William J. Gradishar, MD, FACP

2012-2013 BCRF Project:
(made possible by generous support from The Housewares Charity Foundation)
Co-Investigator: Vincent L. Cryns, MD, University of Wisconsin, Madison, WI

In 2011-12, Drs. Cryns and Gradishar have demonstrated that the cell stress protein αB-crystallin promotes brain metastasis by enhancing the adhesion of breast cancer cells to cells that make up blood vessels in the brain. This occurrence appears to facilitate penetration of the blood-brain barrier (BBB) — the biggest barrier in current therapies to treat cancers that have spread (metastasized) to the brain. The team has also demonstrated that αB-crystallin is a key regulator of breast cancer metastasis by preventing cell death that normally occurs when tumor cells detach from surrounding cells in the breast and escape into the bloodstream, an early step in metastasis. Taken together, these studies point to αB-crystallin as an important molecular regulator of metastasis in basal-like breast cancer and a promising drug target for these poor prognosis breast tumors.

In addition, basal-like tumors are a newly recognized type of breast cancer that are clinically aggressive and lack targeted therapies because they are estrogen receptor negative (ER-) and HER2 negative (HER2-). This type of tumor is collectively referred to as triple negative breast cancer. Drs. Cryns, Gradishar, and colleagues have shown that a cell stress protein called aB-crystallin contributes to the aggressive behavior of basal-like tumors in part by making them resistant to chemotherapy. More recently, these researchers have developed new in vivo models of basal-like breast cancer that metastasize from the breast to the brain and other organs. Using these in vivo models, this team has demonstrated that aB-crystallin is a key regulator of breast cancer metastasis.

During the next year of BCRF funding, Drs. Cryns, Gradishar, and their colleagues will use these existing models and develop new in vivo models to better understand the molecular mechanisms of metastasis and to evaluate new anti-metastatic therapies for basal-like tumors. One particularly exciting therapeutic strategy is the use of nanotechnology to improve drug delivery to tumors. In this way, these studies may provide novel insights into the mechanisms of breast cancer metastasis, a largely fatal stage of the disease with limited treatment options, and ultimately lead to improved therapies.

Mid-year Progress: During the current year of BCRF funding, the researchers have created a new genetic model of breast cancer in which the αB-crystallin gene is deleted to study its role in metastasis. The team has also demonstrated that αB-crystallin allows cells to survive in the setting of p53 mutation and Rb gene inactivation, two common molecular abnormalities in basal-like breast cancer. Notably, reducing the levels of αB-crystallin in basal-like breast cancer cells with p53 and Rb abnormalities makes them more sensitive to chemotherapy. These studies provide novel insights into the molecular mechanisms of basal-like breast cancer and point to αB-crystallin as a promising drug target in these poor-prognosis breast tumors

Bio:
Dr. Gradishar is Professor of Medicine in the Division of Hematology and Medical Oncology, Department of Medicine, at the Feinberg School Medicine at Northwestern University in Chicago, Illinois, and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. He also serves as Director of Breast Medical Oncology, Associate Director of the Lynn Sage Comprehensive Breast Program, and Program Director of Northwestern University's Hematology/Oncology Fellowship Training Program. His research focuses on the development of novel therapeutics for the treatment of breast cancer.

A Fellow of the American College of Physicians, Dr. Gradishar is also a member of the American Association for Cancer Research, the American Federation for Clinical Research, and the Association of Subspecialty Professors. He is the immediate past chair of the Oncology Training Program Committee of the American Society of Clinical Oncology (ASCO) as well as a member of ASCO's Program Committee. He is a member of the Breast Cancer Core Committee of the Eastern Cooperative Oncology Group, the Committee on Cancer of the American College of Surgeons, the National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines Panel, and the NCCN Breast Cancer Prevention Panel. In addition, he serves as a consultant to the Oncology Drug Advisory Committee of the FDA, serves on several study sections nationally and internationally including: NIH, Komen Foundation, Avon Foundation, American Cancer Society. Alberta Cancer Board and the Imperial Cancer Fund. He is a member of editorial boards and reviewer for numerous journals, including Journal of the National Cancer Institute, Journal of Clinical Oncology, and Clinical Cancer Research. He has published extensively in the area of breast cancer therapeutics, with a focus on new endocrine therapy, chemotherapy and novel targeted therapies.

Dr. Gradishar received his medical degree form the University of Illinois Abraham School of Medicine in Chicago. He completed a residency and chief residency in internal medicine at Michael Reese Hospital and Medical Center in Chicago and a fellowship in medical oncology at the University of Chicago.