENT FOR PROGRESSIVE 371 00:19:18,200 --> 00:19:18,760 DISEASE. 372 00:19:18,760 --> 00:19:24,320 THIS WAS THE FIRST TIME WE 373 00:19:24,320 --> 00:19:26,160 IDENTIFIED A DISTINCT NODULE AT 374 00:19:26,160 --> 00:19:29,280 THE TIME WE DIDN'T KNOW IT WAS A 375 00:19:29,280 --> 00:19:30,720 MALIGNANT PRECURSOR LESION BUT 376 00:19:30,720 --> 00:19:32,160 AFTER THE PATIENT WAS REMOVED 377 00:19:32,160 --> 00:19:44,200 THE STUDY IT THEY UNFORTUNATELY 378 00:19:44,200 --> 00:19:45,320 DECIDE FROM A DISEASE. 379 00:19:45,320 --> 00:19:53,000 WITH THE BENCHMARK STUDY OF THE 380 00:19:53,000 --> 00:19:58,320 TIPIFARBNIB STUDY WE LOOKED IF 381 00:19:58,320 --> 00:20:01,120 WE CAN IMPROVE THE PROGRESSION 382 00:20:01,120 --> 00:20:03,720 FREE SURVIVAL. 383 00:20:03,720 --> 00:20:12,600 YOU SEE AN ANTI-FIBROTIC AGENT 384 00:20:12,600 --> 00:20:15,720 HAD NO EFFECT AND THE ALPHA 2B 385 00:20:15,720 --> 00:20:18,600 DID RESULT IN THE DOUBLING OF 386 00:20:18,600 --> 00:20:25,520 THE TIME TO PROGRESSION AND 2 OF 387 00:20:25,520 --> 00:20:26,520 175 PATIENTS HAT A CONFIRMED 388 00:20:26,520 --> 00:20:45,760 RESPONSE. 389 00:20:45,760 --> 00:20:47,760 AND HERE IN A YOUNG BOY, 3 YEARS 390 00:20:47,760 --> 00:20:50,040 OLD WE SAW HIM FOR THE FIRST 391 00:20:50,040 --> 00:20:56,880 TIME WITH THE HEAD AN NECK AND 392 00:20:56,880 --> 00:20:59,280 PLEXIFORM NEUROFIBROMA AND BY 393 00:20:59,280 --> 00:21:05,800 THE TIME HE WAS 16 HIS TUMOR 394 00:21:05,800 --> 00:21:10,960 MORE THAN TRIPLED AND HAD 395 00:21:10,960 --> 00:21:13,880 DEVELOPED BOWEL INCONTINENCE AND 396 00:21:13,880 --> 00:21:14,600 CLEARLY MAD TO MAKE PROGRESS IN 397 00:21:14,600 --> 00:21:19,720 THE TUMORS AND HAD TO WANTED TO 398 00:21:19,720 --> 00:21:23,720 SEE IF WE MADE PROGRESS IN THE 399 00:21:23,720 --> 00:21:27,720 PLEXIFORM NEUROFIBROMA AND WE 400 00:21:27,720 --> 00:21:31,560 DID A TRIAL BUT PRECLINICAL DATA 401 00:21:31,560 --> 00:21:36,640 BECAUSE WHEN WE STARTED THERE 402 00:21:36,640 --> 00:21:40,480 WERE NO PRECLINICAL MODELS AND 403 00:21:40,480 --> 00:21:44,400 WE SAW IN ALMOST EVERY PATIENT A 404 00:21:44,400 --> 00:21:45,960 VOLUMETRIC REGRESSION SHOWING 405 00:21:45,960 --> 00:21:51,040 THIS WAS IMPORTANT FOR PLEXIFORM 406 00:21:51,040 --> 00:21:52,640 NEUROFIBROMAS AND 17 OF THE 407 00:21:52,640 --> 00:21:54,440 PATIENTS HAD A POSITIVE RESPONSE 408 00:21:54,440 --> 00:21:57,600 AND THE RESPONSES WERE OBSERVED 409 00:21:57,600 --> 00:22:00,400 AT 60% OF THE ADULT RECOMMENDED 410 00:22:00,400 --> 00:22:00,840 DOSE. 411 00:22:00,840 --> 00:22:03,440 PRIOR TO STARTING THE STUDY IT 412 00:22:03,440 --> 00:22:05,320 WAS ALMOST IMPOSSIBLE TO GET A 413 00:22:05,320 --> 00:22:07,280 PHARMACEUTICAL PARTNER TO AGREE 414 00:22:07,280 --> 00:22:10,520 TO DO THE STUDY BECAUSE WE 415 00:22:10,520 --> 00:22:14,600 WANTED TO TREAT CHILDREN AND MEK 416 00:22:14,600 --> 00:22:16,080 INHIBITERS WERE NOT TESTED IN 417 00:22:16,080 --> 00:22:18,600 CHILDREN AND A WANT TO THANK 418 00:22:18,600 --> 00:22:20,080 AUSTIN DOYLE FOR ALLOWING US TO 419 00:22:20,080 --> 00:22:21,600 DO THIS TRIAL WITHOUT THE 420 00:22:21,600 --> 00:22:23,200 SUPPORT FROM CTEP I DON'T KNOW 421 00:22:23,200 --> 00:22:25,880 WE WOULD HAVE AN APPROVED AGENT 422 00:22:25,880 --> 00:22:30,400 AT THIS POINT IN TIME. 423 00:22:30,400 --> 00:22:33,800 ON THE CLINICAL PHASE I TRIAL WE 424 00:22:33,800 --> 00:22:36,800 ALSO OBSERVED A BENEFIT AND YOU 425 00:22:36,800 --> 00:22:39,640 SEE HERE THE LARGE FIBROMA THAT 426 00:22:39,640 --> 00:22:43,320 WAS PROGRESSIVELY GROWING AND 427 00:22:43,320 --> 00:22:44,720 DEMONSTRATED SHRINKAGE ON WHEN 428 00:22:44,720 --> 00:22:47,320 WE APPROACHED THE FDA TO SEE IF 429 00:22:47,320 --> 00:22:49,240 WE COULD GET THE BREAKTHROUGH 430 00:22:49,240 --> 00:22:51,520 THERAPY DESIGNATION, THE FDA 431 00:22:51,520 --> 00:22:52,360 TOLD US NO. 432 00:22:52,360 --> 00:22:54,960 YOU HAVE NOT LOOKED AT THIS 433 00:22:54,960 --> 00:22:56,360 PROSPECTIVELY AND KIND OF LOST 434 00:22:56,360 --> 00:22:57,320 THE OPPORTUNITY. 435 00:22:57,320 --> 00:22:59,880 YOU SHOULD HAVE INCLUDED 436 00:22:59,880 --> 00:23:00,880 PATIENT-RECORDED OUTCOMES OR 437 00:23:00,880 --> 00:23:04,840 SOMETHING TO MEASURE THE BENEFIT 438 00:23:04,840 --> 00:23:06,120 IN YOUR PHASE I CLINICAL TRIAL 439 00:23:06,120 --> 00:23:08,160 AND THIS IS AN IMPORTANT LESSON 440 00:23:08,160 --> 00:23:11,400 FOR ANYONE DOING TUMOR IF YOU 441 00:23:11,400 --> 00:23:12,800 HAVE SOMETHING YOU ANTICIPATE 442 00:23:12,800 --> 00:23:15,680 MAY BE WORKING EVEN IN EARLY 443 00:23:15,680 --> 00:23:18,520 TRIALS SUCH AS PHASE 1 AND 444 00:23:18,520 --> 00:23:19,720 INCORPORATING PATIENT BENEFIT IS 445 00:23:19,720 --> 00:23:30,080 A GOOD IDEA. 446 00:23:30,080 --> 00:23:32,840 WE CREATED A TRIAL FOR CHILDREN 447 00:23:32,840 --> 00:23:37,640 WITH NEUROFIBROMAS AND THERE 448 00:23:37,640 --> 00:23:39,520 WERE A HOST OF FUNCTIONAL 449 00:23:39,520 --> 00:23:40,680 END-PATIENT REPORTED OUTCOMES 450 00:23:40,680 --> 00:23:43,640 MEASURES TO SEE IF THE PATIENTS 451 00:23:43,640 --> 00:23:46,280 WITH SYMPTOMATIC TUMORS COULD 452 00:23:46,280 --> 00:23:47,240 MEASURE CLINICAL BENEFIT. 453 00:23:47,240 --> 00:23:50,680 YOU SEE THE PLOT OF RESPONSE 454 00:23:50,680 --> 00:23:54,120 MIRRORS THAT FROM THE PHASE 1 455 00:23:54,120 --> 00:23:54,320 STUDY. 456 00:23:54,320 --> 00:23:56,640 34 OF 50 PATIENTS HAD A 457 00:23:56,640 --> 00:23:57,960 CONFIRMED RESPONSE AND WE ALSO 458 00:23:57,960 --> 00:24:00,120 IN THIS STUDY WERE ABLE TO 459 00:24:00,120 --> 00:24:00,800 DEMONSTRATE BENEFIT WITH 460 00:24:00,800 --> 00:24:04,440 IMPROVEMENT IN PAIN AND 461 00:24:04,440 --> 00:24:04,720 FUNCTION. 462 00:24:04,720 --> 00:24:09,840 HERE YOU SEE AN IMPROVEMENT IN 463 00:24:09,840 --> 00:24:10,440 DISFIGUREMENT WITH A PATIENT 464 00:24:10,440 --> 00:24:13,280 WITH A NECK TUMOR AND THEN 465 00:24:13,280 --> 00:24:16,000 LOOKING AT GLOBAL IMPRESSION OF 466 00:24:16,000 --> 00:24:21,080 CHANGE IN TUMOR-MORBIDITIES AND 467 00:24:21,080 --> 00:24:23,960 THERE WAS A GLOBAL CHANGE AND 468 00:24:23,960 --> 00:24:25,840 IMPROVEMENT AND VERY FEW 469 00:24:25,840 --> 00:24:28,880 PATIENTS REPORTED WORSENING. 