# Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2021 · $435,940

## Abstract

Project Summary
Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women and the deadliest
gynecological cancer in the United States. The current standard treatment for ovarian cancer consists of
surgery followed by platinum drug-based chemotherapy. Platinum drugs could induce DNA interstrand
crosslink (ICL), which results in replication fork stalling and thus decrease cell viability. Although most of
patients initially respond to platinun drug-based chemotherapy and achieve remission, up to 80% of patients
become refractory to platinum drugs over time and ultimately succumb to the disease due to the resistance to
platinum-based therapy. Thus, it is urgent to develop novel approaches to overcome platinum drug resistance
of ovarian cancer (PROC). Fanconi anemia (FA) pathway is critical to repair ICLs and elevated activity of FA
signaling is one of major mechanisms leading to platinum-resistance in ovarian cancer. The role of FA pathway
in repair of ICL has been well studied last decade, however, how the regulatory switch from a stalled
replication fork caused by platinum drugs to initiation of FA signaling and how FA is activated in PROC cells
are poorly understood.
 To elucidate the mechanism regulating initiation of FA signaling, we have conducted the significant
amount of preliminary studies to demonstrate that And-1 is critical for activation of FA signaling and FA-
mediated platinum drug resistance in ovarian cancer. The major objective of this proposal is to determine the
mechanism of how And-1-FANCM axis regulates FA signaling and platinum resistance in PROC. Here, we
propose three specific aims. Aim 1: Determine how And-1 promotes the switch from stalled replication forks to
initiation of FA signaling at ICLs. Aim 2: Determine the role of And-1 in the regulation of platinum drug
resistance in PROC cells. Aim 3: Evaluate the effects of And-1 inhibition on platinum drug resistance using
orthotopic PROC PDX and syngeneic models. The completion of proposed studies will not only elucidate a
novel mechanism regulating platinum resistance in PROC, but also provide an innovative therapeutic strategy
as well as a new potential drug for treatment of PROC patients.

## Key facts

- **NIH application ID:** 10117536
- **Project number:** 1R01CA247684-01A1
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Wenge Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,940
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117536

## Citation

> US National Institutes of Health, RePORTER application 10117536, Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer (1R01CA247684-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117536. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*