Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 1. Cancer cells only 2. Both cancer and normal eukaryotic cells 3. Predominantly in rapidly growing cells like bone marrow precursors 4. Predominantly cancer cells with BRCA mutations Question 2 PARP inhibitors have demonstrated activity in: 1. BRCA 1 mutation carrier breast cancer 2. BRCA 2 mutation carrier breast cancer 3. Triple negative breast cancer 4. 1 and 3 only 5. 1 and 2 only 6. All of the above 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 Cellular Response To DNA Damage 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 DNA Excision Repair Mechanisms 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 PAR XRCC1 Lig3 PNK Polß Base Excision Repair Inhibiting PARP-1 Increases Double-Strand DNA Damage DNA single strand break (SSB) damage PNK 1 XRCC1 pol β LigIII PARP During S-phase, replication fork is arrested at site of SSB Inhibition of PARP-1 prevents -recruitment of DNA repair enzymes -leads to failure of SSB repair -accumulation of SSBs Degeneration into Double strand breaks BRCA1 And 2 Are Required for Efficient Repair of Double Stranded DNA Breaks DNA DSB ATM/R gH2AX BRCA1 MRE11 Non-homologous end-joining Ku 70/80 DNA-PKcs XRCC4 Cancer cell death Ligase IV Predominant in G1 Error-prone Gross Genomic instability Rad50 NBS1 Homologous recombination BRCA2 Rad 51 RPA Rad 52/4 ERCC1 XRCC3 Major pathway for repair Error-free Cell survival Cells with BRCA mutations are deficient in homologous recombination and lack the ability to efficiently repair DSBs. The Concept of Synthetic Lethality (BRCA) (PARP) Ashworth, A. J Clin Oncol; 26:3785-3790 2008 BRCA1 and BRCA2 -/- cells are very sensitive to PARP inhibition Increased levels of chromosomal aberrations in PARP inhibitor treated BRCA2 -/- cells 0 Log surviving fraction -1 Wild type Control -2 Wild type BRCA2 +/BRCA2 -/- -3 -4 0 10-9 10-8 10-7 10-6 10-5 PARP inhibitor concentration (M) + PARP inhibitor BRCA2 -/- 10-4 Control + PARP inhibitor Farmer H et al. Nature 2005;434:917-920 Personal communication, Alan Ashworth PARP Inhibitors in Clinical Development Differing chemical structures Differing toxicity Differing schedules and routes of administration Chemotherapeutic Agents: Double Strand DNA Breaks Alkylators DNA interstrand crosslinks double strand (DS) DNA breaks Cyclophosphamide Platinums Forms adducts with DNA Cisplatin Carboplatin Oxaliplatin Topoisomerase I poisons Arrest of DNA replication forks Etoposide Irinotecan Topotecan Mitoxantrone Topoisomerase II DNA interstrand crosspoisons linking, generation of O2 free radicals Bleomycin Directly damages DNA DS DNA breaks Kennedy R et al. JNCI 2004; 96:1659-1668 Doxorubicin Epirubicin PARP Inhibitors in BRCA 1/2 Mutated Tumors 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 Tumor BRCA No. of pts Response Breast 2 2 1 CR, 1 SD Ovarian 1 or 2 8 8 PRs Fallopian tube 1 1 PR Prostate 2 1 PR Fong PC et al. N Engl J Med 2009; 361:123-134 Phase II Trial of Olaparib in BRCA-deficient Metastatic Breast Cancer Eligibility Confirmed BRCA1 or 2 mutation Stage IIIB/C or IV BC after progression ≥ 1 prior chemotherapy for advanced disease (Non-randomized sequential cohorts) Cohort 1 Cohort 2* Olaparib 400 mg po bid (MTD) Olaparib 100 mg po bid 28-day cycles 28-day cycles (maximal PARP inhibition) 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) Olaparib in BRCA-deficient Metastatic Breast Cancer: Select Toxicities Olaparib 400 mg BID (n = 27) Olaparib 100 mg BID (n = 27) Grade 1/2 Grade 3 Grade 1/2 Grade 3 Fatigue 15 (56) 4 (15) 15 (56) 2 (7) Nausea 11 (41) 5 (19) 15 (56) 0 Vomiting 7 (26) 3 (11) 6 (22) 0 Headache 10 (37) 0 5 (19) 1 (4) Constipation 6 (22) 0 8 (30) 0 Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501) Olaparib in BRCA-deficient Metastatic Breast Cancer: Results Median 3 prior lines of therapy ITT cohort 400 mg BID N = 27 100 mg BID N = 27 ORR 11 (41%) 6 (22%) CR 1 (4%) 0 PR 10 (37%) 