Development of Novel Drugs for High-Risk Triple-Negative Breast Cancer Treatment
Abstract
Triple-negative breast cancer (TNBC) constitutes 10%-20% of all breast cancers, and it is associated with aggressive tumor growth, recurrence, metastasis, and poor patient outcome. The absence of well-defined molecular targets such as estrogen/progesterone receptors or HER2 receptors makes TNBC treatment very challenging. Most patients initially respond to the standard chemo/radiation therapy, but a majority of them relapse and become drug resistant. Hence, novel and inexpensive protocols that are selectively toxic to cancer cells and also that work on drug-resistant cells are urgently needed. High consumption of glucose for energy production (glycolysis) is the hallmark of all advanced stage tumors. The end products of glycolysis are energy-rich nutrients such as pyruvate and lactate. These nutrients are transported in and out of the cells by monocarboxylate transporters 1-4 (MCT1-4) for further energy production. MCT inhibition results in the disruption of the glycolysis and consequently the cancer cells will not be able to proliferate and metastasize. Since glycolysis is a common factor in all the cancer cell lines, this strategy should be applicable to the treatment of several other cancers also. MCTs are upregulated in many breast cancer cell lines, and hence their inhibition has tremendous clinical potential. As the grade of the cancer worsens, it adopts an aggressive glycolytic process for energy production. The number of MCTs on the cell surface increases proportionately to efflux/influx the resulting lactate and this fact is very important in opening other possibilities for treatments of relapsed and metastasized cancers. Because tumor cells upregulate these transporters specifically for their unique metabolic needs, we expect that normal cells will be tolerant to the chemotherapeutic actions, thereby leading to minimal side effects. Over the past 5 years, we have created novel small molecule MCT inhibitors and synthesized and evaluated more than 300 new compounds. Of these, we have discovered several aqueous soluble and potent MCT1/4 dual inhibitors that are active at very low nM concentrations. Anticancer efficacy studies in mice bearing TNBC tumor xenograft and also aggressive stage IV metastatic breast cancer models have shown that these drugs efficiently reduce tumor burden without causing any toxic side effects. We plan to carry out detailed in vivo biological studies to complete the preclinical studies of these potent molecules for TNBC. Successful completion of the project will provide novel drug candidates for the treatment of advanced/relapsed breast and other cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510047
Entities
People
- Venkatram R. Mereddy
Organizations
- United States Army
- University of Minnesota