Therapeutic Targeting of Cancer Stem Cells in Liver Cancer
Abstract
This proposal addresses the fiscal year 2016 Peer Reviewed Cancer Research Program (PRCRP) Idea Award with Special Focus in the topic area of Liver Cancer. This proposal therefore responds to the need for improved treatments and prevention for current and former military Service members and their families. There are two forms of primary liver cancer, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). These liver cancers are rising in incidence in this country and in particular among U.S. Veterans. The incidence is tightly linked to risk factors such as hepatitis C or cirrhosis (liver disease), which is also common among Veterans, and therefore Veterans unfortunately often present with more advanced stages of liver cancer. Medical therapies are scarce for both of these types of liver cancers and can only extend survival approximately 2.7 months. Therefore, this proposal is geared toward addressing the current gaps in treatment and survivorship which profoundly affect an increasing number of U.S. citizens and U.S. Veterans and their families. We will therefore seek to capitalize on knowledge gained in our research laboratory on the biology of cancer stem cells (CSCs) and the tumor microenvironmental signals, which control their expansion to initiate a new preclinical project aimed to identify new therapies against key pathways in liver cancer. Under the umbrella of the Translational Oncology Program (TOP) at the University of Michigan, collaborations will be formed between Dr. Welling, with his lab’s patient-derived liver cancer xenografts, and medicinal chemists at TOP to use new, orally available, candidate drugs that target the particular pathways controlling the CSCs in liver cancer. These CSCs are important to target as this small subset of cells within cancers such as liver cancer is responsible for cancer recurrence following treatment as well as for the process of cancer metastasis or spreading to distant sites during cancer progression. Thus, we hypothesize that drugs antagonizing the microenvironmental tumor signaling of interleukin-6, interleukin-8, or both will have effectiveness against liver cancer. These interleukins were shown in our work to be important to promoting CSC expansion and metastasis. The ultimate applicability of this project is to test novel candidate drugs that are directly targeted to key mechanisms that CSCs utilize for functional expansion. The patient-derived xenografts represent the most relevant preclinical system, which recapitulates the real-life biological complexity seen in liver cancer patients. Therefore, drugs that are biologically specific and having benefit in this preclinical system will be ultimately top candidates to be proposed for eventual clinical trials in liver cancer patients. Since these first-in-class drugs are extremely specific and orally bioavailable, they have a significantly reduced toxicity profile compared to other standard chemotherapies and can be taken by mouth as opposed to intravenously (required for most chemotherapy drugs). Thus, their opportunity to be feasible, tolerable, and efficacious in liver cancer patients, particularly U.S. Veterans and their families is significant.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710555
Entities
People
- Theodore Welling Iii
Organizations
- Grossman School of Medicine
- United States Army