6 (22%) Median PFS 5.7 mo (4.6-7.4) 3.8 mo (1.9 – 5.6) Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501) Best percent change from baseline in target lesions by genotype PARPi Monotherapy in BRCA Mutated tumors Drug Phase Dose Tumor N CBR (%) RR (%) MDR (MOS) PFS (MOS) Olapirib 1 Varies Ovarian 50 46 40 6.5 NR Olapirib 2 400 mg Ovarian BID 33 NR 35 9.6 NR Olapirib 2 100 mg Ovarian BID 24 NR 13 9.0 NR Olapirib 2 400 mg Breast BID 27 NR 41 NR 5.7 Olapirib 2 100 mg Breast BID 27 NR 22 NR 3.8 MK4827 1 Varies Ovarian 19 45 MK4827 1 Varies Breast 4 50 Prior response to platinum may predict response to olaparib in BRCA mutated Ovarian Cancer Gelmon K, et al J Clin Onc 2010 PARP Inhibitors beyond BRCA mutation carriers 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. TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast Cancers (“BRCAness”) Characteristics ER/PR/HER2 status TP53 status BRCA1 status Gene-expression pattern Tumor histology Chemosensitivity to DNAdamaging agents Hereditary BRCA1 Triple Negative/Basal-Like1,2,3 Negative Negative Mutant Mutant Mutational inactivation* Diminished expression* Basal-like Basal-like Poorly differentiated (high grade) Poorly differentiated (high grade) Highly sensitive Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44 1Perou et al. Nature. 2000; 406:747-752 et al.Lancet Oncol 2007;8:235-44 2Cleator 3Sorlie 4 et al. Proc Natl Acad Sci U S A 2001;98:10869-74 Miyoshi et al. Int J Clin Oncol 2008;13:395-400 Targeting DNA Repair Pathway in TNBC Clustering analyses of microarray RNA expression have shown that familial BRCA-1 tumors strongly segregate with basal-like/ triplenegative tumors Suggests that sporadic TNBC may have acquired defects in BRCA1related functions in DNA repair Basal-like = BRCA1+ Sorlie T et al. PNAS 2003;100:8418-8423 = BRCA2+ Predictors of Response to Cisplatin in TNBC Silver, D. P. et al. J Clin Oncol; 28:1145-1153 2010 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 Phase II TNBC Study: Treatment Schema Metastatic TNBC N = 120 RANDOMIZE Gemcitabine (1000 mg/m2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) 21-Day Cycle 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) RESTAGING Every 2 Cycles * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression Safety – Hematologic Toxicity Phase II Gem Carbo +/- Iniparib Gem/Carbo (n = 59) BSI-201 + Gem/Carbo (n = 57) Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 12 (20.3%) 7 (11.9%) 0 (0.0%) 15 (26.3%) 7 (12.3%) 0 (0.0%) Thrombocytopenia, n (%) 7 (11.9%) 6 (10.2%) 6 (10.2%) 4 (7.0%) 6 (10.5%) 7 (12.3%) Neutropenia, n (%) 7 (11.9%) 18 (30.5%) 13 (22.0%) 7 (12.3%) 18 (31.6%) 7 (12.3%) Febrile neutropenia, n (%) 0 (0.0%) 3 (5.1%) 1 (1.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) RBC treatment*, n (%) 5 (8.5%) 5 (8.5%) 2 (3.4%) 3 (5.3%) 5 (8.8%) 2 (3.5%) G-CSF Use, n (%) 6 (10.2%) 6 (10.2%) 3 (5.1%) 4 (7.0%) 5 (8.8%) 1 (1.8%) Anemia, n (%) *Transfusion and/or EPO use O’Shaughnessy J, et al. NEJM 2011 Safety – Non-Hematologic Toxicity Phase II Gem Carbo +/- Iniparib Gem/Carbo (n = 59) BSI-201 + Gem/Carbo (n = 57) Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Nausea, n (%) 10 (16.9%) 2 (3.4%) 0 (0.0%) 7 (12.3%) 0 (0.0%) 0 (0.0%) Vomiting, n (%) 9 (15.3%) 0 (0.0%) 0 (0.0%) 4 (7.0%) 1 (1.8%) 0 (0.0%) Fatigue, n (%) 10 (16.9%) 6 (10.2%) 0 (0.0%) 10 (17.5%) 1 (1.8%) 0 (0.0%) 2 (3.4%) 0 (0.0%) 0 (0.0%) 1 (1.8%) 0 (0.0%) 0 (0.0%) 6 (10.2%) 1 (1.7%) 0 (0.0%) 1 (1.8%) 1 (1.8%) 0 (0.0%) Neuropathy, n (%) Diarrhea, n (%) O’Shaughnessy J, et al. NEJM 2011 Final Results: Phase II: Gem Carbo +/- Iniparib in TNBC O’Shaughnessy J et.al. NEJM 2011 Final Results: Phase II Gem Carbo +/- Iniparib in TNBC O’Shaughnessy J, et.al. NEJM 2011 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 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 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?) 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