470 00:24:28,880 --> 00:24:31,600 DOCTORS AND WALTERS AND MARTIN 471 00:24:31,600 --> 00:24:34,000 LOOK AT THE PAIN SCALE FROM 0 TO 472 00:24:34,000 --> 00:24:37,000 10 AND SHOWED AN OVERALL 473 00:24:37,000 --> 00:24:39,120 DECREASE IN TUMOR PAIN INTENSITY 474 00:24:39,120 --> 00:24:40,600 OVER TREATMENT CYCLES AND ONE 475 00:24:40,600 --> 00:24:42,640 CYCLE IS FOUR WEEKS. 476 00:24:42,640 --> 00:24:49,000 THEY COULD SHOW FROM BASELINE TO 477 00:24:49,000 --> 00:24:50,520 PRE-CYCLE 12 APPROXIMATELY ONE 478 00:24:50,520 --> 00:24:52,000 YEAR THERE WAS AN AVERAGE 479 00:24:52,000 --> 00:24:53,720 DECREASE IN PAIN POINTS BY TWO 480 00:24:53,720 --> 00:24:56,800 OR MORE WHICH IS CLINICALLY 481 00:24:56,800 --> 00:24:58,360 SIGNIFICANT AND NOT JUST 482 00:24:58,360 --> 00:24:58,880 STATISTICALLY SIGNIFICANT. 483 00:24:58,880 --> 00:25:00,480 THIS DATA WAS REALLY IMPORTANT 484 00:25:00,480 --> 00:25:03,480 FOR THE FDA APPROVAL AND I 485 00:25:03,480 --> 00:25:05,760 CANNOT THANK OUR TEAM ENOUGH FOR 486 00:25:05,760 --> 00:25:08,720 THE HARD WORK THEY HAVE DONE AND 487 00:25:08,720 --> 00:25:10,840 FOR THIS CLINICAL TRIAL. 488 00:25:10,840 --> 00:25:12,600 WE ALSO PRESENTED INDIVIDUAL 489 00:25:12,600 --> 00:25:15,160 CASES OF IMPROVEMENT FOR EVERY 490 00:25:15,160 --> 00:25:16,560 PATIENT TO THE FDA AND I WANT TO 491 00:25:16,560 --> 00:25:20,280 SHOW AN EXAMPLE HERE OF THE 492 00:25:20,280 --> 00:25:26,360 PATIENT WITH A NECK PLEXIFORM 493 00:25:26,360 --> 00:25:29,360 NEUROFIBROMA WITH A TRACHEOTOMY 494 00:25:29,360 --> 00:25:31,480 DUE TO AIRWAY BLOCKAGE. 495 00:25:31,480 --> 00:25:38,760 AFTER A YEAR THE TUMOR SHRANK 496 00:25:38,760 --> 00:25:45,040 ENOUGH SHE COULD BE DECANULATED 497 00:25:45,040 --> 00:25:47,760 AND THAT'S A CLEAR SUCCESS FOR 498 00:25:47,760 --> 00:25:50,160 THIS INDIVIDUAL PATIENT. 499 00:25:50,160 --> 00:25:51,200 I'LL SHOW YOU ANOTHER PATIENT 500 00:25:51,200 --> 00:25:53,120 WHEN WE DIDN'T HAVE AN EFFECTIVE 501 00:25:53,120 --> 00:25:53,400 MEDICINE. 502 00:25:53,400 --> 00:25:56,960 TO SHOW THIS PATIENT HERE. 503 00:25:56,960 --> 00:26:00,080 I'VE KNOWN HIM MANY YEARS SINCE 504 00:26:00,080 --> 00:26:02,080 HE WAS YEARS OLD AND 505 00:26:02,080 --> 00:26:03,640 PARTICIPATED IN SIX PRIOR 506 00:26:03,640 --> 00:26:19,000 TREATMENTS BEFORE WE START 507 00:26:19,000 --> 00:26:22,680 SELUMETINIB AND THE PATIENT 508 00:26:22,680 --> 00:26:24,680 RECOVERED CARDIAC FUNCTION AND 509 00:26:24,680 --> 00:26:28,400 WE STARTED SELUMETINIB AND HE 510 00:26:28,400 --> 00:26:29,800 CONTINUES WITH A STABLE TUMOR. 511 00:26:29,800 --> 00:26:32,080 THESE ARE THE PATIENTS WE HAVE 512 00:26:32,080 --> 00:26:32,600 TO THANK. 513 00:26:32,600 --> 00:26:38,200 WITHOUT THEM WE WOULD NOT HAVE 514 00:26:38,200 --> 00:26:40,440 LEARNED WHAT WE KNOW TODAY AND 515 00:26:40,440 --> 00:26:47,040 AN IMPORTANT LESSON IS WE NEED 516 00:26:47,040 --> 00:26:48,760 CONTINUED SELUMETINIB EXPOSURE 517 00:26:48,760 --> 00:26:49,720 FOR RESPONSES. 518 00:26:49,720 --> 00:26:55,840 AND WE USED THE NATURAL HISTORY 519 00:26:55,840 --> 00:26:58,600 TODAY FOR THIS AND IN BLUE YOU 520 00:26:58,600 --> 00:27:01,120 SEE PATIENTS ENROLLED IN THE 521 00:27:01,120 --> 00:27:02,560 NATURAL HISTORY AND IN RED 522 00:27:02,560 --> 00:27:03,920 PATIENTS ENROLLED IN THE TRIAL. 523 00:27:03,920 --> 00:27:06,400 YOU CAN SEE THERE'S A CLEAR 524 00:27:06,400 --> 00:27:08,200 DIFFERENCE IN THE NATURAL 525 00:27:08,200 --> 00:27:15,840 HISTORY BY THE ADMINISTRATION OF 526 00:27:15,840 --> 00:27:16,160 SELUMETINIB. 527 00:27:16,160 --> 00:27:20,560 AND 84% OF PATIENT FREE OF 528 00:27:20,560 --> 00:27:22,000 PROGRESSION AND 15% OF PATIENTS 529 00:27:22,000 --> 00:27:41,160 ON THE NATURAL HISTORY ARM. 530 00:27:41,160 --> 00:27:43,600 AND HERE YOU SEE THE COMPARISON 531 00:27:43,600 --> 00:27:46,920 TO THE PRIOR CLINICAL TRIALS. 532 00:27:46,920 --> 00:27:48,480 IT'S CERTAINLY BE AN ADVANCE. 533 00:27:48,480 --> 00:27:51,080 IT TOOK 30 YEARS THE 534 00:27:51,080 --> 00:27:55,600 IDENTIFICATION OF THE NF1 GENE 535 00:27:55,600 --> 00:28:00,160 BY OTHERS LINKING IT HAVING AN 536 00:28:00,160 --> 00:28:03,120 FDA APPROVED AGENT. 537 00:28:03,120 --> 00:28:09,240 SINCE 2020 WHEN SELUMETINIB WAS 538 00:28:09,240 --> 00:28:13,520 APPROVED IT WAS APPROVED IN 539 00:28:13,520 --> 00:28:14,640 OTHER COUNTRIES AND THEY HAVE 540 00:28:14,640 --> 00:28:16,200 WORKED HARD TO GET THE DATA TO 541 00:28:16,200 --> 00:28:18,040 THE DIFFERENT REGULATORY 542 00:28:18,040 --> 00:28:22,400 AGENCIES IN COLLABORATION WITH 543 00:28:22,400 --> 00:28:23,000 ASTRAZENECA. 544 00:28:23,000 --> 00:28:27,120 IT'S REALLY A MARATHON AND NOT A 545 00:28:27,120 --> 00:28:28,840 SPRINT AND I'LL TALK LATER HOW 546 00:28:28,840 --> 00:28:30,680 WE HOPE TO ACCESS RAIL THIS 547 00:28:30,680 --> 00:28:30,920 PROCESS. 548 00:28:30,920 --> 00:28:32,840 I WANT TO ALSO QUICKLY MENTION 549 00:28:32,840 --> 00:28:39,640 WE HAVE AN ADULT STUDY OF 550 00:28:39,640 --> 00:28:44,840 SELUMETINIB WITH THE SUCCESS IN 551 00:28:44,840 --> 00:28:48,120 CHILDREN AND THIS TRIAL IS 552 00:28:48,120 --> 00:28:50,640 NEARLY COMPLETED ENROLLMENT AND 553 00:28:50,640 --> 00:28:52,080 WE HAVE OBSERVED PARTIAL 554 00:28:52,080 --> 00:28:53,800 RESPONSE RATES SIMILAR TO THE 555 00:28:53,800 --> 00:28:56,480 CHILDREN IMPROVEMENT IN PAIN 556 00:28:56,480 --> 00:28:59,200 INTENSITY AND PAIN INTERFERENCE 557 00:28:59,200 --> 00:29:01,320 AND PROUD TO SAY THE 558 00:29:01,320 --> 00:29:02,720 INTERVENTION RADIOLOGY 559 00:29:02,720 --> 00:29:06,560 DEPARTMENT HAS BEEN FANTASTIC IN 560 00:29:06,560 --> 00:29:08,840 OBTAINING SERIAL BIOPSIES FROM 561 00:29:08,840 --> 00:29:10,120 THE PATIENTS NEVER SHOWN BEFORE 562 00:29:10,120 --> 00:29:16,960 AND HAVE SHOWN TARGET ENGAGEMENT 563 00:29:16,960 --> 00:29:25,200 WITH ADDITIONAL ANALYSES. 564 00:29:25,200 --> 00:29:27,000 ENROLLMENT IS NEARLY COMPLETE 565 00:29:27,000 --> 00:29:35,760 AND I WILL TALK MORE WHERE 566 00:29:35,760 --> 00:29:40,200 WE'RE TAKING TO PLEXI FORM 567 00:29:40,200 --> 00:29:41,520 NEUROFIBROMA'S LATER BUT I 568 00:29:41,520 --> 00:29:43,600 MENTIONED EARLIER WE WERE ABLE 569 00:29:43,600 --> 00:29:48,320 TO IDENTIFY LESIONS THAT WE CALL 570 00:29:48,320 --> 00:29:49,760 DISTINCT NODULE LESIONS. 571 00:29:49,760 --> 00:29:52,560 THE ABILITY TO DO WHOLE BODY AT 572 00:29:52,560 --> 00:29:54,040 THE MRI AT THE NIH CENTER 573 00:29:54,040 --> 00:29:55,720 WITHOUT CHARGING ANYONE HAS BEEN 574 00:29:55,720 --> 00:29:56,560 A MAJOR ADVANCE. 