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Preclinical optimization of statin/BH3 mimetic combinations in multiple myeloma

David Fruman

David Fruman

PhD

University of California, Irvine

Project Term: July 1, 2019 - June 30, 2022

This project will evaluate a novel two-drug combination to improve killing of multiple myeloma (MM) cells. First, we will test the hypothesis that statins increase killing of MM cells by BH3 mimetics including venetoclax and the MCL-1 inhibitor AMG 176. Second, we will identify biomarkers that predict response. This project will have significant positive impact on two fields: repurposing statins for blood cancer, and application of BH3 mimetics to improve health and survival of MM patients.

Lay Abstract

Multiple myeloma (MM) is the second most common blood cancer in adults. The disease causes severe pain and discomfort and is considered to be incurable. New treatments over the last decade have improved disease control and extended survival of many patients. However, the average MM patient lives 4-5 years overall, and this time is even shorter in patients who have their disease come back after treatment. MM cells are highly resistant to cell death, making it difficult to fully eradicate tumor cells. Another obstacle is that MM tumors are heterogeneous, meaning that not all of the cells behave the same, and different cells have different ways to stay alive. This makes it hard to design treatments that will help everyone with MM. This project will test a simple and feasible strategy to better pick therapies for patients. We will study an exciting class of drugs that act directly on proteins that help cancer cells survive. These death-inducing drugs, known as BH3 mimetics, include venetoclax that is approved by the FDA for treating another blood cancer called CLL. Venetoclax shows promising benefit in some MM patients but has not led to a cure. We propose to increase the efficacy of venetoclax using a second drug (a statin) that is safe, well-tolerated, and already used widely in patients worldwide. Statins (for example, Lipitor) are prescribed to millions of people to reduce cholesterol levels and reduce the risk of heart attacks and stroke, with very few side effects. Studies have suggested that statins also could help treat cancer, but so far this potential has been unrealized. A central challenge has been that statins alone do not have powerful anti-cancer effects, and it is unclear how best to combine them with other drugs. We recently published a breakthrough in these efforts to “repurpose” statins for cancer treatment. In studies of CLL and other blood cancers, we found that statins greatly increase the anti-tumor effect of venetoclax. In addition, we analyzed clinical trial data and found that CLL patients taking venetoclax had a much higher response rate if they were also taking statins, compared to non-statin users. We have now carried out similar analyses of clinical trial data from MM patients treated with venetoclax, and again the statin users showed much better responses to therapy. These data provide strong motivation to carry out a prospective clinical trial of statins with venetoclax in MM. However, it will be necessary to first gather more evidence that statins enhance venetoclax efficacy in laboratory studies. Therefore, the objective of this proposal is to study this combination of statins with venetoclax and other BH3 mimetic drugs in MM cells. As part of this work, we aim to identify biomarkers or tools that can predict whether individual MM patients would respond to these combinations. The use of predictive biomarkers is a powerful way to improve the success rate of clinical trials and of personalized medicine in general.

Program
Translational Research Program
Grant Subprogram
TRP Basic
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