Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer which has been rising in incidence over several decades. The overarching goal of this proposal is to evaluate novel therapeutic strategies for the subset of ICC harboring mutations in isocitrate dehydrogenase 1 (IDH1), the most common oncogenic driver in this disease. In early phase clinical trials, pharmacologic inhibitors of mutant IDH provided clinical benefit in some patients, but their mechanism of action remains poorly understood due to a paucity of on-treatment biopsy tissue and relevant model systems. To overcome this hurdle, a protocol to maintain the viability and original architecture of resected ICC tumors as `tumor slice cultures' (TSCs) and evaluate their response to targeted therapies within their native microenvironment has been developed. In the proposal attached, 100 TSCs will be generated for each of the ~50 resected ICCs over the next two years, anticipating 10-15 IDH mutant ICC tumors. We will then assess their response to mutant IDH inhibition by monitoring proliferation, apoptosis, viability and the expression of relevant biomarkers. Finally, we will evaluate possible combinatorial strategies based on top `hits' from unbiased drug screens of IDH mutant preclinical models. Responses will be correlated with underlying tumor genetics and compared to those of IDH wild-type tumors. Overall, these data will serve as proof of concept for a long-term study exploiting ICC TSCs to elucidate the mechanisms underlying IDH inhibition in ICC, identify predictive biomarkers of response and resistance and establish effective combinatorial strategies for subsequent evaluation in a clinical trial setting.

Public Health Relevance

Intrahepatic cholangiocarcinoma (ICC) is a deadly form of liver cancer which carries an average prognosis of less than one year and has been rising in incidence world-wide for several decades. This proposal utilizes an innovative method to culture ICC tumors isolated directly from patients, and evaluate their sensitivity to a variety of new therapies. Thus, the goal of this proposal is to evaluate the efficacy of new therapeutic approaches in ICC, which can serve as a foundation for future clinical trials in this highly lethal malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA231486-02
Application #
9857575
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Alley, Michael C
Project Start
2019-02-01
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109