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Harmonizing Bio-informatics with Clinical Reality Michael Prados, MD University of California San Francisco 2nd Annual CBTTC Investigator Meeting The Westin New Orleans May 24-25 War on Cancer War On Cancer September 28th 2016 | Boston waroncancer.economist.com Announcing this year's War On Cancer event Following a successful inaugural War On Cancer conference attended by 260 health-care leaders, The Economist is pleased to announce its 2016 conference for September 28th in Boston. The event will explore how the promise of technology allows for faster, more precise treatment and more collaborative health care models, inching us closer to moonshot objectives and victory. Join us to discuss how innovation can be scaled across policy and financing, prevention, early detection, treatment and long-term management of this deadly disease. Total NCI Research Project Grants Cancer Centers SPOREs Other P50s/P20s Other Specialized Centers Clinical Cooperative Groups R&D Contracts Intramural Research Other Mechanisms* Funding (Dollars in Millions) 2010 2011 2012 $5,098.1 $5,058.1 $5,067.3 2,168.1 2,163.7 2,150.6 295.9 278.3 279.9 133.8 121.9 113.5 38.8 35.2 33.4 142.7 162.7 186.0 254.5 243.9 229.8 613.8 587.0 589.7 805.3 833.7 857.8 645.4 631.8 626.5 2013 $4,789.0 2,000.2 262.2 104.3 21.5 146.0 235.4 616.0 811.6 591.8 2014 $4,932.4 2,012.6 281.8 104.6 18.2 139.2 271.6 652.3 845.1 607.0 Percent Change by Mechanism Total NCI Research Project Grants Cancer Centers SPOREs Other P50s/P20s Specialized Centers Clinical Cooperative Groups R&D Contracts Intramural Research Other Mechanisms* 2010 to 2011 -0.8% -0.2% -5.9% -8.9% -9.3% 14.0% -4.2% -4.4% 3.5% -2.1% 2011 to 2012 0.2% -0.6% 0.6% -6.9% -4.9% 14.4% -5.8% 0.5% 2.9% -0.8% 2012 to 2013 -5.5% -7.0% -6.3% -8.1% -35.8% -21.5% 2.4% 4.5% -5.4% -5.5% 2013 to 2014 -3.6% -6.3% -8.2% -20.6% -23.6% 25.4% 0.4% 1.0% 3.9% -8.3% 2010 to 2014 -3.3% -7.7% -11.4% -22.1% -44.6% 2.3% -7.5% 0.4% 0.8% -8.3% NCI Pediatric Cancer Research Portfolio Therapeutically Applicable Research To Generate Effective Treatments (TARGET) The Biomarker, Imaging and Quality of Life Studies Funding Program (BIQSFP) The NCI-supported Childhood Cancer Survivor Study The Center for Cancer Research’s Pediatric Oncology Branch The Epidemiology and Genomics Research Program The Tumor Microenvironment Network (TMEN) Pediatric CNS Tumor Funding 1. NCI gets about $4.8 Billion for cancer funding (2015; 2016 appropriations about $5.2 Billion) 2. “Total” amount for all of pediatric cancers = $185 millions (45% treatment) 3. PBTC annual budget = $2.7million (includes the Operations Office component, and indirect costs, so what filters down for actual clinical trials is hard to sort out) 4. COG annual budget = $30 million; portion linked to CNS tumors is just under $2 million (also not certain exactly how much of that supports clinical trials per se) 5. Phase-1 consortium = $3 million 6. NCI Pediatric Branch = $3.01 million (all pediatric malignancies): perhaps around $600,000 towards CNS tumors (small amount towards clinical trials, more towards other research efforts) Approximately 4% for Pediatric Cancer, < 1% for CNS Tumors Estimated 47,631 years of potential life lost due to CNS tumors in 2009 in the US alone DIPG – 1996 20 years ago Natural History “Diffuse tumors have terrible prognosis with most patients dead in 12 months.” Treatment “The most common neoplasm is the diffuse variety. These are malignant. Can be diagnosed on basis of MRI (pontine). Biopsy felt unnecessary. Radiation offered as palliation.” “MR scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: A report from the children's cancer group” (Albright et al, 1993) DIPG (DFCI Protocol 10-321) 10 years ago PBTC concept submitted 2006; declined by CTEP New protocol structure required by Harvard Clinical Trial Office September 14, 2009 IND submitted March 10, 2010 granted July 16 2010 Submitted for Harvard Scientific Review Oct 6, 2010 Scientific review approval March 10, 2011 IRB review March 21,2011; IRB approval Sept 1, 2011 IDE requirement as of February 2011 Submitted March 2011, IDE review end of Sept 2011 Accrual started in 2012, closed in 2015 (25 sites) PNOC Translational Genomics Research Institute | www.tgen.org H3F3A TP53 ATRX PDGFRA KDR KIT MET PPM1D HIST1H3B IGF1R BRAF PIK3R1 PTEN CRKL MAPK1 79% 79% 36% 29% 21% 21% 21% 14% 7% 7% 7% 7% 7% 7% 7% Significant Alterations & Treatment Recommendations Treatment recommended PNOC-003-01 Etoposide, dasatinib PNOC-003-02 Cabozantinib, etoposide, mebendazole PNOC-003-04 Temozolomide, sertraline PNOC-003-05 Panobinostat, mebendazole PNOC-003-06 Panobinostat, mebendazole PNOC-003-07 Panobinostat, everolimus, sertraline, mebendazole PNOC-003-08 Panobinostat PNOC-003-09 Panobinostat PNOC-003-10 Vemurafenib/dabrafenib, trametinib, minocycline, panobinostat PNOC-003-11 Etoposide, metformin, mebendazole, sertraline PNOC-003-12 Panobinostat, everolimus, mebendazole, valproic acid PNOC-003-13 Panobinostat, mebendazole, cabozantinib, valproic acid PNOC-003-14 Panobinostat, cabozantinib, valproic