# Exploring novel SRC-regulated pathways in IDH mutant intrahepatic cholangiocarcinoma

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $382,471

## Abstract

PROJECT SUMMARY/ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is a highly lethal form of liver cancer which has been rising in incidence
worldwide and carries a prognosis of under one year. The current standard of care for the majority of patients
who present with advanced stage disease remains toxic combination chemotherapy. However, recent genetic
studies have determined that many ICC tumors harbor mutations which can be treated with ‘targeted therapies.’
Such targeted therapies may often be given as a pill form and generally have fewer side effects than
chemotherapy. As a result, there is now hope for a shift in the therapeutic paradigm for ICC, from the current
standard of combination chemotherapy for all patients to targeted therapies for ICC patients who have
‘targetable’ mutations. The most common of these mutations in ICC fall within a gene called isocitrate
dehydrogenase (IDH). Although clinical trials are currently underway to evaluate the efficacy of targeted therapy
in IDH mutant ICC, early trial results suggest that sequential or combinatorial strategies will be needed to induce
durable remissions in this disease. In our previous work, we used laboratory models of IDH mutant ICC such as
human cancer cell lines and patient-derived xenografts (PDXs) to show that IDH mutant ICC cells are extremely
sensitive to a targeted therapy called dasatinib. Dasatinib acts to kill IDH mutant ICC cells by inhibiting the activity
of a protein called SRC. Interestingly, this dependence on SRC activity appears to be highly specific to IDH
mutant ICC cells when compared to cells from ICC tumors that do not have IDH mutations or tumor cells from
any other cancer tested. This proposal aims to couple traditional molecular biology and biochemical approaches
with advanced technologies such as phosphoproteomics, CRISPR/Cas9-mediated genome editing, and
polyribosome profiling to uncover the unique functional role that SRC plays in IDH mutant ICC and to elucidate
why this specific genetic subset of ICC is so dependent on SRC activity. This work will be benefited by our unique
reagents, consisting of a large panel of ICC model systems, including human cell lines and PDXs as well as the
rich and highly collaborative scientific environment at the Fred Hutchinson Cancer Research Institute. Ultimately,
the long-term goal of our work is to improve our understanding of the distinct biology underlying these tumors in
hopes of developing more effective, and less toxic, therapeutic options for ICC patients.

## Key facts

- **NIH application ID:** 10815548
- **Project number:** 5R01CA255015-04
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Sita Kugel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,471
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815548

## Citation

> US National Institutes of Health, RePORTER application 10815548, Exploring novel SRC-regulated pathways in IDH mutant intrahepatic cholangiocarcinoma (5R01CA255015-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10815548. Licensed CC0.

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