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PARP Inhibitors: Usurping DNA repair to target cancer

PARP Inhibitors: Usurping DNA repair to target cancer. Lee Schwartzberg MD, FACP Chief Medical Officer The West Clinic. Question 1. DNA repair mechanisms are important in Cancer cells only Both cancer and normal eukaryotic cells

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PARP Inhibitors: Usurping DNA repair to target cancer

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  1. PARP Inhibitors:Usurping DNA repair to target cancer Lee Schwartzberg MD, FACP Chief Medical Officer The West Clinic

  2. Question 1 DNA repair mechanisms are important in • Cancer cells only • Both cancer and normal eukaryotic cells • Predominantly in rapidly growing cells like bone marrow precursors • Predominantly cancer cells with BRCA mutations

  3. Question 2 PARP inhibitors have demonstrated activity in: • BRCA 1 mutation carrier breast cancer • BRCA 2 mutation carrier breast cancer • Triple negative breast cancer • 1 and 3 only • 1 and 2 only • All of the above

  4. All cells are under constant risk of DNA damage • Ultraviolet light • Ionizing radiation • Man-made and natural chemicals • Reactive oxygen species • most are generated “endogenously” • 10,000 Single Strand Breaks/ cell/day • ~100,000,000,000,000,000 DNA lesions in a human body every day1-3 1. Jackson SP. Biochem Soc Trans 2001;29:655-661 2. Lindahl T. Nature 1993;362:709-715 3. Jackson SP, Bishop CL. Drug Discovery World 2003;(Fall):41-45

  5. Cellular Response To DNA Damage

  6. Cancer cells are highly susceptible to DNA repair inhibition • Undergo deregulated proliferation • Less time for DNA repair than in normal cells • Grow under stress, which causes ongoing DNA damage • Have DNA repair defects • P53, BRCA1, BRCA 2, ATM, Fanconi’s Anemia • Allow growth despite ongoing genome instability • Are reliant on the DNA repair pathways they still retain

  7. DNA Excision Repair Mechanisms

  8. Poly(ADP-Ribose) Polymerase (PARP) A key role in the repair of DNA single-strand breaks Through the base excision repair pathway (BER) Binds directly to sites of DNA damage Once activated, it uses NAD as a substrate, and generates large, branched chains of poly (ADP-ribose) polymers on multiple target proteins Recruits other DNA repair enzymes Polß PNK XRCC1 Lig3 PAR

  9. Base Excision Repair

  10. DNA single strand break (SSB) damage PNK 1 XRCC1 pol β LigIII • Inhibition of PARP-1 prevents • recruitment of DNA repair enzymes • leads to failure of SSB repair • -accumulation of SSBs PARP During S-phase, replication fork is arrested at site of SSB Inhibiting PARP-1 Increases Double-Strand DNA Damage Degeneration into Double strand breaks

  11. BRCA1 And 2 Are Required for Efficient Repair of Double Stranded DNA Breaks Cancer cell death Cellsurvival DNA DSB ATM/R gH2AX BRCA1 Rad50 MRE11 NBS1 Non-homologous end-joining Homologous recombination Ku 70/80 BRCA2 Rad 51 RPA Rad 52/4 DNA-PKcs ERCC1 XRCC3 XRCC4 LigaseIV Predominant in G1 Error-prone Gross Genomic instability Major pathway for repair Error-free • Cells with BRCA mutations are deficient in homologous recombination and lack the ability to efficiently repair DSBs.

  12. The Concept of Synthetic Lethality (BRCA) (PARP) Ashworth, A. J Clin Oncol; 26:3785-3790 2008

  13. Log surviving fraction 0 - 1 - 2 Wild type BRCA2 +/- - 3 BRCA2 -/- - 4 10-9 10-8 10-7 10-6 10-5 10-4 0 PARP inhibitor concentration (M) BRCA1 and BRCA2 -/- cells are very sensitive to PARP inhibition Increased levels of chromosomal aberrations in PARP inhibitor treated BRCA2 -/- cells Wild type Control + PARP inhibitor BRCA2 -/- Control + PARP inhibitor Farmer H et al. Nature 2005;434:917-920 Personal communication, Alan Ashworth

  14. PARP Inhibitors in Clinical Development • Differing chemical structures • Differing toxicity • Differing schedules and routes of administration

  15. Chemotherapeutic Agents: Double Strand DNA Breaks Kennedy R et al. JNCI 2004; 96:1659-1668

  16. PARP Inhibitors in BRCA 1/2 Mutated Tumors

  17. Phase I Trial of Olaparib in Patients with Solid Tumors • Escalation and expansion phase, n = 60 • Recommended phase II dose: 400 mg PO BID • Toxicities • Nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), anorexia (12%), anemia (5%) • Clinical activity = 12/19 patients with BRCA mutations Fong PC et al. N Engl J Med 2009; 361:123-134

