Member, Department of Cell Biology and Genetics
Memorial Sloan Kettering Cancer Center
New York, New York
Studies are focused on new therapeutic targets to treat aggressive breast cancers.
Laboratory experiments will test a new drug called AGX-51 and identify potential combinations with AGX 51 to enhance cancer cell killing.
These studies may lead to new combination approaches to improve response to therapy and patient outcomes.
Breast cancer metastasis remains one of the greatest clinical challenges in breast cancer. Thus, identification of new therapeutic agents that are effective in inhibiting the development of metastasis is critical.
Dr. Benezra's laboratory is studying a class of proteins called DNA binding/differentiation (Id) proteins as potential therapeutic targets to prevent metastasis. Id proteins are overexpressed in primary and metastatic breast tumors, and importantly, knocking out these proteins using genetic tools leads to a near complete inhibition of metastasis in experimental models.
Dr. Benezra's team identified an agent called AGX-51 that reduces the levels of Id1 and Id3, leading to a decrease in lung metastases. When combined with the commonly used chemotherapy drug Taxol, AGX-51 further reduces lung metastases in a model of aggressive breast cancer.
In the coming year, they will work to better understand the mechanism of AGX-51 activity by determining the structure of AGX-51 when bound to Id1 and the mechanics of their interaction. They will also identify FDA-approved drugs that when combined with AGX-51 enhance cancer cell killing. These experiments are key to assessing the potential for novel anti-Id therapeutics in the prevention of metastatic breast cancer.
Robert Benezra, PhD, is a Member at Memorial Sloan Kettering Cancer in the Department of Cell Biology and a Professor of Biology at Cornell Graduate School of Medical Sciences in New York City. As a postdoctoral fellow he identified the Id proteins as dominant negative regulators of the helix-loop-helix protein family and has since gone on to identify these proteins as key regulators of tumor growth, angiogenesis and metastasis. In addition, while at Sloan Kettering, Benezra and his colleagues identified the first human mitotic checkpoint gene, hsMad2, and demonstrated that its deregulation leads to chromosome instability, tumor progression and drug resistance. His program continues to focus on the molecular basis of tumor angiogenesis, tumor instability and metastasis. His current project supported by BCRF is to characterize and exploit a subset of patients' own white blood cells, called neutrophils, that act to inhibit early spread of breast cancer cells to distant organs.