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Susan B. Horwitz, PhD
Distinguished Professor Emerita
Department of Molecular Pharmacology
Rose C. Falkenstein Chair in Cancer Research
Albert Einstein College of Medicine
New York, New York
Goal: To identify new therapeutic options for triple-negative and BRCA-driven breast cancers.
Impact: Drs. McDaid and Horowitz are testing new drugs that may overcome common drug resistance and cause fewer side effects than currently approved therapies, while also investigating the reasons underlying relapse after chemotherapy. Their work could lead to improved outcomes for patients with aggressive breast cancer.
What’s next: The team will continue to screen novel targeted anti-cancer therapies in triple-negative breast cancer (TNBC). They also plan to develop biomarkers to accurately detect senescent tumor cells. Senescent (dormant) tumor cells are often resistant to anti-cancer treatment and are known to drive cancer recurrence that leads to metastasis.
While many breast cancer patients have excellent survival following anti-cancer therapy, some patients are resistant to treatment or may have an incomplete response, leading to relapse after a period of remission. The BCRF research led by Drs. McDaid and Horowitz is focused on defining the fate of cancer cells that survive anti-cancer therapy. They are conducting laboratory studies to identify more effective and less toxic drugs for patients with TNBC and pursuing biomarkers to identify dormant tumor cells involved in metastasis and drug resistance.
Full Research Summary
Research goal: Identifying targeted therapies and new combination approaches to counter drug resistance and improve outcomes for patients with triple-negative and BCRA-driven breast cancer.
Impact: While many patients with triple-negative breast cancer (TNBC) respond well to therapy, others have an incomplete response and/or relapse after a period of remission. Those who have inherited mutations in genes that control DNA damage repair, such as BRCA, often have a particularly high risk of relapse following treatment. Drs. McDaid and Horowitz are investigating the causes of resistance to therapy particularly therapy with drugs like Taxol, an anti-tubulin drug. The results of their studies will provide insight into how tubulin-interacting agents bind to tubulin and how that binding causes breast cancer cell death. This will enable the development of targeted therapies to overcome resistance.
Current investigation: The team will continue their investigations to define the mechanism of action for tubulin-targeting drugs to advance the field of drug discovery for patients with aggressive TNBC. Since the ability of cancer cells to lay dormant leads to cancer recurrence, they will examine a type of cellular dormancy that is sometimes caused by cancer therapy, including chemotherapy.
What they’ve learned so far: Drs. McDaid and Horowitz have found that the action of tubulin binding drugs is dependent on the form of tubulin present. Therefore, they have engineered a variety of tubulins that can be used to evaluate how conventional and novel tubulin-interacting molecules bind to different types of tubulin. To understand the reasons underlying relapse after chemotherapy, they are studying a type of cellular dormancy that is sometimes caused by cancer therapy. They have found that while senescent cancer cells are damaged and do not divide, they do produce inflammatory proteins that can promote the growth of neighboring non-damaged tumor cells thereby leading to treatment resistance, recurrence, or metastasis.
What’s next: The team will continue investigating potential drug candidates for treatment of TNBC that both strongly induce tumor cell death and have a low risk of inducing cellular dormancy. In addition, they will delineate the molecular signatures of senescence that can be exploited to develop new drugs to eradicate these tumor cells.
Dr. Susan Band Horwitz is a Distinguished University Professor at the Albert Einstein College of Medicine. She grew up in Boston and after graduating from Bryn Mawr College, received her PhD in Biochemistry from Brandeis University.
Dr. Horwitz has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her laboratory has made Taxol, a drug isolated from the yew plant, Taxus brevifolia, a major focus of its work and today it is given to over a million patients. Dr. Horwitz' research played an important role in encouraging the development of Taxol by the National Cancer Institute.
Dr. Horwitz and her collaborators demonstrated that the effects of Taxol were due to a novel interaction between the drug and microtubules that identified Taxol as a prototype of a new class of anti-tumor drugs. Dr. Horwitz also has made significant contributions to our understanding of the molecular mechanisms underlying Taxol resistance in tumor cells.