Defining the Impact of Tumor Heterogeneity in Intrahepatic Cholangiocarcinoma

About This Grant

PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (iCCA) is a cancer of the bile ducts with an incidence rate in the United States of 1.19 persons per 100,000 per year and a devastating 9% 5-year survival rate with few therapeutic options. A critical gap in knowledge to improve outcomes in iCCA is an incomplete understanding of the impact of tumor heterogeneity on disease progression, therapeutic failure, and metastatic dissemination. Higher tumor heterogeneity can fuel resistance to therapy because of the emergence of subclonal cell populations harboring disparate molecular signatures, leading to differential responses to treatment. The overall objective of this proposal is to determine alterations in the genome, transcriptome, and tumor microenvironment that contribute to tumor heterogeneity, cancer evolution, and adaptation in iCCA. The central hypothesis is that iCCA is characterized by multiple, diverse subclonal populations within both an individual tumor and across primary and metastatic tumors within the same patient, and that this heterogeneity can underlie tumor recurrence, resistance to therapy, and metastatic progression. Specific aims are (1) to interrogate the genomic and spatial transcriptomic heterogeneity between matched human primary and metastatic iCCA and (2) to determine the impact of intratumor heterogeneity on drug sensitivity in novel mouse models of iCCA. The justification for the use of animal models is the need to investigate intratumor heterogeneity in vivo, using sophisticated mouse models carrying gene inactivations that are functionally identical to those found in human patients. These animal models are expected to enhance the discovery of drug resistance mechanisms and therapeutic vulnerabilities in human patients. The proposed project will shed critically important light on associations between heterogeneity, cancer evolution, metastasis, and therapeutic outcomes. The contribution will be significant because the impact of iCCA intratumor and intrapatient heterogeneity upon patient outcomes in the United States is currently poorly understood. Successful completion of the specific aims will lead to an improved understanding of molecular alterations and evolutionary processes that lead to recurrence after surgery, treatment resistance, and metastatic capacity. Together with our existing and proposed intratumor heterogeneity results, our investigation of metastatic evolution will robustly inform the design and delivery of targeted and immunotherapy strategies, with the ultimate goal of improving survival rates and quality of life for patients afflicted by this refractory disease.