575 00:29:56,560 --> 00:29:59,400 ON THE LEFT YOU SEE A PATIENT 576 00:29:59,400 --> 00:30:06,800 WITH A TYPICAL LARGE PLEXIFORM 577 00:30:06,800 --> 00:30:09,880 NEUROFIBROMA AND ANOTHER PATIENT 578 00:30:09,880 --> 00:30:11,440 BUT WITH THREE DISTINCT NODULE 579 00:30:11,440 --> 00:30:15,320 LESIONS. 580 00:30:15,320 --> 00:30:17,320 AFTER WE IDENTIFIED THEM WE SAW 581 00:30:17,320 --> 00:30:19,840 THEM IN A NUMBER OF PATIENTS AND 582 00:30:19,840 --> 00:30:22,960 OUTSIDE OF PLEXIFORM 583 00:30:22,960 --> 00:30:23,280 NEUROFIBROMAS. 584 00:30:23,280 --> 00:30:26,520 WHEN WE LOOKED AT PET SCANNING 585 00:30:26,520 --> 00:30:28,400 WE SAW THESE TUMORS WERE IN 586 00:30:28,400 --> 00:30:36,040 CONTRAST TO THE SURROUNDING 587 00:30:36,040 --> 00:30:39,240 PLEXIFORM NEUROFIBROMA AND THEY 588 00:30:39,240 --> 00:30:44,520 WELL DEVELOPED AND DEVELOPED 589 00:30:44,520 --> 00:30:48,120 OVER TIME. 590 00:30:48,120 --> 00:30:52,040 THIS WAS A 15-YEAR-OLD AND HER 591 00:30:52,040 --> 00:30:55,800 MOTHER BECAUSE SHE SAID YOU ARE 592 00:30:55,800 --> 00:30:59,120 THE EXPERTS AND A STUDY WITH A 593 00:30:59,120 --> 00:31:02,400 FIBROMA WITH A DISTINCT NODULE 594 00:31:02,400 --> 00:31:04,800 AND AT THAT TIME THE BIOPSY 595 00:31:04,800 --> 00:31:06,960 SHOWED A NEUROFIBROMA AND THE 596 00:31:06,960 --> 00:31:09,200 LESION PERSISTS BUT DIDN'T GROW 597 00:31:09,200 --> 00:31:11,200 IN VOLUME AND WHEN IT HAD A PET 598 00:31:11,200 --> 00:31:15,040 SCAN OF 10.8 WE DID ANOTHER 599 00:31:15,040 --> 00:31:18,720 BYPASS AND IT WAS AN ATYPICAL 600 00:31:18,720 --> 00:31:19,120 NEUROFIBROMA. 601 00:31:19,120 --> 00:31:22,600 THEY SAID DON'T WORRY BECAUSE 602 00:31:22,600 --> 00:31:25,000 THESE DON'T METASTASIZE AND THAT 603 00:31:25,000 --> 00:31:27,240 IS VERY TRUE HOWEVER, AFTER WE 604 00:31:27,240 --> 00:31:28,600 FOLLOWED THE PATIENT FOR SOME 605 00:31:28,600 --> 00:31:30,680 TIME WITHIN SIX MONTHS THIS 606 00:31:30,680 --> 00:31:34,000 TUMOR DID NOT METASTASIZE BUT 607 00:31:34,000 --> 00:31:37,960 TRANSFORMED TO A HIGHLY 608 00:31:37,960 --> 00:31:45,360 AGGRESSIVE NPNST AND HAD SURGERY 609 00:31:45,360 --> 00:31:47,760 AND DIED IN QUITE A BIT OF 610 00:31:47,760 --> 00:31:49,080 INTOLERABLE PAIN AND MANY TIMES 611 00:31:49,080 --> 00:31:51,760 I WONDERED IF I WOULD HAVE KNOWN 612 00:31:51,760 --> 00:31:53,080 THIS WOULD HAVE HAPPENED WOULD 613 00:31:53,080 --> 00:31:55,480 WE HAVE EMBARKED IN THIS 614 00:31:55,480 --> 00:31:58,280 PROCEDURE THOUGH IT WAS IN A 615 00:31:58,280 --> 00:31:58,880 DIFFICULT PLACE. 616 00:31:58,880 --> 00:32:00,600 IT'S A PATIENT IL WILL NEVER 617 00:32:00,600 --> 00:32:00,840 FORGET. 618 00:32:00,840 --> 00:32:02,840 TAKING FORWARD WE HAVE A PATIENT 619 00:32:02,840 --> 00:32:04,680 WITH A SIMILAR SITUATION AND 620 00:32:04,680 --> 00:32:06,120 KNEW WE HAD TO STUDY THIS MORE. 621 00:32:06,120 --> 00:32:11,720 THE NCI AND A FOUNDATION WANTS 622 00:32:11,720 --> 00:32:13,800 US TO HAVE A STATE OF THE 623 00:32:13,800 --> 00:32:16,400 SCIENCE MEETING TO LOOK AT HOW 624 00:32:16,400 --> 00:32:19,040 TO MAKE PROGRESS IN NF1 IN 625 00:32:19,040 --> 00:32:21,760 TUMORS AND WE IDENTIFIED THESE 626 00:32:21,760 --> 00:32:22,480 PATIENTS WHO DEVELOP THESE 627 00:32:22,480 --> 00:32:25,560 NODULE LESIONS AS YOU CAN SEE ON 628 00:32:25,560 --> 00:32:30,960 A PANEL OVER TIME, MANY TIMES 629 00:32:30,960 --> 00:32:35,000 HAVE CDK AND 2A LOSS AND A 630 00:32:35,000 --> 00:32:36,240 CHARACTERISTIC OF THESE FIBROMAS 631 00:32:36,240 --> 00:32:39,920 AND WHEN WE LOOKED AT THE GROWTH 632 00:32:39,920 --> 00:32:42,600 CHARACTERISTICS OF DOMINANT 633 00:32:42,600 --> 00:32:44,280 FIBROMAS THAT DO NOT GROW IN 634 00:32:44,280 --> 00:32:47,840 ADULTS OR VERY LITTLE THE IT 635 00:32:47,840 --> 00:33:09,320 DISTINCT NODULAR LESIONS AND WE 636 00:33:09,320 --> 00:33:12,240 HAVE IDENTIFIED A LESION THAT IS 637 00:33:12,240 --> 00:33:18,080 A NEOPLASM OF UNCERTAIN BIOLOGIC 638 00:33:18,080 --> 00:33:21,200 POTENTIAL AS TUMOR THAT MAY BE 639 00:33:21,200 --> 00:33:23,920 AT GREATER RISK FOR MALIGNANT 640 00:33:23,920 --> 00:33:28,440 TRANSFORMATION AND HAVING THE 641 00:33:28,440 --> 00:33:28,800 BO 642 00:33:28,800 --> 00:33:30,200 PATHOLOGIST HERE AT NCI WAS 643 00:33:30,200 --> 00:33:32,400 AMAZING AND WE IDENTIFIED THE 644 00:33:32,400 --> 00:33:37,520 NEED TO CHARACTERIZE THE LESIONS 645 00:33:37,520 --> 00:33:42,960 AND 646 00:33:42,960 --> 00:33:46,240 ANDS AND WE STUDIED THE PATIENTS 647 00:33:46,240 --> 00:33:50,240 OUT OF BELGIUM AND ENGLAND AND 648 00:33:50,240 --> 00:33:56,200 AT THE NCI WITH ATYPICAL NEURO 649 00:33:56,200 --> 00:33:56,600 FIB 650 00:33:56,600 --> 00:33:59,640 FIBROMA AND THERE WERE 63 651 00:33:59,640 --> 00:34:02,200 PATIENTS WITH TYPICAL 652 00:34:02,200 --> 00:34:04,440 NEUROFIBROMAS AND THE MEDIAN AGE 653 00:34:04,440 --> 00:34:10,120 OF DIAGNOSIS WAS 27 YEARS. 654 00:34:10,120 --> 00:34:12,120 PAIN WAS THE MOST FREQUENT 655 00:34:12,120 --> 00:34:14,000 PRESENTING FEATURE. 656 00:34:14,000 --> 00:34:18,000 HOWEVER, 13 ATYPICAL NEURO 657 00:34:18,000 --> 00:34:19,760 NEUROFIBROMAS AN 17% HAD NO 658 00:34:19,760 --> 00:34:23,200 SIGNS OF SYMPTOMS AND 21 OF 63 659 00:34:23,200 --> 00:34:27,720 PATIENTS HAVE A HISTORY OF AN 660 00:34:27,720 --> 00:34:29,000 MPNST AFTER THE DEVELOPMENT OF A 661 00:34:29,000 --> 00:34:30,320 TYPICAL FIBROMA. 662 00:34:30,320 --> 00:34:32,440 THE PROPORTION OF THE DISEASE 663 00:34:32,440 --> 00:34:36,680 WITH MANIFESTATIONS THE 664 00:34:36,680 --> 00:34:41,280 ATYPICALS OR THE MPNST AND THE 665 00:34:41,280 --> 00:34:46,560 MEDIAN WAS 51 YEARS. 