Repurposing a Drug for Amyotrophic Lateral Sclerosis to Treat Triple-Negative Breast Cancer
Abstract
The overarching challenge we propose to address is to revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Breast cancer remains the most common cancer suffered by women, with nearly 233,000 women diagnosed with the disease in the United States every year. Despite many advances over the last three decades, unfortunately breast cancer still remains the second leading cause of cancer death in women, resulting in approximately 40,000 deaths per year. Most breast cancers make proteins, such as the estrogen receptor (ER) or HER2, that doctors can target with drugs. However, approximately 15% of breast cancers make neither ER, progesterone receptor (PR), nor HER2. This form of breast cancer is referred to as "triple-negative breast cancer" (TNBC). TNBCs are aggressive, more frequently lethal tumors, and, because there are currently no useful protein "targets" known, the only drugs effective against TNBC are chemotherapy drugs. Consequently, there is an urgent need to identify proteins in TNBC that can be targeted by drugs to stop tumor growth and kill tumor cells. Even better would be to identify drugs that can treat TNBC without a lot of toxicity and be given to patients as pills instead of by vein. Such a discovery would represent a major advance in the treatment of TNBC and could have the potential to have a significant impact on morbidity and mortality from TNBC within a decade. It could also improve the quality of life of TNBC patients through more effective therapy that requires lower doses of chemotherapy. We believe that we have identified such a drug, which can be given by mouth and has an excellent safety profile. This drug, riluzole, is normally used to treat the fatal nerve disease amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig s disease). To lay the groundwork for a strategy to use this nontoxic drug in drug combinations used to treat TNBC and allow us to begin immediate clinical trials, we therefore propose a systematic approach to studying its mechanism in breast cancer. We base these studies in part on experiments that have demonstrated anticancer effects of riluzole against melanoma, a form of skin cancer. Although in melanoma riluzole appears to act primarily by inhibiting the activity of glutamate, which can bind to proteins on the cell surface and make tumors grow, in breast cancer and other cell types, riluzole appears to act also through other proteins. In particular, we suspect that it works by affecting the activity of voltage-gated ion channels (VGSCs). These are channels that let ions pass through the membranes of cells in response to voltage changes. They are very important in transmitting nerve signals. However, they also control growth signals in cells other than nerve cells, particularly cancer cells, such as breast cancer and prostate cancer. We have already tested riluzole against TNBC and found that it works in cell culture and mouse models of TNBC. However, we do not know whether riluzole works by acting on glutamate receptors (the proteins that bind glutamate), ion channels, or both. We therefore believe that riluzole blocks TNBC growth through a combination of glutamate receptors and mechanisms that do not depend on glutamate. That is why we propose to test which of these is true through an exploratory study to determine if riluzole can be used against TNBC by identifying these mechanisms and determining their relative importance. We will answer the following three questions: (1) What are the mechanism(s) through which riluzole inhibits TNBC growth that depend(s) on glutamate? (2) What are the mechanisms that do not depend on glutamate important in TNBC that are affected by riluzole? (3) How can we use riluzole, either alone or in combination with chemotherapy, to treat breast cancer and decrease the toxicity of breast cancer treatments? We will test in cell culture a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510468
Entities
People
- David Gorski
Organizations
- United States Army
- Wayne State University