Development of a Cellular State Prediction Model of Sensitivity and Resistance to Dual PI3K/BET Inhibitors in Hepatocellular Carcinoma
Abstract
Liver cancer is the second most common cause of cancer death worldwide and is a Fiscal Year 2017 Topic Area for the Peer Reviewed Cancer Research Program. The number of liver cancers diagnosed each year and the number of patients dying from liver cancer are both increasing in the United States. Infection with hepatitis C virus (HCV) is a major risk factor for the development of liver cancer, and rates of HCV infection are at least two times higher in the Veteran population in comparison to the general US population. In fact, two-thirds of Veterans with liver cancer are infected with HCV. Therefore, the Military Relevance Focus Area of this proposal is Hepatitis C. Treatment of liver cancer remains a challenge. Food and Drug Administration-approved drugs for liver cancer, such as sorafenib, prolong life for an average of only 2-3 months and can have significant side effects. While most anti-cancer drugs have a single target, we are studying a novel class of investigational drugs (i.e., SF1126 and SF2523) that we developed to simultaneously target two proteins that are overactive in liver cancer, phosphatidylinositol 3-kinase (PI3K) and bromodomain-containing 4 (BRD4). This is a “first-in-class” approach to liver cancer treatment by hitting two central signaling nodes of the liver cancer cell with one agent. Our preliminary experiments demonstrate that this novel strategy kills liver cells and prevents the growth of liver cancer tumors in mice. Our data also suggest that SF1126 makes sorafenib work better, with the combination of the two therapies killing liver cancer cells in synergy. I currently am leading a Phase I clinical trial of SF1126 to determine if this drug is safe and effective in liver cancer patients. We have now created a stronger dual PI3K/BRD4 inhibitor, SF2523. The objective of this project is to establish a rationale for the use of SF2523 for the treatment of liver cancer and to use a large database of genetic information from liver cancer patients to develop a model to predict which patients will respond to SF2523 therapy. The goal is to profile liver cancer tissue to separate patients into one of four groups and to match patients in each of those groups to targeted therapies like SF1126/SF2523 that are specific to their subgroup of liver cancer. My research focus is paired with a clinical practice treating patients in medical oncology with liver cancer and other gastrointestinal cancers that continues to drive my curiosity about the how to study liver cancer in the laboratory. Receipt of this award would provide me with the tools to work with my mentorship team, who have significant expertise in liver cancer and drug development research, and allow me to advance my career and foster my development as a scientist and physician. More importantly, it has strong potential for benefiting patients, including our nation’s Veterans with high risk of developing liver cancer, as our work develops new drugs and a companion prediction model for which patients will respond to them.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810333
Entities
People
- Adam Burgoyne
Organizations
- United States Army
- University of California, San Diego