666 00:34:46,560 --> 00:34:53,600 ALLOWED US TO DETERMINE THEY DO 667 00:34:53,600 --> 00:34:55,520 NOT DEVELOP AS PREVIOUSLY 668 00:34:55,520 --> 00:34:57,200 THOUGHT BUT LIKELY MANY DEVELOP 669 00:34:57,200 --> 00:35:03,360 THROUGH THE STAGE OF AN ATYPICAL 670 00:35:03,360 --> 00:35:06,320 NEUROFIBROMA CHARACTERIZED BY 671 00:35:06,320 --> 00:35:10,280 CDK AND ADDITIONAL MUTATIONS WIN 672 00:35:10,280 --> 00:35:14,440 DEVELOPMENT OF AN MPNST AND WE 673 00:35:14,440 --> 00:35:18,120 LOOKED AT STRATEGIES TO PREVENT 674 00:35:18,120 --> 00:35:23,400 AN MPNST AND AN IMPORTANT 675 00:35:23,400 --> 00:35:26,240 TREATMENT MODALITY WAS RESECTION 676 00:35:26,240 --> 00:35:30,480 OF FIBROMAS AND A NEW SURGEON AT 677 00:35:30,480 --> 00:35:32,360 NINDS HAS BEEN OUR KEY 678 00:35:32,360 --> 00:35:35,040 COLLABORATOR AND CONDUCTED 679 00:35:35,040 --> 00:35:36,040 SURGERIES IN MORE THAN 40 680 00:35:36,040 --> 00:35:37,760 PATIENTS AT THE NIH AT THIS 681 00:35:37,760 --> 00:35:42,120 POINT IN TIME WHICH HAVE BEEN 682 00:35:42,120 --> 00:35:49,040 SAFE AND FEASIBLE AND RARE 683 00:35:49,040 --> 00:35:50,200 REOCCURRENCE RATE UNLIKE 684 00:35:50,200 --> 00:36:02,200 AGGRESSIVE NMPNST -- MPNST AND 685 00:36:02,200 --> 00:36:06,520 THEY CAN DO IT WITHOUT LACK OF 686 00:36:06,520 --> 00:36:07,520 DEVELOPMENT OF MOBILITY BECAUSE 687 00:36:07,520 --> 00:36:11,760 A NODULE THAT ENLARGED AND 688 00:36:11,760 --> 00:36:17,400 REMOVING THEM DOESN'T INJURE AND 689 00:36:17,400 --> 00:36:20,680 MOST THE PATIENTS HAVE FUNCTION 690 00:36:20,680 --> 00:36:22,240 SIMILAR TO PRESURGERY. 691 00:36:22,240 --> 00:36:26,240 WE TALKED ABOUT IMAGING AND HOW 692 00:36:26,240 --> 00:36:29,240 WE DETECT THE TUMORS AND A 693 00:36:29,240 --> 00:36:31,920 TENURE TRACK INVESTIGATOR IN THE 694 00:36:31,920 --> 00:36:34,200 PEDIATRIC ONCOLOGY BRANCH LOOKED 695 00:36:34,200 --> 00:36:36,360 AT THIS BY SAYING CAN WE USE 696 00:36:36,360 --> 00:36:38,320 BLOOD SAMPLES TO DETECT 697 00:36:38,320 --> 00:36:39,600 SOMETHING THAT WILL TELL US THAT 698 00:36:39,600 --> 00:36:45,040 A TUMOR HAS BECOME MALIGNANT. 699 00:36:45,040 --> 00:36:46,200 THEY'VE DEVELOPED A NICE ASSAY 700 00:36:46,200 --> 00:36:51,480 FOR DETECTION OF MPNST AND ALL 701 00:36:51,480 --> 00:36:54,280 THE TUMOR SAMPLES UNDER GO 702 00:36:54,280 --> 00:36:57,000 GENOMIC DISSECTION AND MANY 703 00:36:57,000 --> 00:36:58,720 UNDER GO SINGLE CELL SEQUENCING 704 00:36:58,720 --> 00:37:01,520 TO UNDERSTAND THE MALIGNANT 705 00:37:01,520 --> 00:37:02,080 TRANSFORMATION BETTER. 706 00:37:02,080 --> 00:37:08,200 WITH US CHARACTERIZING A TYPICAL 707 00:37:08,200 --> 00:37:10,800 NEUROFIBROMAS WE TARGETED 708 00:37:10,800 --> 00:37:15,200 CLINICAL TRIALS AND DR. GROSS IS 709 00:37:15,200 --> 00:37:17,880 LEADING A PHASE 1 TRIAL OF A 710 00:37:17,880 --> 00:37:20,000 RATIONAL TREATMENT FOR PATIENTS 711 00:37:20,000 --> 00:37:21,840 THAT HAVE CDK LOSS. 712 00:37:21,840 --> 00:37:24,000 THE TRIAL HAS THE PRIMARY 713 00:37:24,000 --> 00:37:32,360 OBJECTIVE TO LOOK AT TUMOR 714 00:37:32,360 --> 00:37:33,640 SHRINKAGE BUT HAVE CORRELATIVE 715 00:37:33,640 --> 00:37:35,080 STUDIES TO INFORM US MORE ABOUT 716 00:37:35,080 --> 00:37:36,040 THE TUMORS. 717 00:37:36,040 --> 00:37:40,200 FINALLY, OVER THE PAST TWO 718 00:37:40,200 --> 00:37:45,640 YEARS, TWO NEW MOUSE MODELS HAVE 719 00:37:45,640 --> 00:37:47,200 BEEN DESCRIBED TO TRANSCRIBE 720 00:37:47,200 --> 00:37:50,200 FROM THE TUMORS AND WE CAN 721 00:37:50,200 --> 00:37:52,360 EMBARK IN COLLABORATION WITH 722 00:37:52,360 --> 00:37:54,600 OTHER CLINICAL TRIALS. 723 00:37:54,600 --> 00:37:55,920 THIS SHOWS THE NICE WORK THAT 724 00:37:55,920 --> 00:37:58,280 WAS A COLLABORATIVE EFFORT 725 00:37:58,280 --> 00:38:04,000 BETWEEN THE NCI AND WASHINGTON 726 00:38:04,000 --> 00:38:05,400 UNIVERSITY WHERE THEY TOOK 727 00:38:05,400 --> 00:38:11,800 HEALTHY VOLUNTEER SAMPLES AND 728 00:38:11,800 --> 00:38:15,800 MPNTS SAMPLES AND PERFORMED 729 00:38:15,800 --> 00:38:17,800 ULTRA LOW WHOLE GENOME 730 00:38:17,800 --> 00:38:19,600 SEQUENCING AND THEN USED THE 731 00:38:19,600 --> 00:38:25,120 FRAGMENT LENGTHS AND COPY NUMBER 732 00:38:25,120 --> 00:38:27,560 OF VARIATIONS TO DISTINGUISH 733 00:38:27,560 --> 00:38:32,840 TUMOR FROM NON-TUMOR AND PLASMA 734 00:38:32,840 --> 00:38:37,080 CELL FREE DNA WAS ABLE TO 735 00:38:37,080 --> 00:38:39,400 DISTINGUISH THE DIFFERENCE WITH 736 00:38:39,400 --> 00:38:44,000 AN ACCURACY OF 8 6% AND 737 00:38:44,000 --> 00:38:46,520 CORRELATED WITH TUMOR SIZE ON 738 00:38:46,520 --> 00:38:46,800 IMAGING. 739 00:38:46,800 --> 00:38:50,920 THIS MAY BE SOMETHING WE CAN USE 740 00:38:50,920 --> 00:38:53,200 IN FUTURE CLINICAL TRIALS TO 741 00:38:53,200 --> 00:38:54,080 PREDICT RESPONSE POTENTIALLY 742 00:38:54,080 --> 00:38:57,320 EARLIER THAN WHAT WE CAN DO WITH 743 00:38:57,320 --> 00:38:59,640 IMAGING STUDIES AND TO LOOK TO 744 00:38:59,640 --> 00:39:02,720 THE DEVELOPMENT OF MAG MALIGNANT 745 00:39:02,720 --> 00:39:03,160 TRANSFORMATION. 746 00:39:03,160 --> 00:39:07,720 THIS IS SOMETHING THAT WILL BE 747 00:39:07,720 --> 00:39:09,520 APPLICABLE TO OTHER TUMOR 748 00:39:09,520 --> 00:39:09,960 SYNDROMES AS WELL. 749 00:39:09,960 --> 00:39:15,240 I'M SHOWING YOU ON THE NEXT 750 00:39:15,240 --> 00:39:20,880 SLIDE EXCITING DATA OF HUMAN NF1 751 00:39:20,880 --> 00:39:21,120 TUMORS. 752 00:39:21,120 --> 00:39:27,000 WHAT YOU SEE HERE SINGLE CELL 753 00:39:27,000 --> 00:39:28,760 SEQUENCING WHERE EACH DOT 754 00:39:28,760 --> 00:39:29,880 REPRESENTS AN INDIVIDUAL CELL 755 00:39:29,880 --> 00:39:32,400 AND THERE WERE 600,000 756 00:39:32,400 --> 00:39:33,200 INDIVIDUAL CELLS REPRESENTED IN 757 00:39:33,200 --> 00:39:33,800 THE ANALYSIS. 758 00:39:33,800 --> 00:39:37,800 THIS IS FOR TUMORS AT DIFFERENT 759 00:39:37,800 --> 00:39:38,040 STAGES. 760 00:39:38,040 --> 00:39:45,960 DOWN YOU SEE THE SCHWAN'S CELLS 761 00:39:45,960 --> 00:39:49,880 AND HIGHER UP THE TUMORS THAT 762 00:39:49,880 --> 00:39:52,280 HAVE BECOME AGGRESSIVE MALIGNANT 763 00:39:52,280 --> 00:39:52,600 TUMORS. 764 00:39:52,600 --> 00:39:55,080 IN THIS WORK COLLEAGUES ARE ABLE 765 00:39:55,080 --> 00:40:00,600 TO CATALOG THE CELLULAR 766 00:40:00,600 --> 00:40:01,960 HETEROGENEITY PRESENT AND HAVING 767 00:40:01,960 --> 00:40:04,560 A DETAILED TRANSCRIPTOMIC MAP WE 768 00:40:04,560 --> 00:40:06,640 HOPE OFFER THE COURSE OF TIME 769 00:40:06,640 --> 00:40:08,640 WILL HELP UNDERSTAND THE CELL 770 00:40:08,640 --> 00:40:10,040 POPULATIONS AND BE A STRATEGY TO 771 00:40:10,040 --> 00:40:14,600 DEVELOP BETTER TREATMENTS FOR 772 00:40:14,600 --> 00:40:15,320 THE TUMORS. 773 00:40:15,320 --> 00:40:16,360 I WANT TO THANK THOSE WHO HAVE 774 00:40:16,360 --> 00:40:18,400 DIDN'T THE WORK. 775 00:40:18,400 --> 00:40:20,440 I WANT TO THANK THOSE WHO 776 00:40:20,440 --> 00:40:22,160 PROVIDED THEIR EXPERTISE AND 777 00:40:22,160 --> 00:40:24,640 EVERY PATIENT ENROLLED IN HER 778 00:40:24,640 --> 00:40:26,400 OMICS PROTOCOL AND I WANT TO 779 00:40:26,400 --> 00:40:29,000 THANK MICKY WHO DID MULTIPLE 780 00:40:29,000 --> 00:40:31,120 TRIPS TO THE O.R. TO GET THE 781 00:40:31,120 --> 00:40:33,080 TUMORS IN THE FASHION IT'S 782 00:40:33,080 --> 00:40:33,360 NEEDED. 