Mechanism and Clinical Application of Statin/Venetoclax Combinations in Blood Cancer
Abstract
Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Blood Cancers, Lymphoma FY19 PRCRP Military Health Focus Area: Gap in treatment of Veterans and general public Scientific Objective and Rationale: This project will advance a novel strategy to improve treatment of acute myeloid leukemia (AML) and other blood cancers. The project will build upon work we have previously published; namely, that statin drugs have great potential to improve responses to a new blood cancer drug called venetoclax. Statins are prescribed to millions of people in the USA and throughout the world, to safely control cholesterol levels and reduce the risk of heart attack and stroke. Why should these cholesterol-lowering medications be useful to treat cancer? Hallmarks of cancer cells are that they divide too much and avoid normal processes of cell death. It turns out that in addition to reducing cholesterol production, statins reduce production of other fats (lipids) that are crucial for cell division and cell survival. Consequently, there has long been interest in “repurposing” statins for cancer. However, statins are not very effective on their own against cancer, and no one had identified a way to use them to enhance efficacy of other anti-cancer drugs. Venetoclax is a relatively new drug, first approved in 2016 for the treatment of chronic lymphocytic leukemia (CLL) and in 2018 for treatment of AML. Venetoclax works by inhibiting an important protein that is a gatekeeper for cell survival. We discovered that when AML and other blood cancer cells are exposed to venetoclax in combination with statins, there is a greater killing effect than with venetoclax alone. We also identified possible mechanisms to explain this combination killing effect. To harness the full potential of this combination, we need to learn more about these mechanisms in laboratory studies. We also need to determine cellular signatures (called biomarkers) that distinguish tumor cells that respond to statins from those that do not respond. This will enable a “precision medicine” approach in which treatment is given only to patients most likely to respond. Lastly, we seek to conduct the first prospective trial of statin/venetoclax combinations in human blood cancer patients, to determine safe doses to test later in larger populations. To summarize, the objectives of this proposal are: (1) Resolve the mechanism by which statins sensitize blood cancer cells to killing by venetoclax. (2) Identify predictive biomarkers of statin response. (3) Implement a phase I trial to establish the recommended phase II dose of statin to test in combination with venetoclax in AML and CLL. Near-Term Impact and Applicability: This research will have a near-term impact on patients with AML and CLL, two of the most common blood cancers (a FY19 Topic Area). Although CLL (and a related lymphoma called SLL) mostly affects people over the age of 40, AML can occur at any age from childhood onwards. The studies have potential to increase the percentage of AML and CLL/SLL patients that achieve disease control (remission) when treated with venetoclax, and to lengthen the duration of disease control. The information gained from this work could eventually be applied to several other common blood cancers including lymphomas. One of the greatest attractions of the statin/venetoclax combination is that both drugs are well tolerated. Statins have a very good safety record in millions of patients, and venetoclax is a “smart” cancer drug with fewer side effects compared to traditional chemotherapies. Therefore, the risk to patients of this novel combination is lower than most untested cancer therapy regimens. The timeline to achieving a patient-related outcome is quite short. We propose to complete patient accrual to the phase I clinical trial of statin/venetoclax combination within 2 years, and to identify the recommended phase II dose of statin within 3 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010867
Entities
People
- David A Fruman
Organizations
- United States Army
- University of California, Irvine