Nanovesicle-Mediated Targeting of YAP in Cholangiocarcinoma to Enhance Chemotherapy Sensitivity
Abstract
Scientific Objective and Rationale: The goal of these studies is to determine if a new type of treatment strategy, specifically nanovesicle-based small interfering RNA therapy, can be used to target the specific proteins, yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), in cholangiocarcinoma. YAP, and it closely related protein, TAZ, function in cells by driving the production of RNA from DNA, thus increasing the growth of cells. In cancers, these proteins can not only assist in development of cancer, but also can function to limit the effectiveness of standard chemotherapy. Cholangiocarcinoma, a primary liver cancer that arises from the bile ducts, has very high levels of YAP, and in this tumor YAP is noted to be in the nucleus, which indicates an active protein. Standard approaches to targeting YAP and/or TAZ have not been possible, since there are no specific receptors tied to these proteins, and direct chemical inhibitors have not been found. Small-interfering RNA is a way to decrease the amount of specific proteins and is used routinely in individual cells. Applying this technology to whole living organisms has been complicated by the rapid deterioration of the small-interfering RNA that occurs in a human/animal. One method of protecting the RNA is to encapsulate it in a nanovesicle for delivery to a tumor. The ability to target the nanovesicles to specific areas/tumors has been enhanced by including a targeting molecule, called an aptamer, on the surface of the nanovesicle. In cholangiocarcinoma, the cell surface molecule epithelial cell adhesion molecule (EPCAM) is common and can be utilized as the target of this targeting aptamer. This proposal seeks to test this novel approach in multiple pre-clinical models of cholangiocarcinoma. Applicability of the Research: The proposed research has significant applicability for patients suffering from cholangiocarcinoma. The protein YAP is active in a majority of these cancers, and is an attractive target. In fact, greater than 90% of cholangiocarcinomas that are studied have activated YAP. Positive results from these preclinical studies would provide a new treatment algorithm for these patients and the initial safety/tolerability in the animals would be addressed with these studies as well. Clinical trials would be possible in the short term (2-3 years) after additional toxicity/tolerability studies in animal models. While this proposal is focused on cholangiocarcinoma specifically, its applicability to other types of cancers is likely if positive results are obtained. First, multiple other cancer types (lung, breast, colon) have been shown to have activated YAP. Furthermore, the paradigm of utilizing a targeted nanovesicle to deliver small interfering RNA could be explored with multiple different combinations of both targeting aptamer as well specific target small-interfering RNA. This would allow therapeutic intervention on targets that have, to date, been considered untargetable and allow application to other difficult-to-treat cancers. Military Relevance: The proposed research will benefit the 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. The Fiscal Year 2020 Peer Reviewed Cancer Research Program Military Health Focus Area to be studied is mission readiness through addressing the lack of treatments available for this devastating cancer affecting Service Members, VA beneficiaries, family, and the general public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110798
Entities
People
- Rory L Smoot
Organizations
- Mayo Clinic
- United States Army