783 00:40:33,360 --> 00:40:37,880 IT'S TEAM WORK TO GET TO THIS. 784 00:40:37,880 --> 00:40:41,480 I WANT TO PROVIDE ANOTHER 785 00:40:41,480 --> 00:40:47,080 PATIENT PICTURE ANY 11-YEAR-OLD 786 00:40:47,080 --> 00:40:51,440 FEMALE WITH NF1 AND WHOLE GENE 787 00:40:51,440 --> 00:40:53,200 DELETION. 788 00:40:53,200 --> 00:40:59,760 SHE DEVELOPED AN PMPST AND YOU 789 00:40:59,760 --> 00:41:02,400 SEE THE PRIMARY TUMOR AND THEN 790 00:41:02,400 --> 00:41:10,920 FOR THE METASTATIC LESION AND -- 791 00:41:10,920 --> 00:41:12,520 MPNST AND WE CAN LOOK AT THE 792 00:41:12,520 --> 00:41:15,920 LYMPHOCYTES TO PROVIDE MORE 793 00:41:15,920 --> 00:41:17,320 DETAIL AND THE BIOLOGY OF THE 794 00:41:17,320 --> 00:41:17,680 TUMORS. 795 00:41:17,680 --> 00:41:19,800 WE TALKED ABOUT THE NATURAL 796 00:41:19,800 --> 00:41:22,000 HISTORY STUDY AND WHEN TO STOP 797 00:41:22,000 --> 00:41:23,440 THE NATURAL HISTORY STUDY AND 798 00:41:23,440 --> 00:41:25,880 I'M HERE TO SAY WE'LL BE CLOSING 799 00:41:25,880 --> 00:41:27,600 OUR NATURAL HISTORY STUDY BUT 800 00:41:27,600 --> 00:41:29,560 ONLY TO BE OPENING A NEW NATURAL 801 00:41:29,560 --> 00:41:32,200 HISTORY STUDY THAT WILL HAVE A 802 00:41:32,200 --> 00:41:34,120 DEDICATED FOCUS ON STUDYING 803 00:41:34,120 --> 00:41:36,680 PATIENTS THAT HAVE INCREASED 804 00:41:36,680 --> 00:41:39,040 RISK FOR MPNST. 805 00:41:39,040 --> 00:41:41,600 OUR PRIMARY GOAL IS TO 806 00:41:41,600 --> 00:41:43,200 CHARACTERIZE THE GOAL OF 807 00:41:43,200 --> 00:41:46,400 ATYPICAL AND MALIGNANT REASONS 808 00:41:46,400 --> 00:41:49,800 WE CAN IDENTIFY USING AN 809 00:41:49,800 --> 00:41:52,520 ALGORITHM WE HAVE WORKED ON FOR 810 00:41:52,520 --> 00:41:54,600 SOME TIME. 811 00:41:54,600 --> 00:41:56,880 PATIENTS WITH NF1 AND ONE OF THE 812 00:41:56,880 --> 00:41:59,760 RISK FACTORS IDENTIFIED HERE 813 00:41:59,760 --> 00:42:03,200 WILL BE ELIGIBLE TO UNDER GO 814 00:42:03,200 --> 00:42:04,760 CLINICAL INVESTIGATION AND 815 00:42:04,760 --> 00:42:08,360 DIFFUSION WEIGHTED IMAGING AND 816 00:42:08,360 --> 00:42:10,960 PET WITH MRI AS CONTRAST AS 817 00:42:10,960 --> 00:42:13,280 INDICATED AND WE'LL FOLLOW THE 818 00:42:13,280 --> 00:42:16,600 PATIENTS FOR SIGHT SOW KINES AND 819 00:42:16,600 --> 00:42:18,640 OTHER -- CYTOKINES AND OTHER 820 00:42:18,640 --> 00:42:21,360 BIOMARKERS AND LOOKING AT RISK 821 00:42:21,360 --> 00:42:27,160 FACTORS AND WILL DETERMINE THE 822 00:42:27,160 --> 00:42:31,120 MANAGEMENT USING OUR ALGORITHM 823 00:42:31,120 --> 00:42:32,400 WITH BIOPSY OR RECEPTION. 824 00:42:32,400 --> 00:42:36,520 THIS IS A HUGE COLLABORATIVE 825 00:42:36,520 --> 00:42:37,080 EFFORT. 826 00:42:37,080 --> 00:42:38,560 I WANT TO THANK THOSE WHO 827 00:42:38,560 --> 00:42:40,280 PROVIDED STATISTICAL GUIDANCE 828 00:42:40,280 --> 00:42:41,960 FOR ALL OF OUR NF1 AND MANY OF 829 00:42:41,960 --> 00:42:45,120 OUR SOLID TUMOR TRIALS. 830 00:42:45,120 --> 00:42:47,760 WITH THAT THANK YOU VERY MUCH 831 00:42:47,760 --> 00:42:50,800 FOR BEING THERE FOR US. 832 00:42:50,800 --> 00:42:52,480 I'D LIKE TO QUICKLY HIGHLIGHT AN 833 00:42:52,480 --> 00:42:58,200 IMPORTANT ASPECT OF OUR WORK, 834 00:42:58,200 --> 00:42:59,040 INTRAMURAL, EXTRAMURAL 835 00:42:59,040 --> 00:43:00,440 COLLABORATION AND WHERE THEY 836 00:43:00,440 --> 00:43:08,440 FURTHER ENHANCE HOW THE NIH 837 00:43:08,440 --> 00:43:09,400 CLINICAL CENTER IS AT THE HEART 838 00:43:09,400 --> 00:43:10,240 OF THIS. 839 00:43:10,240 --> 00:43:15,200 I HAVE NO MOUSE MODELS AND FOR 840 00:43:15,200 --> 00:43:17,360 PLEXIFORM NEUROFIBROMA AND THE 841 00:43:17,360 --> 00:43:20,640 LAB IN CINCINNATI AND IN INDIANA 842 00:43:20,640 --> 00:43:23,400 DEVELOP PRE-CLINICAL AND 843 00:43:23,400 --> 00:43:26,600 TRANSGENIC MOUSE MODELS OF NF1 844 00:43:26,600 --> 00:43:32,680 AND EXCITINGLY, THEY FIRST 845 00:43:32,680 --> 00:43:48,000 DEMONSTRATED THE SELL-- 846 00:43:48,000 --> 00:43:49,160 SELUMETINIB WORKS AND IT WORKS 847 00:43:49,160 --> 00:43:50,800 IN THE MOUSE AND PEOPLE. 848 00:43:50,800 --> 00:43:59,520 THIS IS A VALIDATED MOUSE MODEL 849 00:43:59,520 --> 00:44:02,360 AND ALL WILL GO THROUGH ONE OF 850 00:44:02,360 --> 00:44:10,000 THOSE MOUSE MODELS GOING 851 00:44:10,000 --> 00:44:10,240 FURTHER. 852 00:44:10,240 --> 00:44:16,240 AND AND THE KINASE INHIBITOR 853 00:44:16,240 --> 00:44:18,160 SHRINKS TUMORS. 854 00:44:18,160 --> 00:44:19,560 THE NF1 CLINICAL TRIAL 855 00:44:19,560 --> 00:44:21,080 CONSORTIUM DEPARTMENT OF DEFENSE 856 00:44:21,080 --> 00:44:24,200 FUNDED CONDUCTED A CLINICAL 857 00:44:24,200 --> 00:44:31,400 TRIAL OF CABODANTINIB. 858 00:44:31,400 --> 00:44:36,120 BECAUSE IT CAN CAUSE A NUMBER OF 859 00:44:36,120 --> 00:44:38,800 TOXICITIES THEY LIMITED IT TO 860 00:44:38,800 --> 00:44:41,400 PATIENTS 16 YEARS AND OLDER AND 861 00:44:41,400 --> 00:44:45,600 THE RESPONSE RATE WAS 42%. 862 00:44:45,600 --> 00:44:47,200 IT SHOWED THE PRE-CLINICAL 863 00:44:47,200 --> 00:44:50,000 MODELS CAN PREDICT FOR RESPONSE. 864 00:44:50,000 --> 00:44:51,760 AND THE CONSORTIUM HAS BECOME 865 00:44:51,760 --> 00:44:54,800 VERY IMPORTANT TO CONDUCTING 866 00:44:54,800 --> 00:44:56,040 CLINICAL TRIALS AT MULTIPLE 867 00:44:56,040 --> 00:44:56,240 SITES. 868 00:44:56,240 --> 00:44:59,560 THIS STUDY I'M PRESENTING YOU 869 00:44:59,560 --> 00:45:01,800 HERE IS VERY IMPORTANT EFFORT, I 870 00:45:01,800 --> 00:45:02,200 BELIEVE. 871 00:45:02,200 --> 00:45:14,400 IT WILL BE LED BY DR. ANDREA 872 00:45:14,400 --> 00:45:17,440 GROSS AND SELUMETINIB SHRINK 873 00:45:17,440 --> 00:45:20,240 TUMORS BUT CAN IT PREVENT THE 874 00:45:20,240 --> 00:45:21,680 DEVELOPMENT OF MORBIDITY? 875 00:45:21,680 --> 00:45:23,560 IMAGINE THIS YOUNG KID HERE IF 876 00:45:23,560 --> 00:45:26,080 WE CAN TREAT HER AT 11 MONTHS OR 877 00:45:26,080 --> 00:45:28,880 17 MONTHS OPPOSED TO 3 YEARS 878 00:45:28,880 --> 00:45:32,600 WHEN SHE HAS A DISFIGURING 879 00:45:32,600 --> 00:45:32,800 TUMOR. 