# Therapeutic strategies for targeting PARP1 in small cell lung cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

Project summary/abstract
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 identif...

## Key facts

- **NIH application ID:** 9970194
- **Project number:** 5R01CA207295-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Lauren Averett Byers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970194

## Citation

> US National Institutes of Health, RePORTER application 9970194, Therapeutic strategies for targeting PARP1 in small cell lung cancer (5R01CA207295-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970194. Licensed CC0.

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