Leveraging DNA damage repair pathways as therapeutic targets in womens cancers

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Project 1. Therapeutic modulation of cell cycle checkpoint pathways in HGSOC. Cell cycle checkpoints e.g., ATR and CHK1 are the major regulators of DNA damage response (DDR) pathways. 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 (prex) (NCI 14-C-0156; NCT02203513) is the first demonstration of monotherapy activity of the ATR/CHK1 pathway inhibitor in recurrent HGSOC with comprehensive translational studies (Lancet Oncology 2018 and Science Translational Medicine 2023). In this proof-of-concept trial of CHK1i, I separately examined the role of CHK1i in the background of BRCA mutation (BRCAm) and BRCA wild-type (BRCAwt) HGSOC and have characterized the possible subsets of HGSOC patients (pts) who most likely benefit from CHK1i. My current and future research is focusing on the clinical development of novel drugs and/or novel drug combinations targeting of DDR pathways in recurrent HGSOC complemented by the mechanistic translational studies. SA 1. Clinical development of CHK1i in molecularly selected platinum-resistant (PR) HGSOC pts. I initiated a collaboration with Acrivon Therapeutics and participated in the development of molecular signature which identifies the subset of HGSOC pts for CHK1i response. Based on our findings, a multi-center registration-intent phase II trial of ACR-368 (a.k.a. prex) was launched for PR-HGSOC and I am the Study Chair (GOG-3082; NCT055482962). The trial requires pretreatment fresh biopsies to provide the first prospective evidence of replication stress (RS)-related biomarker subgroups. If positive, this aim will identify the predictive biomarker for CHK1i and change the standard of care therapy (SOC) for PR-HGSOC pts. SA 2. Development of ATR/CHK1 pathway blockade combination therapy in HGSOC. I conducted a quantitative high throughput drug combination screen for CHK1i with NCATS/NIH. Several compounds targeting the PI3K/AKT pathway were found to be synergistic with CHK1i. Mechanistically, my lab identified combined inhibition of the PI3K/AKT pathway and CHK1 resulted in lethal RS and cell death in BRCAwt PR-HGSOC preclinical models. My lab also performed another drug combination screen using a ATR inhibitor (ATRi). In this screen, ATRi (ceralasertib) was found to be synergistic with drugs targeting the cell cycle, the PI3K/AKT pathway and other pathways important in cell growth and proliferation. We chose to combine PI3K/AKT pathway inhibitors with ATRi given that PI3K/AKT signaling is associated with chemoresistance, and poor prognosis in HGSOC. a. Mechanistic investigation of the ATRi and AKT inhibitor (AKTi) combination. Recent data suggest aberrant R-loops, which consist of a DNA:RNA hybrid and a displaced ssDNA, induce genomic instability and RS. I hypothesize that R-loop-mediated RS may contribute to cell death caused by dual inhibition of ATR/CHK1 and PI3K/AKT pathways in PARPi-resistant HGSOC. My lab identified the novel function of AKT1 which directly binds to the sites of R-loops in concert with the 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 (manuscript submitted). b. Clinical evaluation of the ATRi and PI3K/AKT pathway inhibitor combination. While conducting mechanistic in vitro studies, my lab also performed mouse experiments which showed the combination significantly reduced tumor growth and prolonged survival compared to monotherapy. My letter of intent (LOI) for a new investigator-initiated phase I/Ib clinical trial of ATRi and PI3K/AKT pathway inhibitor combination was approved by NCI/CTEP (LOI#10591). Discussions are ongoing with the drug companies. c. Investigation of novel combination with antibody drug conjugates (ADCs). I initiated a collaboration with Gilead Sciences (CRADA#3391) to develop preclinical models of the Trop2-targeting ADC, sacituzumab govitecan [SG], and cell cycle checkpoint blockade combination. Trop2 is a 36 kDa transmembrane glycoprotein encoded by the TACSTD2 gene and is expressed ubiquitously in many cancers including 80-90% of OC. My lab is now investigating cytotoxicity of SG and cell cycle checkpoint blockade combination in a panel of HGSOC cell lines and characterize key modulators of DDR pathways. My lab is also evaluating the combination therapy effectiveness in drug-resistant OC mouse models. Discussions are ongoing with the company for the development of new investigator-initiated clinical trials. Project 2: Immune checkpoint blockade (ICB) with PARPi olaparib (O) and VEGFR tyrosine kinase inhibitor (TKI) cediranib (C) combination in PR-OC. Another project includes the development of O and C combination for PR-HGSOC. I serve as a Study Chair on the multi-center phase II/III NRG-GY005 trial (NCT02502266) of O+C combination vs SOC chemotherapy in PR-HGSOC. This international trial has enrolled 540 pts and data will be reported in 1Q 2024. Building on my work with O+C combination, I am exploring anti-PDL1, durvalumab (D) with O+C in PR-OC. My phase I trial (15-C-0145; NCT02484404) is the first-in-human study of D in combination with O and/or C. My group also reported the clinical and translational study results from the phase II study of D+O in recurrent OC and demonstrated that the activity of ICB and PARPi combination may vary depending on the clinical and molecular characteristics. My current and future research is focusing on the clinical development of ICB-based combination therapies in recurrent PR-OC and to investigate molecular correlates to find predictive biomarkers of response and/or resistance to ICB-based combination therapies. SA 1. Investigation of molecular correlates of response to O+C combination therapy with anti-PDL1 a. NRG GY023 multi-center phase II study. I designed and chair a multi-center phase II trial (NRG-GY023; NCT04739800) testing the D+O+C combination versus SOC in PR-OC pts who had prior bevacizumab. The primary end point was PFS with planned accrual of 164 pts. Interim analysis data will be reported at the 2023 ESMO congress. The NRG-GY023 study required mandatory submission of archival tissue samples for further correlative studies. We will identify the exceptional responders and investigate their molecular and clinical characteristics in collaboration with NRG Oncology. b. NCI 15-C-0145 single center phase II study. My NCI phase II study of D+O+C arm (15-C-0145) is near completion of accrual. This study requires baseline and on-treatment fresh tumor biopsies and serial blood collections for comprehensive correlative study endpoints. Correlative studies include (1) DNA-seq for specific DDR genes mutational analysis and BRCA reversion mutations, (2) RNA-seq to identify molecular characteristics and correlate them with clinical outcome, (3) to evaluate the expression of genes involved in IFN response and their interactions with other pathways, and study an IFN gamma-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.