880 00:45:32,800 --> 00:45:35,200 THIS WILL BE THE QUESTION 881 00:45:35,200 --> 00:45:42,000 DR. GROSS WILL ADDRESS AND GLAD 882 00:45:42,000 --> 00:45:48,720 WE HAVE COLLABORATION BECAUSE WE 883 00:45:48,720 --> 00:45:54,440 WOULDN'T BE ABLE TO AT THE NIH 884 00:45:54,440 --> 00:45:57,960 CENTER AND ONE QUESTION IS ONCE 885 00:45:57,960 --> 00:46:01,240 WE IDENTIFY ASYMPTOMATIC 886 00:46:01,240 --> 00:46:05,240 PLEXIFORM NEUROFIBROMAS IN HIGH 887 00:46:05,240 --> 00:46:07,320 RISK LOCATIONS AND TREAT AND 888 00:46:07,320 --> 00:46:09,960 OBSERVE WILL WE SHOW WE PREVENT 889 00:46:09,960 --> 00:46:13,880 THE DEVELOPMENT OF MORBIDITY AND 890 00:46:13,880 --> 00:46:17,440 IN PATIENTS WHO RESPOND TO MEK 891 00:46:17,440 --> 00:46:19,000 INHIBITION, CAN WE SWITCH THE 892 00:46:19,000 --> 00:46:21,160 PATIENTS TO AN INTERMITTENT 893 00:46:21,160 --> 00:46:22,840 DOSING SCHEDULE WHICH WILL 894 00:46:22,840 --> 00:46:27,000 HOPEFULLY HAVE LESS TOXICITY AND 895 00:46:27,000 --> 00:46:27,520 SUSTAIN ACTIVITY. 896 00:46:27,520 --> 00:46:30,640 DR. GROSS WAS AWARDED A TRIAL 897 00:46:30,640 --> 00:46:39,920 AND AS TRA -- ASTRAZENECA IS 898 00:46:39,920 --> 00:46:44,920 PROVIDING FUNDS FOR THE MRIs AND 899 00:46:44,920 --> 00:46:52,200 THE LAST IS SPEARHEAD ED BY 900 00:46:52,200 --> 00:46:55,000 OTHERS AND HAS THREE PRIMARY 901 00:46:55,000 --> 00:46:55,280 PROJECTS. 902 00:46:55,280 --> 00:47:05,000 ONE IS NF1 PLEXIFORM 903 00:47:05,000 --> 00:47:10,560 NEUROFIBROMAS AND A THIRD ON 904 00:47:10,560 --> 00:47:12,200 LEUKEMIA THAT OCCURS MORE 905 00:47:12,200 --> 00:47:15,440 FREQUENTLY IN COLLABORATION WITH 906 00:47:15,440 --> 00:47:21,120 THE SPORE THEY HAVE BLOCKED 907 00:47:21,120 --> 00:47:26,160 PROGENITORS AND DO CORRELATES 908 00:47:26,160 --> 00:47:28,400 FOR STUDIES AND EVALUATE 909 00:47:28,400 --> 00:47:31,680 PRE-CLINICAL AGENTS FOR CLINICAL 910 00:47:31,680 --> 00:47:32,360 TRIALS. 911 00:47:32,360 --> 00:47:35,640 ONE SOON TO BE STARTING AND 912 00:47:35,640 --> 00:47:42,800 CURIOUS WILL BE A PHASE II TRIAL 913 00:47:42,800 --> 00:47:51,640 COMBINI 914 00:47:51,640 --> 00:47:54,600 COMBINING SELUMETINIB AND OTHERS 915 00:47:54,600 --> 00:47:57,480 AND WE ARE LOOKING AT THE 916 00:47:57,480 --> 00:48:00,320 RESEARCH AND COLLABORATION AND 917 00:48:00,320 --> 00:48:01,440 THERE'S CLINICAL TRIALS WITH US 918 00:48:01,440 --> 00:48:06,800 COLLABORATING FOR A NUMBER OF 919 00:48:06,800 --> 00:48:15,760 YEARS AND I AM THANK FOR DENISE 920 00:48:15,760 --> 00:48:17,960 REINKE'S SUPPORT AND OTHER 921 00:48:17,960 --> 00:48:19,040 CLINICAL TRIALS THAT DR. KIM AND 922 00:48:19,040 --> 00:48:22,480 I CONDUCTED UNFORTUNATELY WE 923 00:48:22,480 --> 00:48:23,600 HAVE NOT SEEN PARTIAL RESPONSES 924 00:48:23,600 --> 00:48:26,840 AND THE MEDIAN SURVIVAL RATE HAS 925 00:48:26,840 --> 00:48:28,000 TYPICALLY BEEN AROUND TWO 926 00:48:28,000 --> 00:48:28,480 MONTHS. 927 00:48:28,480 --> 00:48:29,720 IT'S VERY SOBERING AND NEED TO 928 00:48:29,720 --> 00:48:32,120 DO BETTER FOR THESE TUMORS. 929 00:48:32,120 --> 00:48:45,280 WE ARE COUNTURRENTLY CONDUCTING A 930 00:48:45,280 --> 00:48:47,800 TRIAL WHERE WE SAW TUMOR 931 00:48:47,800 --> 00:48:49,520 SHRINKAGE IN THE PATIENTS WITH 932 00:48:49,520 --> 00:48:53,640 THE PARTICIPATING IN THE TRIAL 933 00:48:53,640 --> 00:48:56,200 OF THE NIH CLINICAL CENTER AND 934 00:48:56,200 --> 00:49:00,320 USING FDG PET AS A PHARMACO 935 00:49:00,320 --> 00:49:03,600 DYNAMIC READOUT AND WE'RE 936 00:49:03,600 --> 00:49:04,600 PROCEEDING TO THE SECOND STAGE 937 00:49:04,600 --> 00:49:10,280 WHICH MEANS A MINIMUM AMOUNT OF 938 00:49:10,280 --> 00:49:17,600 ACTIVITY HAS BEEN DEAN -- SEEN 939 00:49:17,600 --> 00:49:20,240 AND THERE'S A TRIAL THAT 940 00:49:20,240 --> 00:49:24,760 DEMONSTRATES SUBSTANTIAL TUMOR 941 00:49:25,000 --> 00:49:27,760 SHRINKAGE OF AN INHIBITER AND 942 00:49:27,760 --> 00:49:29,400 CHECKPOINT INHIBITOR AND I'M 943 00:49:29,400 --> 00:49:31,160 VERY MUCH HOPING THIS WILL 944 00:49:31,160 --> 00:49:33,400 TRANSLATE IN MORE CLINICAL 945 00:49:33,400 --> 00:49:35,760 ACTIVITY THAN WE HAVE SEEN TO 946 00:49:35,760 --> 00:49:37,520 DATE. 947 00:49:37,520 --> 00:49:40,200 WE HAVE BEEN LIVING WITH VIRTUAL 948 00:49:40,200 --> 00:49:42,680 MEETINGS AND WANT TO HIGHLIGHT 949 00:49:42,680 --> 00:49:46,920 HOW IMPORTANT IN PERSON MEETINGS 950 00:49:46,920 --> 00:49:48,760 ARE AND HOW MUCH THE NF1 951 00:49:48,760 --> 00:49:52,600 COMMUNITY HAS GROWN GOING FROM 952 00:49:52,600 --> 00:49:55,200 THE FIRST INTERNATIONAL 953 00:49:55,200 --> 00:49:57,600 CONSORTIUM FOR THE MOLECULAR 954 00:49:57,600 --> 00:50:00,840 BIOLOGY IN 2000 IN ASPEN, 955 00:50:00,840 --> 00:50:03,160 COLORADO TO THE LAST NON-VIRTUAL 956 00:50:03,160 --> 00:50:10,640 MEETING IN SAN FRANCISCO AND I 957 00:50:10,640 --> 00:50:13,480 CAN ATTEST TO HOW MUCH PERSONAL 958 00:50:13,480 --> 00:50:15,800 INTERACTIONS HELP US ADVANCE 959 00:50:15,800 --> 00:50:16,960 SCIENCE AND BEING IN BEAUTIFUL 960 00:50:16,960 --> 00:50:18,880 SETTINGS WHERE WE CAN THINK 961 00:50:18,880 --> 00:50:19,600 ABOUT THINGS DIFFERENTLY. 962 00:50:19,600 --> 00:50:22,560 IT TOOK SO LONG TO MAKE PROGRESS 963 00:50:22,560 --> 00:50:24,320 IN NF1 I'M THINKING HOW TO MAKE 964 00:50:24,320 --> 00:50:25,400 PROGRESS FASTER. 965 00:50:25,400 --> 00:50:27,000 THE LAST TWO OR THREE SLIDES I 966 00:50:27,000 --> 00:50:31,000 WANT TO MENTION TWO EFFORTS I'M 967 00:50:31,000 --> 00:50:31,640 EXCITED ABOUT. 968 00:50:31,640 --> 00:50:38,040 THE FDA RECENTLY PROVIDED 969 00:50:38,040 --> 00:50:38,920 GUIDANCE IN NATURAL HISTORY 970 00:50:38,920 --> 00:50:41,000 GUIDANCE AND THE FIRST EFFORT IS 971 00:50:41,000 --> 00:50:43,600 ONE THAT WILL FOCUS ON MAKING 972 00:50:43,600 --> 00:50:47,080 PROGRESS IN CHILDREN THAT HAVE 973 00:50:47,080 --> 00:50:48,800 TUMORS THAT HAVE EITHER RAS 974 00:50:48,800 --> 00:50:51,360 MUTATIONS OR PATHWAY ALTERATIONS 975 00:50:51,360 --> 00:50:55,800 OR IN PATIENTS THAT HAVE NF1 976 00:50:55,800 --> 00:50:57,800 WHERE THERE'S A GERM LINE 977 00:50:57,800 --> 00:51:00,280 MUTATION THAT RESULTS IN PATHWAY 978 00:51:00,280 --> 00:51:00,720 ACTIVATION. 