acid, mebendazole PNOC-003-16 Panobinostat, mebendazole, propranolol, valproic acid Gain Deletion Mutation (Missense, Nonsense, Frameshift) PNOC Meeting Two Weeks Ago! What really constitutes “Precision Medicine”? Just profile and treat (is that research?) With what “targets” (mutations, pathways, microenvironment, altered immunity) With how many agents (one, two, more?) How to deliver (oral, IV, intra-nasal, intra-tumor, CED, ?others) How to monitor response/progression (MRI, PET, circulating tumor DNA, CSF, clinical) How to treat at relapse How should we prioritize: only 300-400 cases/year What genomics platform should we use How can we afford to do the research DIPGs exhibit a higher mutation rate than PLGGs, but a lower rate compared to adult cancers DIPG Methylation profiling reveals three molecular subgroups of DIPG Nat Genet. 2014 May; 46(5): 451–456. Molecular subgroups of DIPG share common clinical features and recurrent genomic events(a) Clinical and genomic features such as gender, histology, frequency of recurrent mutations, alternative lengthening of telomeres and copy number alterations are represented in a DIPG subgroup specific manner. (b) Probability of two mutational or structural features of DIPG co-occurring based on odds ratio suggests statistically significant association between K27MH3.3 and PDGFRA amplifications (OR = 8.0, p = 0.0127) and between K27M-H3.1 and ACVR1 mutations (OR = 15.8, p < 0.001). (C) Probability of mutations or structural event of DIPG occurring with a clinical feature such as gender or tumor histology based on odds ratio shows statistically significant correlation between P53 mutations and GBM histology (OR = 10.8, p < 0.005), among others. Nat Genet. 2014 May; 46(5): 451–456. “Google map” of glioma subtypes Genomics Institute at UCSC has developed Tumor Map, a tool that lays out cancer samples according to the similarity of their genomic profiles for interactive exploration, new data overlay visualization, and statistical analysis. Tumor Map plots individual tumors as dots that form a landscape-like topology representing genomic similarity in a framework that will be familiar to any user of Google Maps. Heterogeneity Exists in DIPG Nat Genet. 2014 May; 46(5): 444–450. Biology, Maps, Precision How to get from point A to B to C and back again Translational Genomics Research Institute | www.tgen.org Mutational Burden (Somatic Coding) Sample IVY-01-016 IVY-01-019 Non-hypermutated cases (Median, Range) 2,819 1,549 64 (40-135) 121 93 6 (3-12) Circos Plot Full Strexome (~20,000 genes) # SNV and indels GEM Panel ~567 genes # Mutations in Genes Covered by Panel ATRX I1680T ARHGAP33 R303Q TNFRSF10A I38M CDK16 I231V Patient1 RAB8A SPLICE_SITE_ACCEPTOR PARPBP Q59E ARHGAP17 EGFR TNFRSF10B PDGFRA P777S A289V T125 L1108F EGFR I106S ATM E281* ARHGEF19 A686D MAP3K5 E512K SPLICE_SITE_ACCEPTOR S229C C2F E495 Primary Relapse Post-Relapse NOTCH3 EGFR PIK3AP1 SLIT1 EGFR A289D Patient 01 network analysis ‘Ideal’ Therapeutic Pipeline biology pre-clinical testing human trials Development of Brainstem Tumor Model NSCID Nude Biopsy Rat Brainstem injection NSCID SC injection High Grade SF8628 hTERT Low Grade SF7761 + LTR GAG BamHI Primary cell culture SV40 blast LTR EcoRI hTERT modification Immortalized cells Luciferase modification H3K27M Mutation in DIPG Cells 1. Levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient cell lines (H3.3K27M) 2. H3K27me3 and Ezh2 are dramatically increased at hundreds of gene loci in H3.3K27M cells 3. Gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. GSK-J4 Inhibits Tumor Growth in vivo Nature Medicine 20(12):1394 (2014) GSK-J1 – Selective JMJ Demethylase Inhibitor Nature 488:404-8 (2012) Therapeutic Pipeline - Challenges biology • Key biologic correlative studies performed with difficulty • Pure science (initially) may not have a translational link pre-clinical testing • Limited emphasis placed on model development • Are relevant models used? • Throughput? • Role of NCI? human trials • Study design for conventional phase I trials does not favor novel treatment strategies • Participation of drug company essential is often limiting factor (orphan drug) Therapeutic Pipeline - Recommendations biology • Comprehensive molecular analyses required • Centralized data review and prioritization pre-clinical testing human trials • Tightly linked to predicted biologic endpoints • Standardized model systems • Parallel inclusion of pharma; incentives required • NCI/NIH (?) • Surgical templates • Early inclusion of regulatory agencies • Most pediatric CNS tumors should be viewed as rare disease problems • Separate delivery and efficacy Biology, Maps, Precision How to get from point A to B to C and back again Overall therapeutic approach Newly diagnosed children (< 25 years) with High Grade Glioma (HGG) or DIPG (n=60) • HLA2 + and • H3.3K27 M + PNOC007: K27M peptide Vaccine trial • • • • HGG (DIPG excluded) Fully resected HLA2 negative or H3.3K27M negative PNOC012: Dendritic Cell Vaccine trial Anti-PD-1 plus XRT • Not suitable for PNOC012 or 07 CED CPT11 for DIPG Precision Medicine Approach