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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. Their work may could lead to the identification of new approaches to target mutant p53 for destruction in a broad spectrum of breast tumors.
What’s next: The team will continue to screen libraries of chemical compounds to identify drugs that block the interaction between alphaB-crystallin and p53 and test them in laboratory studies
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 alphaB-crystallin binds to mutant p53 (the most commonly mutated gene in cancer) and keeps it active, promoting tumor growth. The team will now test drugs that block the interaction between alphaB-crystallin and p53, which may benefit those with triple negative and other forms of breast cancer.
Full Research Summary
Research goal: Developing new approaches to target basal-like tumors.
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). 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 alphaB-crystallin and p53 are predicted to cause tumor cell death.
What they’ve learned so far: Drs. Cryns and Gradishar showed that alphaβ-crystallin promotes survival of breast cancer stem cells—specialized cells that are suspected to drive metastasis— by increasing expression of a molecule called IL-6 that is involved in inflammatory response. This suggests that it may be a target for stopping metastasis.
What’s next: During the next year, the team will test promising drugs in laboratory models of breast cancer, including miniature tumors grown in a dish.
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.