David H. Gorski, MD, PhD

In the 11 months since the project began, Dr. Gorski and his collaborators have achieved: 1) Construction of a DNA vector containing the human GRM1 gene, which is presently being introduced into breast cancer cells to determine if it transforms them into malignant cells, and 2) Verification that blockade of the protein that the GRM1 gene makes (mGluR1) with the glutamate blocking drug Riluzole inhibits the growth of some breast cancer cell lines in cell culture and inhibits angiogenesis (new blood vessel formation, a capability of tumor cells that allows them to hijack the body’s blood vessels to provide oxygen and nutrients to feed their growth).

Going forward, Dr. Gorski's immediate plan is to test the ability of Riluzole, a glutamate blocking drug, to inhibit tumor growth in laboratory models of breast cancer using human breast cancer cell lines that both do and do not express GRM1 in order to determine whether (1) Riluzole inhibits their growth as predicted and (2) inhibition of tumor growth observed correlates with the presence or absence of mGluR1.

By fall 2008, Dr. Gorski anticipates beginning 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.

Mid-year Progress Report:
Dr. Gorski’s proposed and ongoing research funded by the BCRF through the ASCO Foundation involves studying the role of glutamate in breast cancer. Three years ago in another cancer (melanoma), Dr. Gorski's collaborators found that glutamate might have a role in promoting the transformation of the pigmented cells in the skin (melanocytes) into the deadly skin cancer melanoma. What was so unusual about this is that the protein that was identified on the cell surface of melanoma that binds to glutamine, which triggers cell growth and division, is normally found only in the brain and central nervous system, where disorders that affect the protein have been implicated in the devastating neurological disorder amyotropic lateral sclerosis (ALS, also known as Lou Gehrig's disease). However, when made inappropriately by melanocytes, this protein, known as metabotropic glutamate receptor-1 (mGluR1), contributes to malignancy. More importantly for therapy, it was found that this protein can be blocked with drugs, and, specifically, in melanoma cell lines and tumor models of melanoma using a drug originally designed to treat ALS and already FDA-approved for that indication (Riluzole) can inhibit the growth of melanoma. Since then, this protein has also been found on the cell surface in 60% of human breast cancer cell lines.

Since the start of the project funded by the BCRF through ASCO, Dr. Gorski's laboratory has thus far shown that treating these cells with Riluzole to block glutamate binding to mGluR1 results in (1) decreased growth at low doses and programmed cell death at higher doses; (2) a decrease in the chemical signaling inside of breast cancer cells that is associated with cell growth; and (3) an inhibition of the growth and activity of cells that are responsible for the ingrowth of new blood vessels into tumors. Currently, Dr. Gorski is focusing on testing whether glutamate blockade blocks breast cancer growth in laboratory models and whether introducing the gene for mGluR1 in order to make normal breast cells produce mGluR1 when they are not supposed to will convert normal breast cells into cancerous cells. Finally, a phase 0 clinical trial protocol for testing whether taking Riluzole before surgery results in the inhibition of growth pathways in human breast cancer is being reviewed by his institution’s IRB, and it is expected that patient accrual will begin in the spring.

Bio:
David H. Gorski, MD, PhD, FACS is the Program Leader for the Breast Cancer Biology Program at the Barbara Ann Karmanos Cancer Institute, a position he has held since October 2008, and Associate Professor of Surgery at the Wayne State University School of Medicine. Dr. Gorski graduated with a BS in Chemistry from the University of Michigan and then attended medical school at the University of Michigan. Following graduation, he pursued a residency in surgery at Case Western Reserve University in Cleveland. 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, after which he accepted a position at The Cancer Institute of New Jersey. In March 2008, he accepted a position at the Barbara Ann Karmanos Cancer Institute, 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.