Lewis A. Chodosh, MD, PhD
J. Samuel Staub Professor
Chair, Department of Cancer Biology
Abramson Family Cancer Research Institute
University of Pennsylvania School of Medicine
2013-2014 BCRF Project:
(The Hamptons Paddle & Party for Pink Award)
The hormone prolactin, which is normally produced by the pituitary gland, is a central regulator of the normal development of the breast. Recent studies have shown that prolactin is also synthesized in breast epithelial cells and in some human breast cancers, but the regulation of its production and its functional significance are unknown. In previous studies supported by BCRF, Dr. Chodosh and his team have discovered that production of prolactin in the breast is controlled by the PI3K-Akt signaling pathway, which is one of the most commonly activated oncogenic pathways in human breast cancers, and that prolactin produced by the breast is required for the proper onset of lactation in laboratory models. Their findings provide the first demonstration of what regulates prolactin synthesis in the breast, identify a physiological function for prolactin, and reveal a direct connection between the production of prolactin and pathways known to be involved in the pathogenesis of breast cancer. Their study raises the possibility that prolactin may play a role in breast cancer development. Further investigation will be required to determine whether therapeutic approaches aimed at blocking prolactin action in the breast will be beneficial in the treatment of breast cancer patients. Dr. Chodosh’s laboratory has also developed a novel algorithm, termed energy-paired scoring (EPS), which can predict whether a signaling pathway is activated in a tumor using gene expression patterns. Over the past year they validated this approach using the prolactin pathway as an example. These results may be useful for helping select which patients are likely to benefit from treatment with a drug that targets this pathway.
The propensity of breast cancers to recur following surgery, radiation, and adjuvant therapy is the most important determinant of clinical outcome, since recurrent breast cancer is treatable but often incurable. Residual cancer cells that remain following treatment constitute a cellular reservoir from which recurrent breast cancers can arise. Consequently, the survival of these cells represents a major obstacle to the successful treatment of breast cancers in women. Accordingly, understanding the mechanisms that residual cancer cells employ to survive following treatment is a critical priority. Dr. Chodosh’s findings, published in Cancer Cell, have identified down-regulation of the tumor suppressor par-4 as a mechanism of tumor cell survival and recurrence following targeted therapy and chemotherapy in laboratory models and women. His team found that par-4 down-regulation provides a survival advantage to model and human breast cancer cells treated with chemotherapeutic agents or with targeted therapies that block the HER2 oncogene, which is activated in 15-20% of human breast cancers. They have further found that par-4 is down-regulated in residual breast cancer cells that survive chemotherapy in patients, and that low par-4 predicts a decreased response to neoadjuvant chemotherapy as well as a higher risk of breast cancer recurrence in patients receiving neoadjuvant chemotherapy. Together, these findings suggest that developing therapies that target pathways repressed by par-4 – or that restore par-4 expression – may hold significant clinical promise. Moreover, these studies contribute to our understanding of the mechanisms of resistance to targeted therapies.
Dr. Lewis Chodosh joined the faculty of the University of Pennsylvania School of Medicine in 1994 and currently serves as Chairman of the Department of Cancer Biology. Dr. Chodosh holds appointments as an Professor with Tenure in the Departments of Cancer Biology, Cell & Developmental Biology, and Medicine in the Division of Endocrinology, Diabetes and Metabolism. In addition, Dr. Chodosh is an Investigator of the Abramson Family Cancer Research Institute. As a physician-scientist, Dr. Chodosh is principally dedicated to leading a research laboratory of 23 graduate students, technologists and postdoctoral fellows in a comprehensive research program aimed at eradicating breast cancer.
Dr. Chodosh's scientific career is founded on academic achievement. He graduated summa cum laude, Phi Beta Kappa from Yale University in 1981 with Distinction in Molecular Biophysics and Biochemistry. In 1989, Dr. Chodosh simultaneously received his M.D. from Harvard Medical School, where he graduated magna cum laude, and his Ph.D. in Biochemistry at the Massachusetts Institute of Technology under the mentorship of Nobel laureate, Dr. Phillip Sharp. After a residency program in Internal Medicine at the Massachusetts General Hospital, Dr. Chodosh completed a clinical fellowship in Endocrinology at the Massachusetts General Hospital in 1992 and a postdoctoral research fellowship with Dr. Philip Leder at Harvard Medical School in 1994.
As a clinical and scientific trainee, Dr. Chodosh has received numerous honors including the Leon Reznick Memorial Prize for Excellence in Research from Harvard Medical School, the Emerson Tuttle Cup for Distinguished Academic Achievement from Yale University, the Cornell Ingenuity in Mathematics and Science Award, the Harvard Book Prize, the Bausch and Lomb Honorary Science Award, the Merck Research Laboratories MD/PhD Fellowship, the Charles E. Culpeper Foundation Scholarship in Medical Science, and the AACR-Sidney Kimmel Cancer Symposium for Cancer Research Scholar Award. Dr. Chodosh was elected to the American Society for Clinical Investigation in 2002.
As an independent investigator at the University of Pennsylvania, Dr. Chodosh has focused his clinical and research training on developing new experimental approaches to understanding, treating and preventing breast cancer. Dr. Chodosh is particularly interested in identifying the mechanisms by which human cancers become resistant to therapy, as well as in understanding how normal events in a woman's life can be protective against breast cancer. In pursuit of these goals, Dr. Chodosh's laboratory has developed several novel genetically engineered mouse models for breast cancer, as well as a number of innovative approaches to analyzing large microarray gene expression profiling data sets.
In addition, Dr. Chodosh serves as an Attending Physician on the Endocrine Consult Service at Hospital of the University of Pennsylvania. Dr. Chodosh also serves as an advisor to the Harvard Nurses Health Study, is the senior editor of the scientific journals Breast Cancer Research and an editor of Cancer Biology and Treatment, and is on the Editorial Board of the Journal of Mammary Biology and Neoplasia.