  18. Phase II Trial of Olaparib in BRCA-deficient Metastatic Breast Cancer (Non-randomized sequential cohorts) Cohort 1 Olaparib 400 mg po bid (MTD) 28-day cycles Cohort 2* Olaparib 100 mg po bid (maximal PARP inhibition) 28-day cycles Primary Endpoint: Response rate *Following an interim review, patients in the 100 mg bid cohort were permitted to crossover to receive 400 mg bid Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

  19. Olaparib in BRCA-deficient Metastatic Breast Cancer: Select Toxicities Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

  20. Olaparib in BRCA-deficient Metastatic Breast Cancer: Results Best percent change from baseline in target lesions by genotype Median 3 prior lines of therapy Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

  21. PARPiMonotherapy in BRCA Mutated tumors

  22. Prior response to platinum may predict response to olaparib in BRCA mutated Ovarian Cancer Gelmon K, et al J Clin Onc 2010

  23. PARP Inhibitors beyond BRCA mutation carriers

  24. Triple Negative Breast Cancer (TNBC) • ‘Triple negative’: ER-negative, PR-negative, HER2-negative • Depending on thresholds used to define ER and PR positivity and methods for HER2 testing • TNBC accounts for 10–17% of all breast carcinomas • Significantly more aggressive than other molecular subtype tumors • Higher relapse rate than other subtypes • No specific targeted therapy Reis-Filho JS, et al. Histopathology 2008;52:108-118.

  25. TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast Cancers (“BRCAness”) *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44 1Perou et al. Nature. 2000; 406:747-752 2Cleator et al.Lancet Oncol 2007;8:235-44 3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-74 4 Miyoshi et al. Int J Clin Oncol 2008;13:395-400

  26. Targeting DNA Repair Pathway in TNBC • Clustering analyses of microarray RNA expression have shown that familial BRCA-1 tumors strongly segregate with basal-like/ triple-negative tumors • Suggests that sporadic TNBC may have acquired defects in BRCA1-related functions in DNA repair Basal-like = BRCA1+ = BRCA2+ Sorlie T et al. PNAS 2003;100:8418-8423

  27. Predictors of Response to Cisplatin in TNBC Silver, D. P. et al. J Clin Oncol; 28:1145-1153 2010

  28. Phase II Study of the PARP inhibitor Iniparib in Combination with Gemcitabine/Carboplatin in Triple Negative Metastatic Breast Cancer Background and Rationale • PARP1 • Upregulated in majority of triple negative human breast cancers1 • Iniparib (BSI-201) • Small molecule IV PARP inhibitor • Potentiates effects of chemotherapy-induced DNA damage • No dose-limiting toxicities in Phase I studies of BSI-201 alone or in combination with chemotherapy • Marked and prolonged PARP inhibition in PBMCs O’Shaughnessy J, et al. NEJM 2011

  29. Phase II TNBC Study: Treatment Schema Metastatic TNBC N = 120 RANDOMIZE 1st -3rd line MBC Eligible BSI-201(5.6 mg/kg, IV, d 1, 4, 8, 11) Gemcitabine (1000 mg/m2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) Gemcitabine(1000 mg/m2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) 21-Day Cycle RESTAGING Every 2 Cycles * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression

  30. Safety – Hematologic ToxicityPhase II Gem Carbo +/- Iniparib *Transfusion and/or EPO use O’Shaughnessy J, et al. NEJM 2011

  31. Safety – Non-Hematologic ToxicityPhase II Gem Carbo +/- Iniparib O’Shaughnessy J, et al. NEJM 2011

  32. Final Results:Phase II: Gem Carbo +/- Iniparib in TNBC O’Shaughnessy J et.al. NEJM 2011

  33. Final Results:Phase II Gem Carbo +/- Iniparib in TNBC O’Shaughnessy J, et.al. NEJM 2011

  34. Phase I: Olaparib + Paclitaxel in 1st and 2nd line MBC • BKG: Olaparib single agent activity in BRCA 1/2 mutated MBC • Olaparib + paclitaxel, N=19, 70% 1st line, unselected for BRCA mutations • 33-40% RR; no CRs • Median PFS: 5.2-6.3 months • Hematologic toxicity high, requires G-CSF • Dose reductions common • Unclear whether combination be taken forward

  35. Resistance to PARP Inhibitors: Reversion of BRCA2 mutations • Partial function of BRCA2 is restored and cells become competent for homologous recombination repair Edwards SL et al. Nature 2008; 451:1111-1115

  36. The Future of PARP inhibitors: Many Unanswered Questions • Can we use these agents more broadly? • To treat other tumors with specific DNA repair defects, i.e. sporadic loss of BRCA 1/2, tumors with PTEN mutations • Challenge is to identify them • Timing of PARP inhibitor in relation to cytotoxic agent (before it, with it, how long to continue it?)

  37. Conclusions • Targeting DNA repair mechanisms in tumor cells is a rational target • PARP is an integral enzyme in DNA repair • Multiple PARP inhibitors are available • Preliminary results show activity in BRCA mutated cancers (Breast and Ovarian) • Preliminary results show activity of iniparib with chemotherapy in TNBC • Phase III results forthcoming

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