HDAC Inhibitors and PARP inhibitors Suresh Ramalingam, MD Associate Professor Chief of Thoracic Oncology Emory University School of Medicine Histone Acetylation HAT Ac Ac Ac Ac HDAC Ac Ac Ac Ac mrna
DACs are Implicated in Cancer by Modulating Histone and Non-Histone Proteins Involved in Oncogenesis DAC DAC DAC DAC DAC Proteins modulated by DACs Histone p53 a-tubulin HIF-1a HSP90 Histone proteins are implicated in epigenetic modifications that could cause cancer Non-histone proteins are implicated in multiple oncogenic pathways HDAC Inhibitors in Solid Tumors: Monotherapy Author Agent Disease Response Traynor Vorinostat NSCLC 0/13 Krug Vorinostat Mesothelioma 2/13 Ramalingam Belinostat Mesothelioma 0/13 Blumenschein Vorinostat Head & Neck 0/14 Chew Vorinostat Breast 0/13
SAHA/Vorinostat (Suberoylanilide Hydroxamic Acid) Small molecule (MW < 300) Binds inside the catalytic site of HDAC Blocks substrate access to the active zinc ion Zinc Part of a new class of drugs that target select members of class I and II HDACs Marks PA, et al. Nat Rev Cancer. 2001;1:194-202; Villar-Garea A, et al. Int J Cancer. 2004;112:171-178. Vorinostat: Early Clinical Experience Tolerated at doses up to 400 mg PO QD (2 weeks on, 1 week off) Common toxicities Nausea, emesis, fatigue, thrombocytopenia Approved for treatment of refractory CTCL Disease stabilization noted in NSCLC patients
Vorinostat + Chemotherapy Promising anti-cancer activity in advanced NSCLC 10/19 objective responses; 4 patients with SD. Objective Response In A Patient With Advanced NSCLC Baseline After 2 Cycles
Rand Phase II Study N=94 Patients Stratification Factors: Gender Brain metastasis - Maximum of 6 cycles - No cross over - No maintenance therapy 2 1 Carboplatin (AUC=6 mg/ml X min) (d 3) Paclitaxel 200 mg/m 2 (d 3) Vorinostat 400 mg QD(d1-14) Carboplatin (AUC = 6 mg/ml X min) (d 3) Paclitaxel 200 mg/m 2 (d 3) Placebo QD (d 1-14) Ramalingam et al, J Clin Oncol, 2010 Non-Hematological Toxicity Toxicity Vorinostat (%) Gr 3/4/5 Placebo (%) Gr 3/4/5 Nausea 16/5/0 6/0/0 Vomiting 16/3/0 9/0/0 Diarrhea 8/0/0 9/0/0 Anorexia 13/2/0 9/0/0 Fatigue 30/3/0 21/3/0 Constipation 5/0/0 9/3/3 Neuropathy 16/0/0 16/3/0 Infection 0/3/0 0/0/3 Dehydration 3/10/0 - Sodium, Serum-low 0/17/2 0/9/0 Treatment-related deaths 3% -
Efficacy Response rate (RECIST) Vorinostat Placebo Hazard Ratio P 34% 12.5% 0.021 Median PFS 6.0 m 4.1 m 0.79 0.33 Median survival 13 m 9.7 m 0.67 0.17 1-year survival rate 53% 35% Next Steps A phase III study conducted by Merck & Co. was closed early due to futility A shorter schedule of 5 days of vorinostat every 3 weeks is currently under evaluation (in combination with carboplatin and paclitaxel)
Potential Applications of HDAC Inhibitors Comb with Tamoxifen ER alpha Comb with platinum DNA Repair HDAC inhibition Hsp Func Combination with Hsp inhibitors TS 5-FU, Pemetrexed-based combinations Adapted from Glaser, Biochem Pharmacol, 2007 HDAC: Strategies Under Evaluation HDAC inhibitors + chemotherapy HDAC inhibition + EGFR inhibition HDAC inhibition + Demethylating agents Optimal utilization requires strategy to select predictive biomarkers
PARP is an Important Mediator of DNA Repair From Plummer, H., and Calvert,, H. (2007) Clin Can Res, 13, 6252-56 PARP Activated in response to DNA damage Facilitates DNA repair At least 17 members of PARP family have been described PARP-1 localizes to the site of DNA damage and recruits proteins that mediate repair Double knockout of PARP 1 & 2 results in embryonal lethality to mice
