David H. Gorski, MD, PhD

2009-2010 BCRF Project:
ASCO Cancer Foundation Advanced Clinical Research Award, in honor of Larry Norton, MD

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. In addition, the researchers have noted the MGluR1 appears to be made at a higher level in estrogen receptor-positive 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. A phase 0 clinical trial protocol for testing whether taking Riluzole before surgery results in the inhibition of growth pathways in human breast cancer has been approved by his institution's IRB, and patient accrual has commenced. Finally, from data from the nervous system and Dr. Gorski's own work, he and his team have reason to believe that mGLuR1 interacts with the estrogen receptor (ER). They are now actively exploring whether there is indeed such an interaction in breast cancer cells and whether they can target it.

Mid-Year Progress Report:
Dr. Gorski and colleagues continue to test 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. A phase 0 clinical trial protocol for testing whether taking Riluzole before surgery results in the inhibition of growth pathways in human breast cancer has finally been approved, and Dr. Gorski recently learned that he may start accruing patients to it.

Finally, from data from the nervous system and his own work, Dr. Gorski has reason to believe that mGluR1 interacts with the estrogen receptor (ER). His team is also beginning experiments, both in cell culture and in models, to determine if blocking mGluR1 will increase the effectiveness of anti-estrogen drugs or even restore sensitivity to anti-estrogen drugs in ER(+) breast cancer cell lines resistant to Tamoxifen.

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.