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William J. Gradishar, MD, FACP
Betsy Bramsen Professor of Breast Oncology
Director, Maggie Daley Center for Women’s Cancer Care
Robert H. Lurie Comprehensive Cancer Center
Feinberg School of Medicine
Goal: To improve outcomes in breast cancer by identifying aberrant cell processes that lead to tumor formation and progression.
Impact: Drs. Gradishar and Cryns are studying a cell stress protein called alphaβ-crystallin, which contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC). They have shown that it interacts with a mutant form of p53, the most commonly mutated gene in cancer, and links p53 to Akt, a growth-promoting protein that is often upregulated in cancer. Their work may lead to the identification of new approaches to target oncogenes in a broad spectrum of breast tumors.
What’s next: The team will identify the specific role of alphaβ-crystallin in promoting tumor growth by common cancer-causing genes.
Basal-like tumors, which include those classified as triple negative, are aggressive and lack targeted therapies. Drs. Gradishar and Cryns have shown that a protein called alphaβ-crystallin contributes to the aggressive behavior of these tumors and regulates the spread of breast cancer to organs such as the brain. Recently, they discovered that alphaβ-crystallin binds to mutant p53 protein, promoting tumor growth. They have also discovered that this pathway links p53 and with a growth-promoting factor called Akt. The team will now study alphaβ-crystallin’s role in regulating these pathways.
Full Research Summary
Research goal: Developing new approaches to treat aggressive breast cancers.
Impact: Basal-like triple negative breast cancers are aggressive and lack targeted therapies because they don’t depend on the estrogen or progesterone hormones or HER2 for growth, thus the term “triple-negative.” Drs. Gradishar and Cryns are investigating a cell stress protein called alphaβ-crystallin that contributes to the aggressive behavior of basal-like/triple-negative breast cancer (TNBC) by interacting with cancer-promoting proteins. Their findings may inform new targeted therapies that would prevent this protein from promoting metastasis.
Current investigation: The team is screening libraries of chemical compounds to identify drugs that block the interaction between alphaβ-crystallin and p53, the most commonly mutated gene in cancer. Alphaβ-crystallin binds directly to mutant p53 and keeps it active, thereby promoting tumor growth. Drugs that block the interaction between alphaβ-crystallin and p53 are predicted to cause tumor cell death.
What they’ve learned so far: Drs. Gradishar and Cryns showed that blocking alphaβ-crystallin binding to p53 prevents p53 from promoting tumor formation. They also discovered that this pathway directly links p53 and Akt, a potent growth factor.
What’s next: During the next year, the team will identify the specific role of alphaβ-crystallin in keeping p53 and Akt active and in promoting tumor growth by these genes.
William J. Gradishar is Betsy Bramsen Professor of Breast Oncology in the Division of Hematology and Medical Oncology at the Feinberg School Medicine at Northwestern University and a member of the Robert H. Lurie Comprehensive Cancer Center. He is Director of the Maggie Daley Center for Women’s Cancer Care. He has been Chair of the Annual Lynn Sage Breast Cancer Symposium since its inception. 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 past chair of the Oncology Training Program Committee and Communications Committee of the American Society of Clinical Oncology (ASCO). He is Chair-elect of the ASCO Professional Development Committee and a member of ASCO’s Scientific Program Committee. He is a member of the Breast Cancer Core Committee and Co-Chair of the Developmental Therapeutics Working Group 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. He also serves as a consultant to the Oncology Drug Advisory Committee of the FDA. He has served on numerous study sections and is a member of the editorial board for the Journal of Clinical Oncology, Oncology, Clinical Breast Cancer, Journal Watch, European Journal of Clinical and Medical Oncology and Clinical Cancer Research.