PARP Activity in Cancer Overexpression of PARP-1 has been reported in several cancers Enhances the ability of cells to withstand genotoxic stress and induces resistance to DNA-damaging agents PARP-1 also plays a role in angiogenesis Olaparib in BRCA-mutated Tumors Fong et al, N Engl J Med, 2009
BSI-201: A Novel PARP Inhibitor Randomized phase II study Triple negative breast cancer N=123 pts Carbo + Gem Carbo+ Gem + BSI-201 Response rate 16% 48% (P=0.002) Median PFS 3.3 m 6.9 m (P<0.0001) Median survival 5.7 m 9.2 m (P = 0.0005) O Shaughnessy et al, ASCO 2009 Rationale for PARP Inhibition in Lung Cancer BRCA mutations are rare in lung cancer Platinum compounds are the cornerstone for treatment of lung cancer Other DNA damaging agents such as topoisomerase inhibitors are also active agents PARP inhibition enhances the lethality of DNA-damaging agents
Veliparib (ABT 888): PARP Inhibitor Potent Inhibitor PARP-1, 2 K i = 5, 3 nm Cellular EC 50 = 2 nm Orally bioavailable % F human = > 80% Pharmaceutical properties Low molecular weight Highly soluble Crosses BBB Metabolic profile Not a PgP substrate H 2 N Donawho, Clin Cancer Res. 13(9):2732, (2007) O N N H H 3 C N H In vivo preclinical activity with: Cisplatin Carboplatin Cyclophosphamide Irinotecan Topotecan Temozolomide (TMZ) Radiation Penning, Chemistry in Cancer Research Conference, ACS/AACR, (2007) Veliparib + Carboplatin
Veliparib + Cisplatin Veliparib + Radiotherapy
ABT-888: PAR Inhibition in Tumor Biopsies Ph 0 Study Kummar et al, J Clin Oncol, 2009 A Phase I Study of ABT-888 in combination with carboplatin and paclitaxel in advanced solid malignancies NCI 7967
Study Endpoints Primary objective To determine the recommended dose of ABT-888 that can be administered in combination with carboplatin and paclitaxel in patients with advanced solid malignancies. Secondary objectives To evaluate the pharmacokinetic parameters of ABT-888, carboplatin and paclitaxel when administered as a combination To conduct correlative science studies including determination of the effect of ABT-888 on carboplatin-induced DNA adduct formation in PBMC and in tumor specimens Phase I Study of ABT-888 in Combination with Carboplatin and Paclitaxel ABT- 888 Carbo Pacli PK PBMC Bx Cy # 1 X X X X X Cy # 2 X X X X X X Determination of DLT in cycle 2 Paired Tumor Bx at the Phase II Dose ABT-888 given on days 1-7 of each cycle Carbo/Pac given on day 3 of each cycle Emory University, Penn State, U Pittsburgh
Current Status 40 Patients enrolled to date one DLT reported thus far (fever with neutropenia) Escalation to 50 mg BID of ABT-888 at dose level 6 Partial responses noted in NSCLC, Head and neck cancer, breast cancer and bladder cancer PK analysis ongoing Accrual continues
Phase I Study of ABT-888 in Combination with Radiation Therapy Patients who require WBXRT To evaluate the feasibility of combining ABT- 888 with XRT to brain Currently enrolling patients PARP Inhibition: Future Directions Rand phase II study of carboplatin, paclitaxel and ABT-888 Combination of PARP inhibitors with radiotherapy Other novel PARP inhibitors under development (BSI 206, Olaparib)
Conclusions HDAC and PARP inhibition are novel strategies for the treatment of NSCLC Neither strategies are likely to be effective as monotherapy in NSCLC Optimal combinations hold the key Randomized studies are soon to be initiated with PARP inhibitors in NSCLC