# ATR inhibitor-mediated reversal of PARP inhibitor resistance in high-grade serous ovarian cancer (HGSOS)

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2024 · $393,712

## Abstract

SUMMARY
High-grade serous ovarian cancer (HGSOC) frequently harbors defects in DNA repair pathways that confer
homologous recombination (HR) repair deficiency, as well as compromised stability of stalled DNA replication
forks. Such defects frequently involve BRCA alterations and confer sensitivity to inhibitors of poly (ADP-ribose)
polymerase (PARP) inhibitors. These agents have now entered the routine HGSOC armamentarium both in the
advanced and maintenance settings. An overarching objective of this project is to address the emerging problem
of PARP inhibitor resistance that will assume greater importance as PARP inhibitor use increases. The project
focuses on inhibition of Ataxia telangiectasia and Rad3-related (ATR) as a strategy designed to reverse the two
major mechanisms of acquired PARP inhibitor resistance, including restoration of HR repair and stabilization of
DNA replication forks. Three Specific Aims are proposed. In Aim 1, we will assess the activity and mechanisms
of the ATR inhibitor AZD6738 as monotherapy and in combination the PARP inhibitor olaparib in in vitro and in
vivo BRCA-mutated cell line, organoid culture and patient-derived xenograft (PDX) models of HGSOC with
acquired PARP inhibitor resistance. This work will prepare the way for a clinical trial in Aim 2 combining AZD6738
and olaparib with a schedule that maximizes ATR inhibition in patients with PARP inhibitor-resistant BRCA-
mutated HGSOC. Once the maximum tolerated doses are established, we will confirm tolerability and assess
preliminary antitumor activity in an expansion cohort of twelve patients. Paired biopsies will be procured for
proof-of-mechanism pharmacodynamic studies in which HR is assessed with an immunohistochemical RAD51
assay and replication fork stability is assessed with a DNA fiber assay in organoid cultures. In Aim 3, we will
determine the activity of ATR inhibition alone and in combination with gemcitabine in HGSOCs with a high degree
of replication stress but are intrinsically unresponsive to PARP inhibition. AZD6738 and gemcitabine will be
studied in cell line, organoid and PDX models harboring high-level CCNE1 or MYC amplification. We will analyze
replication stress in these models and its exacerbation by ATR inhibition and gemcitabine using
immunohistochemical, cytological and gene expression signature biomarkers of ATR pathway activation. Lastly,
we will leverage a recently completed study of gemcitabine vs. gemcitabine combined with the ATR inhibitor
M6620 in platinum-resistant HGSOC patients, in which the combination was superior among patients with a
platinum-free interval of less than 3 months. We will test the hypothesis that this group was enriched with tumors
carrying a high degree of replicative stress, defined by CCNE1 or MYC amplification, as well as by biomarkers
developed in the preclinical models. Taken together, these aims will allow us to establish a role for ATR inhibition
in the HGSOC armamentarium, identify new therapeutic ...

## Key facts

- **NIH application ID:** 10895321
- **Project number:** 5P50CA240243-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Geoffrey I. Shapiro
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,712
- **Award type:** 5
- **Project period:** 2020-08-03 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895321

## Citation

> US National Institutes of Health, RePORTER application 10895321, ATR inhibitor-mediated reversal of PARP inhibitor resistance in high-grade serous ovarian cancer (HGSOS) (5P50CA240243-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10895321. Licensed CC0.

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