CDK4 and Immuno-Targeted Therapies in Liver Tumors Formed in Obesity/Type 2 Diabetes
Abstract
Topic and Focus Areas: The Topic Area of this Fiscal Year 2019 (FY19) Peer Reviewed Cancer research Program (PRCRP) Impact Award entitled “CDK4 and Immuno-Targeted Therapies in Liver Tumors Formed in Obesity/Type 2 Diabetes” is Liver Cancer. The FY19 Military Relevance Focus Area is environmental/exposure to chemical carcinogens such as pesticides is a risk factor for liver cancer and have a profound impact on the health of military Service member, Veterans, and their beneficiaries. Scientific Objective and Rationale: Obesity/type 2 diabetes, a current epidemic disease in the US, represents a high risk for liver cancer. Although the precise reasons of this risk are unknown, factors related to elevated fats, including inflammation, and high levels of insulin (at high doses can function as a growth factor increasing proliferation of cancer cells) are likely to contribute. Thus, the liver is an organ exposed to high levels of insulin, coming from the pancreas, and during obesity/type 2 diabetes fatty liver is a common pathology, that if untreated can progress to liver fibrosis and cancer. Rationale: Our laboratory has preliminary studies showing that liver tumors formed in obese/type 2 diabetic, but not in lean/non-diabetic, mice are addictive to a protein complex called Cyclin D1/CDK4, suggesting that destroying or blocking this complex liver cancer does not occur or it can be eliminated. In addition, we have found that human liver cancer specimens derived from obese/type 2 diabetic patients, similar to mouse models, have elevated Cyclin D1/CDK4 complex activity. Importantly, there are current available drugs, called CDK4 inhibitors that block this complex activity, providing a clinical therapeutic treatment. Although tumors initially respond to this treatment and increase patient survival, relapse often occurs and additional therapies are currently needed. Recent and very promising alternatives include immunotherapy (activation of the immune system to destroy and eliminate cancer cells) that might be used as a single or combination treatment. However, and important to this research application, the efficacy of these drug (CDK inhibitors or blockers) and immune therapies are unknown and could be exploited to treat liver cancer in patients with obesity and type 2 diabetes. Scientific Objective: We will determine whether current clinically used CDK4 drug inhibitors or blockers destroy and kill liver cancer and increase immunotherapy efficacy in pre-clinical liver cancer mouse models (including chemical carcinogen exposure and transgenesis) of obesity/type 2 diabetes. To accomplish this scientific objective we propose a series of experimental studies to (1) determine the efficacy of CDK4 blockers to eliminate liver tumors formed in conditions of obesity/type 2 diabetes, and (2) determine the efficacy of two different antibodies (anti-PD1 and anti-PD-L1; immunotherapy treatment), in combination with CDK4 blockers, to eliminate liver tumors formed in conditions of obesity/type 2 diabetes. Near-Term Impact and Ultimate Applicability: The research proposed has a potential near-term impact in liver cancer patients with obesity/type 2 diabetes, particularly in military Veterans that have been exposed to carcinogens, including herbicides or Agent Orange, because it will determine the efficacy of currently used drug and immuno-targeted therapies. Since these treatments are employed in cancer patients the outcomes of this research will support the use of therapies in liver cancer patients and, moreover, it will provide a personalized criteria based on these metabolic diseases. Military Relevance: This research is highly relevant to the healthcare needs of military personnel, because outcomes from these studies will provide innovative and clinical information on liver cancer, particularly in the military and Veteran population with obesity and type 2 diabetes, an epidemic that is higher in US military Veterans. This highe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010594
Entities
People
- Pere Puigserver i Burguera
Organizations
- Dana–Farber Cancer Institute
- United States Army