# Project 2 - Exploiting FGF Receptor Signaling Dependence in Liver Cancer Therapy

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2021 · $176,809

## Abstract

Project Summary 
Intrahepatic cholangiocarcinoma (ICC) ranks among the deadliest cancers, with a 5-year survival 
rate of only 5-15% due to late diagnosis and lack of effective treatment. The discovery that 
receptor tyrosine kinase Fibroblast Growth Factor Receptor 2 (FGFR2) is genetically activated in 
>20% of ICCs, most commonly via FGFR2 gene fusions, is leading to a new therapeutic paradigm 
for a subset of patients with this disease. Indeed, early clinical trials with FGFR inhibitors (FGFRi) 
show significant anti-tumor efficacy, demonstrating true `oncogene addiction' to FGFR2, 
analogous to the role of EGFR mutations or ALK fusions in lung cancer. However, as in lung 
cancer, drug resistance is a vexing challenge: patients treated with BGJ398, the most clinically 
advanced FGFRi, usually progress within 6 months. In this Project, we aim to address key barriers 
to improving care of patients with FGFR2+ ICC. We will define mechanisms of resistance to 
FGFRi's, pr will provide evidence to support both combination strategies as well as the testing of 
a novel class of FGFR2 inhibitors in the clinic. We propose a multi-pronged strategy for impactful 
translational research that leverages serial tumor and liquid biopsies from three FGFRi trials, a 
series of patient-derived xenografts (PDX) and organoids, a genetically engineered mouse model, 
and novel FGFR2 inhibitors. We will systematically address the key barriers to more effective 
targeted therapy against FGFR2 in ICC: 1) the mechanism of FGFRi resistance, either due to 
acquisition of secondary FGFR2 mutations or activation of `bypass' signaling pathways, 2) 
identification of more effective FGFR2 inhibitors, including those that can target the kinase after 
it acquires resistance mutations, and 3) defining novel combination therapies to target bypass 
pathways to counter resistance and prolong initial response. We propose the following Specific 
Aims: 
Aim 1. To identify and credential mutations causing FGFRi resistance in ICC. 
Aim 2. To identify FGFR inhibitors that more effectively target FGFR2. 
Aim 3. To develop combination strategies to overcome FGFR2-independent resistance 
mechanisms.

## Key facts

- **NIH application ID:** 10246350
- **Project number:** 5P50CA127003-13
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $176,809
- **Award type:** 5
- **Project period:** 2007-04-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246350

## Citation

> US National Institutes of Health, RePORTER application 10246350, Project 2 - Exploiting FGF Receptor Signaling Dependence in Liver Cancer Therapy (5P50CA127003-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246350. Licensed CC0.

---

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