Mechanisms of Oncogenesis in the Primary Liver Cell Cancer Cholangiocarcinoma
Abstract
Scientific Objective and Rationale: Cholangiocarcinoma is devastating type of liver cancer with very limited treatment options. Current chemotherapy regimens offer a minimal increase in survival time for patients. In pursuing more effective treatments for patients with this tumor, we have identified molecular changes that we believe are targets for therapy. We have preliminary data suggesting specific mechanisms by which these therapies may be effective, and our proposal seeks to further assess these susceptibilities and to directly evaluate treatment with a targeted therapy in validated animal models of cholangiocarcinoma, including patient-derived xenografts, a model in which human tumors are grown in mice. This unique animal model is available in very few centers worldwide and allows evaluation of treatment efficacy directly in human tumors. Principal Investigator Career Goals: Dr. Smoot’s research goals include an independently funded program evaluating susceptibilities and targeted therapies in primary liver cancers, a Fiscal Year 2017 Peer Reviewed Cancer Research Program Topic Area. The research proposed in this application will advance our understanding of molecular mechanisms underlying development and progression of this tumor. The research will not only provide significant preliminary data that is required for independent granting applications, but is also likely to identify additional avenues of research suggesting other potential therapies for this difficult cancer. The career development plan provides the framework for additional protected research time, research support, and focused mentoring in support of Dr. Smoot’s goals. The additional protected time and research support will allow for a more rapid acquisition of preliminary data and allow exploration of new/alternative research techniques through participation in scientific meetings, workshops, and courses. The focused mentorship will ensure milestones are being achieved and the overall goal of an independently funded research program is reached. Applicability of the Research: The proposed research has significant applicability for patients suffering from cholangiocarcinoma. The mechanistic studies will further the understanding of signaling changes in these cancers that may be targeted in a more specific fashion. The interplay between various regulatory signaling molecules and the hippo pathway is of significant interest and represents a gap in knowledge in cancer biology, one that will be directly addressed by the proposed studies. The therapeutic studies in cell cultures and in the animal models will provide significant insight into the viability of using inhibitors of the Src family kinases against these tumors. Patients with cholangiocarcinoma liver cancer are most likely to benefit from this research; however, insights into treatment of this solid tumor may be applicable to other solid tumors because the pathway being evaluated is abnormal in several other types of tumors as well. The preclinical data obtained from this proposal would make translation of the findings to patient care readily achievable. Military Relevance: The proposed research will benefit the Department of Veterans Affairs (VA) beneficiary population specifically because of the increased risk in this population for developing cholangiocarcinoma. A known risk factor for cholangiocarcinoma formation is the presence of hepatitis C infection, increasing the risk of cholangiocarcinoma by more than two-fold. The rate of hepatitis C infection is elevated in the VA beneficiary population as compared to the general population, thus making new therapeutic options for cholangiocarcinoma important for the US Veteran population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810297
Entities
People
- Rory L Smoot
Organizations
- Mayo Clinic
- United States Army