While cancer genomics and targeted therapies have improved outcomes for a subset of non-small cell lung cancer patients (e.g., EGFR mutations, ALK fusions), the treatment for small cell lung cancer (SCLC) has remained largely unchanged. The majority of patients relapse within months of completing frontline treatment and do not benefit from available second-line treatment, so there is an urgent need for new effective therapies. We previously discovered that PARP1 is expressed at high levels in SCLC and that PARP inhibitors are active in preclinical models. Based on this work, we initiated clinical trials of PARP inhibitors for SCLC patients and preliminary results confirm--for the first time--single-agent activity in a subset of SCLC patients. Based on our preliminary data, we hypothesize that (1) sensitivity to PARP inhibitors in SCLC is determined by the presence of DNA repair deficiencies (e.g., ATM loss), overexpression of SLFN11, and the degree of PARP-DNA trapping (causing cytotoxicity); (2) resistance is driven by activation of compensatory pathways (e.g., the G2 checkpoint kinases Chk1, Wee1, ATR) downregulation of PARP1; and (3) DNA damage repair (DDR) inhibitor therapeutic combinations which prevent DNA repair while simultaneously abrogating the G2 cell cycle checkpoint may be effective in this p53-mutated cancer. We will investigate these hypotheses in the following aims.
In Aim 1, we will determine mechanisms of sensitivity to PARP inhibitors by a) testing the contribution of DDR deficiencies, SLFN11, and PARP trapping to PARP inhibitor response in molecularly characterized human and GEMM-derived cell lines and PDXs; b) testing whether ATM, SLFN11, and other markers directly contribute to response; and c) testing predictive biomarkers in tumors from patients on a Phase II clinical trial of temozolomide the PARP inhibitor veliparib and a Phase I study of single-agent PARP inhibitor talazoparib and correlate with clinical outcomes.
In Aim 2, we will investigate the role of PARP1 in DDR and transcriptional regulation of key oncologic processes and examine mechanisms of resistance to PARP inhibitors by a) investigating the catalytic activity of PARP1 in SCLC using overexpression and knockdown approaches in in vitro and in vivo models; b) identifying mechanisms of PARP inhibitor resistance, including escape from PARP trapping and activation of G2 checkpoint kinases. Finally, in Aim 3, we will develop synthetic lethal approaches to enhance PARP inhibitor activity through DDR inhibitor combinations by a) determining efficacy of DDR inhibitor combinations (e.g., PARP+Chk1, PARP+Wee1, PARP+ATM, PARP+ATR) using pharmacologic and knockdown approaches in cell lines and mouse models and b) identifying genomic and proteomic mechanisms and markers of response to DDR combinations using established molecular profiles and paired pre/post- treatment profiling. I have a track record of productivity in studying SCLC and identifying biomarkers for targeted therapy and have assembled a team with expertise in DDR biology/ targeting, translational lung cancer research, bioinformatics, genetic mouse models, and lung cancer pathology.

Public Health Relevance

There is an urgent, umet need to identify and develop targeted therapies in small cell lung cancer (SCLC), a disease for which treatment has not changed in nearly thirty years. We previously discovered that PARP1 is expressed at high levels in SCLC and that PARP inhibitors are active in preclinical models and our recent clinical trials demonstrate single agent activity of PARP inhibitors in a subset of SCLC patients. This proposal will characterize the mechanisms of sensitivity and resistance to PARP inhibitors using preclinical models and unique sets of clinical SCLC samples and will investigate novel combinations of PARP inhibitors with other inhibitors of the DNA damage response (DDR) to develop personalized, targeted approaches for the treatment of SCLC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Timmer, William C
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
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Sen, Triparna; Gay, Carl M; Byers, Lauren Averett (2018) Targeting DNA damage repair in small cell lung cancer and the biomarker landscape. Transl Lung Cancer Res 7:50-68
Pietanza, M Catherine; Waqar, Saiama N; Krug, Lee M et al. (2018) Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol 36:2386-2394
Ferrarotto, Renata; Cardnell, Robert; Su, Shirley et al. (2018) Poly ADP-ribose polymerase-1 as a potential therapeutic target in Merkel cell carcinoma. Head Neck 40:1676-1684
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Sen, Triparna; Tong, Pan; Diao, Lixia et al. (2017) Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer. Clin Cancer Res 23:6239-6253
Gay, Carl M; Balaji, Kavitha; Byers, Lauren Averett (2017) Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer 116:415-423
Sen, Triparna; Tong, Pan; Stewart, C Allison et al. (2017) CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res 77:3870-3884
Cardnell, Robert J; Li, Lerong; Sen, Triparna et al. (2017) Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget 8:73419-73432