979 00:51:00,720 --> 00:51:03,000 THE FACT WE'VE BEEN ABLE TO 980 00:51:03,000 --> 00:51:05,240 TREAT PATIENTS WITH NF1 WITH 981 00:51:05,240 --> 00:51:06,200 SUCCESS LED TO THIS DEVELOPMENT 982 00:51:06,200 --> 00:51:09,520 OF THE EFFORT WHICH AS A 983 00:51:09,520 --> 00:51:10,680 PRE-CLINICAL COMPONENT THE 984 00:51:10,680 --> 00:51:12,800 NATURAL HISTORY STUDY THAT IS 985 00:51:12,800 --> 00:51:14,800 OPEN NOW AND WE PLAN TO BRING 986 00:51:14,800 --> 00:51:19,360 OUR FIRST PATIENTS TO THE NIH 987 00:51:19,360 --> 00:51:20,480 CLINICAL CENTER IN A PUBLIC 988 00:51:20,480 --> 00:51:22,920 HEALTH GENOMICS APPROACH AND 989 00:51:22,920 --> 00:51:26,720 IT'S A WONDERFUL COLLABORATION 990 00:51:26,720 --> 00:51:28,800 WITH EXTRAMURAL ADVOCACY AND 991 00:51:28,800 --> 00:51:31,400 INTRAMURAL CCR AND THE RAS 992 00:51:31,400 --> 00:51:31,800 INITIATIVE. 993 00:51:31,800 --> 00:51:35,680 I'M SHOWING A LOT OF MORE ABOUT 994 00:51:35,680 --> 00:51:37,800 THIS SOON. 995 00:51:37,800 --> 00:51:44,280 AND I WANT TO BRIEFLY MENTION 996 00:51:44,280 --> 00:51:46,240 TUMOR NETWORK WITH A NATURAL 997 00:51:46,240 --> 00:51:47,520 HISTORY STUDY TO STUDY CHILDREN, 998 00:51:47,520 --> 00:51:50,920 TEENS AND YOUNG ADULTS WITH RARE 999 00:51:50,920 --> 00:51:51,600 SOLID TUMORS. 1000 00:51:51,600 --> 00:51:52,680 THE NATURAL HISTORY PROTOCOL IS 1001 00:51:52,680 --> 00:51:59,880 OPEN FOR ENROLLMENT. 1002 00:51:59,880 --> 00:52:03,480 THERE WAS A HUGE EFFORT BUT WE 1003 00:52:03,480 --> 00:52:06,480 HAVE A NICE PIPELINE TO 1004 00:52:06,480 --> 00:52:07,480 COMPREHENSIVELY EVALUATE THE 1005 00:52:07,480 --> 00:52:08,840 PATIENTS TO PROVIDE GUIDANCE TO 1006 00:52:08,840 --> 00:52:10,200 THE PATIENTS FOR TREATMENT AND 1007 00:52:10,200 --> 00:52:12,680 TO LEARN ABOUT THE TUMORS. 1008 00:52:12,680 --> 00:52:15,000 VERY IMPORTANTLY, ALSO WE CAN 1009 00:52:15,000 --> 00:52:17,200 ENROLL PATIENTS REMOTELY DURING 1010 00:52:17,200 --> 00:52:19,360 THE COVID PANDEMIC WHICH HAS 1011 00:52:19,360 --> 00:52:20,520 MADE IT FEASIBLE FOR PATIENTS TO 1012 00:52:20,520 --> 00:52:22,000 LEARN MORE ABOUT THE TUMORS 1013 00:52:22,000 --> 00:52:25,600 THOUGH THEY COULD NOT COME TO 1014 00:52:25,600 --> 00:52:26,320 THE NIH CLINICAL CENTER. 1015 00:52:26,320 --> 00:52:30,200 ADVOCACY PARTNERSHIP HAS BEEN 1016 00:52:30,200 --> 00:52:35,440 HUGELY IMPORTANT AND THIS SHOWS 1017 00:52:35,440 --> 00:52:37,240 THE NUMBER OF PATIENTS THAT HAVE 1018 00:52:37,240 --> 00:52:40,680 BEEN ENROLLED SINCE THE START IN 1019 00:52:40,680 --> 00:52:40,880 2019. 1020 00:52:40,880 --> 00:52:43,280 IT'S QUITE IMPRESSIVE AND IT'S 1021 00:52:43,280 --> 00:52:46,840 REALLY FOR MANY DIFFERENT STATES 1022 00:52:46,840 --> 00:52:47,480 IN THE UNITED STATES AND 1023 00:52:47,480 --> 00:52:48,680 COUNTRIES AROUND THE WORLD. 1024 00:52:48,680 --> 00:52:53,400 I'M HIGHLIGHTING TWO TUMORS. 1025 00:52:53,400 --> 00:52:55,120 I HAVE LEARNED IT IS TRUE WE 1026 00:52:55,120 --> 00:52:57,120 NEED CHAMPIONS FOR TUMORS TO 1027 00:52:57,120 --> 00:52:58,400 MAKE PROGRESS. 1028 00:52:58,400 --> 00:53:00,400 SOMEBODY HAS TO SAY THIS IS MY 1029 00:53:00,400 --> 00:53:05,480 TUMOR AND WHAT I FOCUS ON AND 1030 00:53:05,480 --> 00:53:15,280 SOME ARE FOCUSSING ON A CHORDOMA 1031 00:53:15,280 --> 00:53:19,000 AND ESTABLISHED A SINGLE CELL 1032 00:53:19,000 --> 00:53:24,160 SEQUENCING AND DEVELOPMENT OF 1033 00:53:24,160 --> 00:53:27,640 CLINICAL TRIALS AND OTHERS HAVE 1034 00:53:27,640 --> 00:53:31,960 TAKEN ON CARDOMA. 1035 00:53:31,960 --> 00:53:36,200 WE HAVE ONLY 30 PATIENTS WITH 1036 00:53:36,200 --> 00:53:40,200 PEDIATRIC CHORDOMA AND IN 1037 00:53:40,200 --> 00:53:43,800 ADVOCATING WE HAD OUR FIRST 1038 00:53:43,800 --> 00:53:47,360 PEDIATRIC CHORDOMA CLINIC AND 1039 00:53:47,360 --> 00:53:49,000 THEY'RE LEADING EXCITING 1040 00:53:49,000 --> 00:53:50,760 CLINICAL TRIAL WITH TWO IMMUNE 1041 00:53:50,760 --> 00:53:55,160 CHECKPOINT INHIBITERS FOR THE 1042 00:53:55,160 --> 00:53:55,400 PATIENTS. 1043 00:53:55,400 --> 00:53:59,600 I'M HOPING HAVING OUR APPROACHES 1044 00:53:59,600 --> 00:54:00,840 WITH THE NATURAL HISTORY STUDY 1045 00:54:00,840 --> 00:54:02,640 OF RARE SOLID TUMORS OUR 1046 00:54:02,640 --> 00:54:04,920 PROGRESS WILL GO MORE QUICKLY. 1047 00:54:04,920 --> 00:54:07,040 I WANT TO THANK FIRST AND 1048 00:54:07,040 --> 00:54:08,920 FOREMOST OUR PATIENTS AND 1049 00:54:08,920 --> 00:54:09,360 FAMILIES. 1050 00:54:09,360 --> 00:54:10,760 I HOPE I HAVE SHOWN YOU HOW MUCH 1051 00:54:10,760 --> 00:54:12,200 THEY GO WITH US AND PARTICIPATE 1052 00:54:12,200 --> 00:54:14,760 AND ARE WILLING TO GO THROUGH 1053 00:54:14,760 --> 00:54:15,400 CLINICAL TRIALS. 1054 00:54:15,400 --> 00:54:19,320 I WANT TO THANK THE NIH, NIH 1055 00:54:19,320 --> 00:54:20,840 CLINICAL CENTER AND NCI. 1056 00:54:20,840 --> 00:54:23,840 THIS IS A FANTASTIC FACILITY TO 1057 00:54:23,840 --> 00:54:24,640 CONDUCT RESEARCH. 1058 00:54:24,640 --> 00:54:27,200 OUR COLLABORATORS AND THE 1059 00:54:27,200 --> 00:54:29,640 FUNDING AGENCIES AND INDUSTRY 1060 00:54:29,640 --> 00:54:31,520 PARTNERS AND OUR NF1 TEAM FOR 1061 00:54:31,520 --> 00:54:38,600 THE HUGE AMOUNT OF WORK THAT 1062 00:54:38,600 --> 00:54:40,760 WENT INTO GETTING SELUMETINIB 1063 00:54:40,760 --> 00:54:43,320 APPROVED AND ALL THE 1064 00:54:43,320 --> 00:54:45,200 COORDINATORS AND SOCIAL WORKERS 1065 00:54:45,200 --> 00:54:48,160 AND POST-BACS AND PSYCHOLOGISTS 1066 00:54:48,160 --> 00:54:49,880 TO GET THIS APPROVED. 1067 00:54:49,880 --> 00:54:51,800 IT'S A TEAM EFFORT. 1068 00:54:51,800 --> 00:54:53,600 THANK YOU SO MUCH. 1069 00:54:53,600 --> 00:54:55,120 >> DR. WIDEMANN THANK YOU VERY 1070 00:54:55,120 --> 00:55:00,280 MUCH FOR THE PRESENTATION. 1071 00:55:00,280 --> 00:55:03,520 WE HAVE A FEW MINUTES AND I NEED 1072 00:55:03,520 --> 00:55:07,360 TO REMIND THE AUDIENCE THEY CAN 1073 00:55:07,360 --> 00:55:08,080 SUBMIT QUESTIONS STILL. 1074 00:55:08,080 --> 00:55:17,160 WE HAVE A FEW MINUTES TO GO. 1075 00:55:17,160 --> 00:55:18,880 AND YOU CAN SUBMIT THE 1076 00:55:18,880 --> 00:55:19,160 QUESTIONS. 1077 00:55:19,160 --> 00:55:23,600 I'M ALSO SUPPOSED TO REMIND 1078 00:55:23,600 --> 00:55:26,000 PEOPLE THAT THE CME CODE FOR THE 1079 00:55:26,000 --> 00:55:27,840 PRESENTATION IS 37924 IF YOU 1080 00:55:27,840 --> 00:55:29,400 TEXT THAT TO JOHNS HOPKINS AND 1081 00:55:29,400 --> 00:55:40,320 MAKE SURE YOU GET CREDIT. 1082 00:55:40,320 --> 00:55:46,400 YOU MENTIONED NF2 AN NICE 1083 00:55:46,400 --> 00:55:49,600 MEETING IN ASPEN AND I DON'T 1084 00:55:49,600 --> 00:55:51,920 THINK IT'S AS COMMON AS NF1 BUT 1085 00:55:51,920 --> 00:55:54,320 ARE THE THINGS YOU LEARNED IN 1086 00:55:54,320 --> 00:56:05,400 NF1 NOT APPLICABLE? 