David H. Gorski, MD, PhD, FACS

Therapies targeted to proteins that are expressed by breast cancer cells but not by the surrounding normal tissue are one means to reach the goal of effective, but less toxic. Thanks to a fortuitous coincidence, Dr. Gorski and his team may have found just such a molecular target serendipitously. Glutamate is the major signaling molecule used to transmit nerve impulses from cell to cell in the central nervous system. Disorders in glutamate signaling are believed to be involved in several neurological diseases, including ALS (Lou Gehrig's disease), epilepsy, damage to neurons in response to trauma, and others.

Until recently, metabotropic glutamate receptors (GRMs) were believed to be restricted to the central nervous system, but recently they have been found in other tissue types as well. Several years ago, while studying fat development, Dr. Gorski's collaborator used a stretch of DNA known to be involved in adipocyte (fat cell) formation to produce a transgenic model. Contrary to expectations, the model had no changes in fat composition but instead developed skin lesions that looked very much like melanoma. Further investigation revealed that the DNA had inserted near a gene for a metabotropic glutamate receptor (Grm1), resulting in greatly increased levels of Grm1 protein. Dr. Gorski's most recent work indicates that GRM1 is also made in approximately 60% of human breast cancers but not in normal breast cells; that it is active; and that it is also made in tumor blood vessels. These observations have led him to hypothesize that GRM1 blockade may represent a promising new therapeutic strategy for breast cancer.

Fortunately, blocking agents for glutamate already exist. Riluzole, for example, is the only FDA-approved treatment for ALS that has been shown to increase life expectancy. It works both by blocking the GRM1 and by inhibiting the release of additional glutamate from nerve cells and exhibits minimal toxicity. Thus, the overall aims of this project will be: (1) to test whether blocking GRM1 can inhibit breast cancer growth in cell culture and tumor models and to identify the growth signaling pathways that such blockade affects; (2) to test whether blocking GRM1 can inhibit tumor angiogenesis and starve tumors of blood and nutrients; and (3) to test in a phase 0 clinical trial whether Riluzole blocks these same pathways in human breast cancer.

These studies will provide the preliminary evidence necessary to support clinical trials designed to test the efficacy of GRM1 blockade in treating breast cancer patients. Because of the low toxicity of these drugs, they have potential as a less toxic alternative to chemotherapy, particularly in tumors that are estrogen receptor-negative and Her-2/neu-negative and thus not responsive to estrogen-blocking drugs like Tamoxifen or existing molecularly targeted therapy like Herceptin.

Mid-Year Progress Report:
In the seven months since the project began, Dr. Gorski has achieved the following milestones: First, with the help of collaborators, he has successfully constructed DNA plasmids that can be introduced into cells to make GRM1. This was a difficult task because the human GRM1 gene is made up of several segments known as exons and these exons had to be isolated and spliced together in the proper order.

Second, he and his collaborators have verified that blockade of GRM1 with the drug Riluzole inhibits the growth of some breast cancer cell lines in cell culture and that it also inhibits angiogenesis. Finally, they have begun to work on introducing GRM1 into normal breast cells in order to determine whether it turns them into cancer and are presently testing the cells to see if they will grow in models.

The researchers’ immediate plans are to test the ability of Riluzole, a glutamate blocking drug, to inhibit tumor growth in laboratory models of breast cancer, and they plan to begin a clinical trial using Riluzole in breast cancer patients to determine whether this drug turns off the same cell signaling pathways in human breast cancer cells as it does in melanoma. The ultimate goal of this project is to test Riluzole and drugs like it in breast cancer patients to determine if they can improve survival when combined with standard chemotherapy regimens.

Bio:
David Gorski is an Associate Professor of Surgery in the Division of Surgical Oncology at UMDNJ-Robert Wood Johnson Medical School and is presently based at The Cancer Institute of New Jersey in New Brunswick, NJ. He graduated with a BS in Chemistry from the University of Michigan and then went on to attend medical school at the University of Michigan. Following graduation, he pursued a residency in general surgery at Case Western Reserve University in Cleveland. While there, between his second and third years of residency, he pursued a PhD in Cellular Physiology at the Department of Physiology and Biophysics at CWRU, where he studied the transcriptional regulation in vascular smooth muscle cells during restenosis and atherosclerosis.

After residency, Dr. Gorski undertook a research fellowship in surgical oncology at the University of Chicago, where he studied the interaction between radiation therapy and anti-angiogenic therapy in laboratory tumor models. At the completion of his fellowship, he accepted his current position at CINJ, where he presently combines a practice in breast cancer surgery with research into his two areas of interest, the transcriptional regulation of endothelial cell phenotype during tumor angiogenesis and the role of glutamate signaling in breast cancer pathogenesis and angiogenesis.