Development of Novel Antibody-Drug Conjugates (ADCs) for the Treatment of Advanced Liver Cancer
Abstract
Hepatocellular carcinoma (HCC) represents 90% of primary tumors in the liver and is commonly known as liver cancer. Our current understanding of HCC is that it is not a single disease entity but several distinct molecular subtypes that originate in a common organ (the liver). In order to improve the treatment outcomes for patients with HCC, it is critical that we identify new approaches that will help gear therapy toward a patients specific tumor make-up. The current one-size-fits-all approach of the currently available therapies is not very effective and is associated with significant side effects. HCC is one of the most common cancers world-wide and is the third leading cause of cancer death. It is commonly associated with chronic liver disease and is especially prevalent in our Veteran population. While HCC is a major health problem in the Unites States, the high incidence of chronic liver disease and subsequent HCC in military personnel represents an especially high burden on our Veterans. The direct link between chronic hepatitis from hepatitis C (HCV) infection and the development of liver cancer (HCC) is well-established, and our military personnel and Veterans are especially at risk given their exposures. It has been well established that the HCV epidemic is responsible for the majority of HCC cases in the United States, with the pivotal data being generated in studies from United States Department of Veterans’ Affairs databases. Despite the new, effective treatments for HCV, we still have still not reached the peak incidence of HCV-related HCC. Still other risk factors for chronic liver disease and the development of HCC are over-represented in our Veteran population, including heavy alcohol use, fatty-liver disease, and diabetes. The treatment options for patients with advanced HCC are limited and associated with side effects and significant cost. The proposed studies are aimed at improving outcomes for patients with newer treatments for HCC. Antibodies to specific proteins are commonly used in other areas of cancer medicine, but liver-directed antibodies have not been successful in HCC. We have identified two unique proteins for antibody targeting in HCC, and the focus of this grant is to validate the new targets as candidates for our approach: Develop a very specific antibody that is linked to a toxin to deliver this directly to the tumor. This is called an antibody drug conjugate (ADC), and these are currently used in other tumor types. In addition, by avoiding the inappropriate use of expensive drugs, we can spare the healthcare system resources spent on treatments that do not benefit an individual patient. This proposal is focused on the FY18 PRCRP Military Relevance Focus Area aimed at improving the prognosis and treatment for patients with advanced HCC. Ultimately, the goal of these studies is to rapidly bring our knowledge from the laboratory to the clinic. We have demonstrated our ability to do this in the development of other drugs in cancer medicine (i.e., palbociclib, the first CDK 4/6 inhibitor in oncology, approved for advanced estrogen positive breast cancer). Given our experience in the field of HCC and cancer drug development, we are well positioned to achieve our goals. Through a data-mining effort we have identified two new potential targets for new drugs for HCC patients. The proposed studies are designed to initially validate our target and generate tool compounds for further study and eventual clinical development, which could occur within 2 to 3 years of completing out work. Most patients with liver cancer have increased expression of our targets on their tumors and may be candidates if we are successful. We hope this work will lead to more effective drugs that are more effective and less toxic. The proposed studies are aimed to validate and develop a new targeted therapy for liver cancer. The current treatment paradigm uses systemic agents without any selection for patients that may
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910787
Entities
People
- Richard Finn
Organizations
- United States Army
- University of California, Los Angeles