Leveraging DNA damage repair pathways as therapeutic targets in womens cancers

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Project 1. Therapeutic modulation of DNA damage response (DDR) pathways. Cell cycle checkpoints e.g., ATR and CHK1 are the major regulators of DDR signaling and DNA replication. ATR and CHK1 function as primary mediators of G2/M cell cycle arrest due to universal TP53 mutation and consequent G1/S cell cycle dysregulation in HGSOC, making them important therapeutic targets. My investigator-initiated phase II trial of the CHK1 inhibitor (CHK1i) prexasertib (NCI 14-C-0156; NCT02203513) is the first demonstration of the ATR/CHK1 pathway inhibitor activity in recurrent HGSOC patients (pts) (Lancet Oncol 2018, Sci Transl Med 2023 and Nat Commun 2024). My current and future research is focusing on the clinical development of novel drugs and/or novel drug combinations targeting of DDR pathways in gynecologic cancers complemented by the mechanistic translational studies. SA 1. Clinical development of CHK1i in molecularly selected platinum-resistant (PR) gynecologic cancers. I initiated a collaboration with Acrivon Therapeutics for the development of replication stress (RS)-related biomarker for CHK1i response. A multi-center registration-intent phase II trial of ACR-368 (a.k.a. prexasertib) was launched for women with PR-HGSOC and PR-endometrial cancer (EC) (GOG-3082; NCT055482962) with testing RS-related biomarker for CHK1i response. Recently, a PR-HGSOC cohort was closed based on interim futility data and EC cohort continues to accrue pts. This aim will identify the predictive biomarker for CHK1i in gynecologic cancer pts. SA 2. Mechanistic investigation of DHX9 inhibitor-based therapy in gynecologic cancers. To capitalize the benefit of ATR/CHK1 pathway inhibitor monotherapy, I conducted a quantitative high-throughput drug combination screen with NCATS. Several compounds targeting PI3K/AKT signaling were found to be synergistic with ATRi or CHK1i. To better understand the mechanisms of action of ATRi and AKT inhibitor (AKTi) combination in drug-resistant HGSOC setting, we studied the key factors involving RS. My lab identified the novel function of AKT1 which directly binds to the sites of R-loops in concert with DHX9 helicase via its kinase domain for R-loop resolution. AKTi thus interrupts DHX9 recruitment to R-loops, leading to R-loop accumulation and consequent RS (Cancer Res 2024). Given the significance of DHX9 in various cellular responses for genome integrity, we initiated a collaboration with Accent Therapeutics (CRADA#092-2024), to test a novel DHX9 inhibitor (DHX9i). Currently, we investigate the molecular subgroups of HGSOC and EC cell lines with differential sensitivities to DHX9i and study the mechanisms of actions of DHX9i and novel combinations with DHX9i. We also envision that the results of our preclinical studies will lead to proof-of-concept, hypothesis-driven clinical studies in women with recurrent HGSOC and EC. SA3. Development of a new clinical trial using antibody drug conjugates (ADCs) I have been collaborating with Gilead Sciences (CRADA#3391) to develop preclinical models of Trop2-targeting ADC, sacituzumab govitecan [SG] in gynecologic cancers. Trop2 is a 36 kDa transmembrane glycoprotein encoded by the TACSTD2 gene and is expressed ubiquitously in many cancers including 80-90% of gynecologic cancers. My lab investigated cytotoxicity of SG in a panel of HGSOC cell lines and characterize key modulators of DDR pathways (iScience 2024). Based on our preclinical data, I opened the investigator-initiated phase II trial of SG monotherapy for gynecologic malignancies (NCT06865677). This study has three cohorts (HGSOC, EC and cervical cancer) and is accruing the pts. Project 2: Immune checkpoint blockade (ICB) with PARPi olaparib (O) and VEGFR tyrosine kinase inhibitor (TKI) cediranib (C) combination in PR-HGSOC. Another project includes the development of O and C combination for PR-HGSOC. I designed and chaired the phase II/III international trial (NRG-GY005; NCT02502266) of O+C combination vs SOC chemotherapy in PR-HGSOC (JCO 2024). Building on my work with O+C combination, I also explored anti-PDL1, durvalumab (D) with O+C in PR-HGSOC (15-C-0145; NCT02484404 and NRG-GY023; NCT04739800). My current research focuses on identifying predictive biomarkers of response and/or resistance to ICB-based therapies. SA 1. Investigation of molecular correlates of response to O+C combination therapy with anti-PDL1 I designed and chaired the multi-center phase II study (NRG-GY023; NCT04739800) of testing the D+O+C combination vs. SOC in PR-ovarian cancer pts who had prior bevacizumab. The primary end point was PFS with planned accrual of 164 pts. Interim analysis showed the D+O+C did not improve PFS compared to SOC (CCR, 2025). To better understand molecular characteristics of pts who achieved clinical benefit, I started investigating clinical samples from my NCI phase II study of D+O+C arm (15-C-0145). Clinical samples include pre-and on-treatment fresh tumor biopsies and serial blood collections. Correlative studies include (1) DNA-seq for specific DDR genes mutational analysis and BRCA reversion mutations, (2) RNA-seq and WES to identify molecular characteristics, (3) to evaluate the expression of genes involved in IFN response and their interactions with other pathways, and study an IFNg-related DNA damage resistance signature, 4) IHC for immune subsets, endothelial markers, and PD-L1 expression in tissue samples, and STING expression by multiplex IHC, 5) blood samples to evaluate immune subsets and cytokines/chemokines. Insights gained from these studies are also expected to inform the development of rational combination strategies and complement the correlative study findings from NRG-GY023. Collectively, this focused clinical and translational approach will make CCR a recognized center focusing on the treatment of women with high-risk OC, with a strong translational research program.