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) Checkpoint signaling is critical for coordination between DNA damage response and cell cycle control. ATR activates CHK1 following DNA damage or replication stress (RS), which deactivates cyclin-dependent kinases to arrest the cell cycles for DNA repair and optimal DNA replication. Due to universal p53 dysfunction and consequent G1 checkpoint defects, HGSOC cells heavily rely on ATR/CHK1-mediated G2/M cell cycle arrest. Thus, targeting cell cycle checkpoints is a promising therapeutic strategy in HGSOC to augment RS while attenuating DNA repair responses. I hypothesized that a CHK1 inhibitor (CHK1i) would induce lethal DNA damage and resultant clinical activity in recurrent HGSOC. To test this hypothesis, I opened a phase II investigator-initiated study of the second generation CHK1 inhibitor (CHK1i), prexasertib (14-C-0156) in HGSOC patients with and without BRCA mutation (BRCAm). Promising clinical activity of CHK1i was observed in heavily pretreated BRCA wild-type (BRCAwt) HGSOC patients (33% response rate [RR] with a median progression free survival of over 7 months; The Lancet Oncology, 2018). I subsequently opened the new two cohorts (biopsy Cohort 5 and non-biopsy Cohort 6) focused on platinum-resistant BRCAwt HGSOC within the 14-C-0156 study to further confirm clinical activity in this difficult-to-treat population. Enrollment is now closed for all ovarian cancer cohorts and work is ongoing to identify biomarkers of response or resistance to the CHK1i. Separately, patients with BRCAm attained only limited benefit from CHK1i treatment. Two of 18 (11%) evaluable patients achieved a RECIST partial response (PR). All patients except one exceptional responder (PR, 41 months on the study) had prior PARP inhibitor (PARPi). The study incorporates tumor biopsies and blood collections, genomic analyses and other molecular investigations to study possible cross-resistance between PARPi and CHK1i to ultimately develop predictive biomarkers of response. (2) In the laboratory I am studying the molecular characteristics that predict the response to CHK1i and potential mechanisms of resistance of cell cycle inhibitors. We developed CHK1i-resistant BRCAwt HGSOC cell lines to recapitulate the patient population of BRCAwt Cohort 2 who progressed on CHK1i therapy. Our findings suggest the development of acquired resistance to CHK1i is associated with a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death (Nair et al. Oncogene 2020). To identify the resistance mechanisms in BRCAm patients separately, we have developed PARPi-resistant BRCAm HGSOC cell lines to recapitulate the BRCAm Cohort 1 patients, and work is in progress to study overlapping mechanisms of resistance between the PARPi and CHK1i. To further improve the efficacy of CHK1i, I conducted a high-throughput drug combination screen in collaboration with the NCATS/NIH. In the screen, several inhibitors of PI3K family, AKT and mTOR pathways induced supra-additive cytotoxic activity with a CHK1i. I have extended this work to other molecular targets within this DNA damage checkpoint pathway (e.g., ATM, ATR, and WEE1) to develop the next generation clinical trials (e.g., combinations that might increase the activity of cell cycle inhibitors). Mechanistically, we found the combination treatment of PI3K/mTOR inhibitor and CHK1i induce a lethal form of RS via CDC45-mediated increased unscheduled origin firing, leading to severe DNA damage followed by apoptosis in HGSOC (Huang et al. Cancer Res 2020). To leverage the therapeutic potential of modulating these two pathways (ATR/CHK1 and PI3K/AKT/mTOR), we have studied an ATR inhibitor and an AKT inhibitor combination in various ovarian cancer preclinical models including PARPi-acquired and -de novo resistant HGSOC cell lines. We found the combinatorial inhibition of ATR and AKT yield greater toxicity in in vitro and in vivo ovarian cancer models. Further mechanistic studies are ongoing. Also, based on the preclinical data from my laboratory, the LOI of a new phase 1/1B study of the combination of ATR inhibitor and AKT inhibitor in recurrent women's malignancies and PARPi-resistant ovarian cancer patients has been reviewed and approved by a CCR Scientific Review Committee and the LOI is currently under review by NCI/CTEP. 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. Inhibition of DNA repair and angiogenesis pathways can modulate immune response by increasing DNA damage and tumor mutational burden and by attenuating immunosuppressive microenvironment. PARPi olaparib (O) and a VEGFR inhibitor (cediranib; C) together were shown to be clinically superior to O alone in platinum-sensitive HGSOC, suggesting an important new direction for ICB combination therapy. I hypothesized that O and C would enhance the anti-tumor activity of ICB, by creating a more immunogenic environment and higher mutational loads. I opened a phase I/II investigator-initiated study (15-C-0145), which tests this hypothesis by combining durvalumab (D; MEDI4736; anti-PD-L1) with O and/or C. The phase I study for D and O or D and C has been published in Journal of Clinical Oncology in 2017 and this work has been highly cited. Also, phase I findings of triple therapy (D plus O and C; Zimmer et al, JITC 2019) and Phase II study of D and O with biomarker analysis in ovarian cancer have been published (Lampert et al, CCR 2020) indicating the potential of combination therapies in ovarian cancer. (2) Based on the work from ovarian cancer cohort of 15-C-0145 study, the concept of randomized Phase II study of triple therapy (D plus O and C) vs. standard care chemotherapy in platinum-resistant ovarian cancer has been approved by CTEP/NCI and NRG Oncology. This randomized multi-center trial is now open and accruing patients (PI: JM Lee, a target accrual of 164 patients). (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 are now published 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 will improve clinical outcome in recurrent HGSOC. The promising activity of the O and C combination led to the development of two NRG Oncology multi-center randomized trials of O and C in platinum-resistant (PI: JM Lee, a late phase II/III study, NRG GY005 [16-C-0088]) and platinum-sensitive recurrent ovarian cancer (NRG GY004). NRG GY005 study has enrolled a target accrual of 208 patients for a phase II part and a phase III part recently completed the accrual of total 540 patients in the U.S., Canada, Japan and South Korea with anticipated data maturation and report in 2Q2022. 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.