Leveraging DNA damage repair pathways as therapeutic targets in womens cancers

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

1) Project 1: Therapeutic modulation of cell cycle checkpoint pathways in women's cancer (1) Cell cycle checkpoints e.g., ATR and CHK1 are the major regulators of cell cycle and DNA repair pathways. CHK1 functions as a primary mediator of G2/M cell cycle arrest in tumors with TP53 mutation and consequent G1/S cell cycle dysregulation, such as HGSOC. I previously opened the first investigator-initiated phase II trial of the CHK1 inhibitor (CHK1i), prexasertib for HGSOC (14-C-0156) to test the hypothesis that inhibition of ATR/CHK1 signaling would result in clinical activity in HGSOC. Early clinical activity of prexasertib was observed in heavily pretreated BRCA wild-type (BRCAwt) HGSOC patients (33% response rate [RR] with a median progression free survival [PFS] of over 7 months). This was the first demonstration of CHK1i clinical activity in ovarian cancer and published in Lancet Oncology in 2018. Based on this promising activity, Acrivon Therapeutics is launching a multi-center late-stage phase II study of prexasertib (ACR-368) in platinum-resistant recurrent HGSOC. I am the Study Chair of this study (GOG-3082) and actively participated in the clinical trial design and collaborated with Acrivon Therapeutics for the validation of their proteomics-based biomarker of CHK1i response. In addition, my analysis of the cohorts of BRCAwt platinum-resistant HGSOC patients (biopsy cohort and non-biopsy cohort of 14-C-0156) confirmed similar clinical activity of prexasertib in this hard-to-treat population (31% [12/39] RR and 59% [23/39] clinical benefit rate [complete response [CR]+ partial response [PR]+ stable disease [SD] lasting longer than 6 months]) (AACR 2022). We collected baseline fresh tissue samples from 15 patients of biopsy cohort and approximately 30 blood samples from both cohorts and are currently analyzing biomarkers to identify mechanisms of sensitivity or resistance to CHK1i. In BRCA mutant HGSOC patients of 14-C-0156 study, we observed modest clinical activity of CHK1i treatment. Two of 18 (11%) evaluable patients achieved PR. All patients except one exceptional responder (PR, 41 months of PFS) had prior PARP inhibitor (PARPi). To study possible cross-resistance between PARPi and CHK1i, we conducted genomic analyses and other molecular investigations using fresh core biopsies and blood samples. BRCA reversion mutations, a well-known mechanism of cross-resistance between PARPi and platinum drugs, were not associated with lack of response to CHK1i. But we found high levels of replication stress measured by high BLM expression and CCNE1 expression or amplification were associated with a response to CHK1i. The manuscript detailing correlative study findings is currently under review. Also, my lab generated preclinical data for an ATR inhibitor (ATRi), another important cell cycle regulator upstream of CHK1, -based combination therapy using PARPi-resistant HGSOC in vitro and in vivo models. The letter of intent (LOI) of phase I/Ib study of ATRi and AKTi has been approved by CTEP/NCI for a multi-center ETCTN study, anticipated study opening in 1/2Q2023. (2) In the laboratory I am studying the molecular characteristics that predict the response to ATR/CHK1 signaling blockade and potential mechanisms of resistance of cell cycle inhibitors or PARPi. For this, my lab has developed PARPi-resistant HGSOC cell lines to recapitulate the PARPi-resistant patients (in revision, Oncogene). Using PARPi-resistant HGSOC cells, I collaborated with NCATS/NIH for a high-throughput drug combination screen for the development of better therapeutic combinations for PARPi-resistant population. In the screen, several inhibitors of PI3K/AKT signaling induced synergistic cytotoxic activity with ATRi or CHK1i. I have extended this work to further understand the mechanisms of underlying synergy and to develop the next generation clinical trials. Mechanistically, we found a novel function of AKT in R-loop mediated replication stress. Specifically, AKT inhibition augments ATRi-induced replication stress by inhibiting the expression of DNA/RNA helicase DHX9 and its recruitment on R-loops, causing significant R-loop-mediated replication stress in PARPi resistant cells. The manuscript detailing mechanistic findings is now under review. 2) Project 2: Therapeutic strategies to complement immune checkpoint blockade (ICB) in HGSOC (1) Immunotherapy has emerged as a major therapeutic modality in oncology, yet most patients with ovarian cancer do not derive benefit from ICB monotherapy, highlighting the need to develop and test rational combination strategies. Data suggest inhibition of DNA repair and angiogenesis pathways may modulate immune response by increasing DNA damage and by attenuating immunosuppressive microenvironment. I previously opened a phase I/II investigator-initiated study (15-C-0145), which tests the hypothesis that DNA damage induced by PARPi olaparib and modulation of immune-suppressive milieu by a VEGFR inhibitor cediranib may improve clinical activity of ICB (anti-PD-L) durvalumab monotherapy which has yielded early activity signal in recurrent ovarian cancer patients (JCO 2017, CCR 2020). (2) Based on my clinical findings from ovarian cancer cohort of 15-C-0145 study, the concept of randomized Phase II study of triple therapy (durvalumab plus olaparib and cediranib) vs. standard care chemotherapy in platinum-resistant ovarian cancer was approved by CTEP/NCI and NRG Oncology. This randomized multi-center Phase II trial is now open and accruing patients (Study Chair: JM Lee, a target accrual of 164 patients, NRG-GY023 [NCI000484]). (3) This 15-C-0145 clinical trial has been expanded to bring these therapeutic opportunities and translational research approaches to other tumor types such as prostate and lung cancers. Phase II findings of D and O in prostate and lung cancer cohorts yielded multiple publications and suggest preliminary clinical activity in subsets of heavily pretreated patients. 3) Project 3: Therapeutic targeting the key proteins of DNA repair and angiogenesis pathways in recurrent HGSOC (1) Angiogenesis and DNA damage repair pathways are active and interactive therapeutic targets in recurrent HGSOC. I hypothesized optimal targeting of PARP and VEGF/VEGFR pathways would improve clinical outcome in recurrent HGSOC. The promising activity of olaparib and cediranib combination led to the development of the NRG Oncology multi-center Phase II/III randomized trial of olaparib and cediranib for platinum-resistant ovarian cancer for which I am the Study Chair (NRG GY005 [16-C-0088]). NRG GY005 study has enrolled a target accrual of 208 patients for a phase II part and a phase III part completed the accrual of total 540 patients in the U.S., Canada, Japan and South Korea with anticipated data maturation and report in 2Q2023. Collectively, this focused clinical and translational approach will make our branch/CCR a recognized center focusing on the treatment of women with genetically high-risk breast and/or ovarian cancer, or those with tumor DNA repair deficient phenotypes with a strong translational research program.