Discover Personalized Medicine: Gordon Mills, PD, PhD
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Discover Personalized Medicine: Gordon Mills, PD, PhD
- 1. Sheikh Khalifa bin Zayed Al Nahyan Institute for Personalized Cancer Therapy John Mendelsohn Gordon Mills Funda Meric-Bernstam Kenna Mills Shaw DELIVERING ON THE PROMISE OF PERSONALIZED MOLECULAR MEDICINE IN OVARIAN CANCER
- 2. Targeted Therapy For Cancer Tumor Capitalizing on the vulnerabilities (Achilles Heel) of cancer
- 3. Ovarian Cancer Karst and Drapkin et al Faculty 1000 Medicine High Grade Serous Ovarian Cancer Is Probably Fallopian Tube Cancer • 22,000 new cases and 15,500 deaths in the USA • Low grade and high grade tumors have distinct genomic aberrations • Low grade and high grade tumors do not interconvert • HGSEOC is the most common and aggressive form of ovarian cancer
- 4. DIFFERENT HISTOLOGICAL SUBTYPES OF OVARIAN CANCER INDICATE DIFFERENT THERAPEUTIC OPPORTUNITIES Serous Endometrioid Mucinous Clear cell High grade low grade High grade low grade Low grade serous KRAS Clear Cell PIK3CA mutations Endometrioid ARID1A mutation and deletion PARP inhibitors Mucinous Probably metastatic colon High grade serous p53, BRCA1/2 copy number long tail of actionable mutations Targeted agents Bevaczumib PARP inhibitors have now been FDA approved
- 5. Interstrand crosslink Double-strand break DNA alkylation O 6-alkylguanine Uracil Abasic site 8-Oxoguanine Single-strand break Ionising radiation Antitumour agents Alkylating agents Ionising radiation Oxygen radicals Spontaneous reactions Antitumour agents (6-4)PP Bulky adduct CPD UV light Polycyclic aromatic hydrocarbons Replication errors A-G mismatch T-C mismatch Insertion Deletion Me Recombinational repair (HR, NHEJ) Direct reversal (AGT, MGMT) Base excision repair Nucleotide excision repair Mismatch repair Modified from Hoeijmakers, J. H. (2001) Nature 114, 366-374. MAJOR MECHANISMS OF DNA DAMAGE AND REPAIR O6BG PaTrin PARPi DNA PKi ATMi
- 6. Normal Cells DNA Damage HR mediated-repair BRCA1 Unknown factors Rad51 RPA Others factors Death DSB SSB PARP mediated repair BRIT1 ATM PARP Others factors HR-deficient Cancer Cells x x BRCA1 BRCA2 PARP inhibitors induce synthetic lethality in HR-deficient cancer cells PARPness: Can we identify patients likely to benefit from PARP inhibitors BRCA1/BRCA2 mutations Germline Somatic BRCA1/2 loss Other members of complex PTEN loss? ARID1A HRD genomic scaring assay regional loss of heterozygosity CLIA assay in development HRD RNA predictor HRD protein predictor PARP inhibitors x x PARP inhibitors x x DNA Damage HR mediated-repair BRCA1 BRIT1 ATM Unknown factors Rad51 RPA Others factors Survival DSB SSB PARP mediated repair BRCA2 PARP Others factors
- 7. Aberrations in BRCA1/2 HR pathway in HGSOC (86% of 574 cases) ATR, ATM, BRCA1/2 are needed for efficient repair Loss of TP53BP1 reverses HR defect induced by BRCA1 deficit and protects from effects of DNA damage TP53BP1 is downregulated by PI3K pathway inhibition (RPPA arrays) C11ORF30 = EMSY EMSY decreases BRCA2 PTEN contributes to HR and PARP sensitivity 0 50 100 150 020406080100 Months Survival %Surviving Gene Set Not Altered Gene Set Altered Logrank test p−value: 0.000042 BRCA1, BRCA2, ATR ATM: homdel exp<-1 mut C11ORF30: amp exp>1 PTEN: homdel, exp<-1 prot<-1 mut TP53BP1: homdel mut exp<-1 prot<-1
- 8. Samples with BRCA1, BRCA2, or RAD51C deficiency Samples with BRCA1 mutations Samples with BRCA2 mutations Samples with BRCA1 low expression or promoter methylation Samples with RAD51C promoter methylation Samples with intact BRCA1, BRCA2, and RAD51C HRD-LOH score HRD genomic scarring LOH Loss of heterozygosity Telomeric Allelic Imbalance Large scale transitions Myriad Hennessey
- 9. Abkevich et al, BJC, 2012 4.1 years 3.1 years TCGA dataset median dicotomized p = 0.00006 HRD prognosticates overall survival
- 10. HRD score predicts PARPi response ARIEL2 Rucaparib HRD Subgroup Median PFS, mo (90% CI) BRCAmut 9.4 (7.3, Not Reached) HRD positive 7.1 (3.7, 10.8) Biomarker Negative 3.7 (3.5, 5.5) Subgroup Comparison Hazard Ratio (90% CI) BRCAmut vs Biomarker Negative 0.47 (0.35, 0.64) HRD vs Biomarker Negative 0.61 (0.41, 0.92) PFS by HRD biomarker status Biomarker Negative 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (months) PFS McNeish and colleagues ARIEL2 HRD positive BRCAmut
- 11. UNEXPECTED HIGH RATE OF FAILURE OF TARGETED THERAPEUTICS Even for patients with the biomarker only subpopulations of patients benefit: Usually short term Three resistance mechanisms Intrinsic (Genetic) Selected (Genetic) Adaptive (Homeostatic loops, cross talk and bypass) Rationale combinatorial therapy Systems are robust to single perturbations. Tumors exhibit decreased robustness and may be more sensitive to multiple perturbations Yarden and Lander CHALLENGES TO PERSONALIZED TARGETED THERAPY
- 12. Combination of a PI3Ki and a PARPi Gerburg Wulf and SU2C PI3K in Women’s Cancer Team
- 13. Ovarian Cancer Breast Cancer PI3K Dream Team http://pi3k.org 77% OvCa gBRCA 57% BrCa gBRCA Non mutant BRCA1/2 2 PR One biopsy: ATR mutant N=46 N=24 BKM and Olaparib demonstrate marked responses
- 14. Time on Treatment PI3K Dream Team http://pi3k.org On study
- 15. 15 COTI-2: A novel and effective p53 normalizing agent N N N H S N N N • Novel small molecule o Formula = C19H24N6S o 3rd generation Thiosemicarbazone • Discovered in a NSCLC screen • Simple 3 step synthesis • Active in >10 xenografts • IND Approved • Phase I trial pending • NSC319726 p53 normalizer is a thiosemicarbazone • NSC319726 is a Zn chelator and transporter allowing refolding of a subset of p53 mutations
- 16. TP53 is the most commonly mutated gene in the human genome R273 R248 R175 R220 Ovary Lung
- 17. COTI-2 is active in naturally occurring p53 mutant lines in vivo Intravenous Oral Established OVAR3 Ovarian Cancer Cell Line (R248Q) 75-100mm3 3xper week
- 18. COTI2 TP53 mutations in ovarian cancer R248 G245 R273 Y220C I195FR175H C242 R273P/G G245C/V R175H/L R248Q/W C275S/F C275