1087 00:56:05,400 --> 00:56:08,560 IT'S REALLY GOOD YOU MENTION 1088 00:56:08,560 --> 00:56:11,200 THIS AND NF2 IS LESS COMMON. 1089 00:56:11,200 --> 00:56:13,360 ONE IN 30,000 PEOPLE. 1090 00:56:13,360 --> 00:56:17,480 THERE'S A HUGE UNMET NEED AND A 1091 00:56:17,480 --> 00:56:18,200 NEUROSURGEON HAS A NATURAL 1092 00:56:18,200 --> 00:56:24,280 HISTORY STUDY FOR THE TUMORS. 1093 00:56:24,280 --> 00:56:34,560 THERE IS ACTIVITY OF TREATMENT 1094 00:56:34,560 --> 00:56:36,800 AND THEY STUDY THE TUMORS AND 1095 00:56:36,800 --> 00:56:39,800 I'M INTERESTED IN OPENING A 1096 00:56:39,800 --> 00:56:41,600 CLINICAL TRIAL WITH THE 1097 00:56:41,600 --> 00:56:44,840 MULTI-TARGETED KINASE INHIBITOR 1098 00:56:44,840 --> 00:56:46,520 OPEN IN THE CLINICAL TRIAL 1099 00:56:46,520 --> 00:56:46,960 CONSORTIUM. 1100 00:56:46,960 --> 00:56:48,520 I'M A LITTLE BIT STRETCHED RIGHT 1101 00:56:48,520 --> 00:56:50,240 NOW BECAUSE WE WOULD NEED MORE 1102 00:56:50,240 --> 00:56:51,800 RESEARCH NURSE SUPPORT TO DO 1103 00:56:51,800 --> 00:56:55,360 THIS BUT IT IS A VERY MUCH UNMET 1104 00:56:55,360 --> 00:56:57,040 NEED AND I'M GRATEFUL THEY'RE 1105 00:56:57,040 --> 00:57:00,160 STUDYING THE TUMORS HERE AND I'M 1106 00:57:00,160 --> 00:57:01,440 HOPEFUL WE CAN DEVELOP CLINICAL 1107 00:57:01,440 --> 00:57:02,680 TRIALS HERE FOR THE DEVASTATING 1108 00:57:02,680 --> 00:57:10,400 TUMORS AS WELL. 1109 00:57:10,400 --> 00:57:12,280 >> WHAT WE HAVE FROM A MEMBER OF 1110 00:57:12,280 --> 00:57:14,360 THE AUDIENCE IS SINCE THE TUMORS 1111 00:57:14,360 --> 00:57:20,200 ARE OFTEN STARTING EARLY IN 1112 00:57:20,200 --> 00:57:24,040 LIFE, IS THERE A DEMONSTRABLE 1113 00:57:24,040 --> 00:57:27,320 IMPACT OF HORMONAL CHANGES 1114 00:57:27,320 --> 00:57:28,880 ASSOCIATED WITH PUBERTY ON THE 1115 00:57:28,880 --> 00:57:30,560 RATE OF TUMOR GROWTH PROGRESSION 1116 00:57:30,560 --> 00:57:36,200 OR IS THEY FACTOR AT ALL? 1117 00:57:36,200 --> 00:57:39,760 >> PATIENTS ASKED US THIS ISSAL 1118 00:57:39,760 --> 00:57:47,000 TE -- THIS ALL THE TIME AND 1119 00:57:47,000 --> 00:57:52,000 WE'RE CONFIDENT AND WE HAVE 1120 00:57:52,000 --> 00:57:56,600 ANECDOTAL DATA FIBROMAS CAN GROW 1121 00:57:56,600 --> 00:58:09,400 RAPIDLY DURING PREGNANCY BUT FOR 1122 00:58:09,400 --> 00:58:12,360 PLEXIFORM NEUROFIBROMAS WE HAVE 1123 00:58:12,360 --> 00:58:13,680 NOT SEEN THAT. 1124 00:58:13,680 --> 00:58:15,200 >> IN THE 30 YEARS YOU'VE SPENT 1125 00:58:15,200 --> 00:58:19,520 IN THE FIELD WHAT ARE THE MOST 1126 00:58:19,520 --> 00:58:21,600 IMPORTANT LESSONS THAT ARE 1127 00:58:21,600 --> 00:58:26,200 APPLICABLE OT STUDY OF CHILDHOOD 1128 00:58:26,200 --> 00:58:26,520 MALIGNANCIES. 1129 00:58:26,520 --> 00:58:29,280 THE THING THAT SURPRISED YOU THE 1130 00:58:29,280 --> 00:58:34,320 MOST OR ANY NEW INVESTIGATOR TO 1131 00:58:34,320 --> 00:58:36,400 THE FIELD AND YOU DON'T HAVE TO 1132 00:58:36,400 --> 00:58:38,800 GO THROUGH THIS TO LEARN X, Y OR 1133 00:58:38,800 --> 00:58:40,400 Z BECAUSE I'LL TELL YOU NOW 1134 00:58:40,400 --> 00:58:43,400 AFTER 30 YEARS OF EXPERIENCE. 1135 00:58:43,400 --> 00:58:46,560 >> I THINK ONE OF THE LESSONS IS 1136 00:58:46,560 --> 00:58:53,680 TO LOOK MORE THAN ASSUME. 1137 00:58:53,680 --> 00:59:02,800 I HAD A NUMBER OF ASSUMPTIONS 1138 00:59:02,800 --> 00:59:04,760 THAT ARE NOW WRONG. 1139 00:59:04,760 --> 00:59:05,600 IF WE PAID MORE ATTENTION TO THE 1140 00:59:05,600 --> 00:59:08,440 PATIENT AND LISTEN AND OBSERVE 1141 00:59:08,440 --> 00:59:13,960 THE PATIENT AND TRUTHFULLY 1142 00:59:13,960 --> 00:59:19,960 HAVING LESS ASSUMPTION AND BEING 1143 00:59:19,960 --> 00:59:22,520 LESS BIASSED IS GOOD ADVICE. 1144 00:59:22,520 --> 00:59:26,320 AND FINALLY, I THINK TAKING A 1145 00:59:26,320 --> 00:59:26,640 RISK. 1146 00:59:26,640 --> 00:59:28,600 I'M A LITTLE BIT AN 1147 00:59:28,600 --> 00:59:30,760 INCREMENTALIST I GO STEP BY STEP 1148 00:59:30,760 --> 00:59:33,720 BUT IF YOU TAKE A RISK, PATIENTS 1149 00:59:33,720 --> 00:59:37,440 ARE WILLING TO TAKE A RISK AND A 1150 00:59:37,440 --> 00:59:38,880 PHASE I PATIENT WOULD TELL ME I 1151 00:59:38,880 --> 00:59:40,560 WANT TO SEE THE TWO DRUGS 1152 00:59:40,560 --> 00:59:42,840 COMBINED AND I TOLD THEM WE 1153 00:59:42,840 --> 00:59:46,800 CAN'T DO THIS BECAUSE WE HAVE TO 1154 00:59:46,800 --> 00:59:49,800 FIRST LEARN IT'S SAFE AND 1155 00:59:49,800 --> 00:59:50,440 THINKING MORE FROM THE 1156 00:59:50,440 --> 00:59:51,360 PERSPECTIVE, WHAT DOES THE 1157 00:59:51,360 --> 00:59:52,960 PATIENT WANT AND CAN WE MAKE IT 1158 00:59:52,960 --> 00:59:55,480 HAPPEN AND NOT NECESSARILY GO BY 1159 00:59:55,480 --> 00:59:56,880 THE RULES WE HAVE ESTABLISHED. 1160 00:59:56,880 --> 01:00:03,840 THAT MAY BE ANOTHER ADVICE. 1161 01:00:03,840 --> 01:00:06,200 >> DR. WIDEMANN, I WANT TO THANK 1162 01:00:06,200 --> 01:00:09,520 YOU AGAIN FOR YOUR WONDERFUL 1163 01:00:09,520 --> 01:00:11,240 TALK AS THE CEO OF THE CLINICAL 1164 01:00:11,240 --> 01:00:13,000 CENTER AND TELL YOU HOW PROUD WE 1165 01:00:13,000 --> 01:00:19,600 ARE TO HAVE SPONSORED THIS 1166 01:00:19,600 --> 01:00:21,640 PRESENTATION AND A YEAR OR SO 1167 01:00:21,640 --> 01:00:23,480 AGO I ALSO WATCHED YOU THROUGH 1168 01:00:23,480 --> 01:00:26,000 THE REMEMBRANCE CEREMONY WHERE 1169 01:00:26,000 --> 01:00:28,160 WE ACKNOWLEDGED THE 1170 01:00:28,160 --> 01:00:30,760 CONTRIBUTIONS OF OUR PEDIATRIC 1171 01:00:30,760 --> 01:00:32,680 PATIENTS WHO HAVE DIED IN A 1172 01:00:32,680 --> 01:00:35,240 FASHION THAT ENABLED US TO LEARN 1173 01:00:35,240 --> 01:00:41,800 MORE ABOUT DISEASE AND IT'S NICE 1174 01:00:41,800 --> 01:00:44,000 TO SEE YOUR REACTIONS THEN AND 1175 01:00:44,000 --> 01:00:45,320 HOW MUCH YOU CARED ABOUT THE 1176 01:00:45,320 --> 01:00:46,800 PATIENTS WHO WERE INVOLVED IN 1177 01:00:46,800 --> 01:00:49,560 THIS WORK AND IT'S VERY NICE TO 1178 01:00:49,560 --> 01:00:52,960 SEE THE KIND OF RESULTS THAT 1179 01:00:52,960 --> 01:00:56,080 THAT WORK HAS PRODUCED SO 1180 01:00:56,080 --> 01:00:59,640 CONGRATULATIONS AS THE ASTUTE 1181 01:00:59,640 --> 01:01:04,000 CLINICIAN FOR 2021 AND THANK YOU 1182 01:01:04,000 --> 01:01:05,000 TO THE AUDIENCE FOR DIALING IN 1183 01:01:05,000 --> 01:01:06,160 AND EVERYBODY HAVE A GREAT 1184 01:01:06,160 --> 01:01:07,600 WEDNESDAY AFTERNOON. 1185 01:01:07,600 --> 01:02:30,840 >> THANK YOU SO MUCH.