Robert Benezra, PhD

2009-2010 BCRF Project:
(made possible by generous support from Play For P.I.N.K.)

Cancer related mortality is usually associated with a spreading of the disease to distant organs (metastasis). What determines the site of future metastasis? Previous studies show that the primary tumor can modify distant organs and prepare them for the arrival of tumor cells. Modification of distant tissues by the primary tumor can enhance the metastatic process.

Dr Benezra's preliminary data suggests that the primary tumor also induces an anti-metastatic immune response and delays the formation of distant metastases. This response is mediated by neutrophils - a subset of white blood cell usually associated with inflammation and with fighting infections. The neutrophils are stimulated by the primary tumor and recruited to the future site of metastasis where in a mechanism that is still unknown, they inhibit tumor cell colonization. The Benezra team proposes to study how the primary tumor stimulates neutrophils as well as the mechanism by which neutrophils inhibit tumor cell colonization in the future metastatic site. These studies could ultimately help us enhance the activity of the neutrophils specifically at the future sites of metastasis to prevent tumor spread in a variety of clinical settings.

Previously, with BCRF support Dr. Benezra and his colleagues developed a new strategy that allows for specific inhibition of the expression of the protein Id1 in tumor blood vessel cells. Treatment of experimental tumors in laboratory models with this new drug, interfered with tumor angiogenesis, rendered the tumors more susceptible to chemotherapeutic treatment and blocked both primary tumor growth and metastatic spread to the lung. The researchers have now expanded the utility of this tool to also directly target tumor cells and other tumor-associated cell types, allowing for the development of new targeted therapeutic agents against breast tumor cell invasion and metastasis.

Mid-Year Progress Report:
With the help of BCRF, Dr. Benezra and his team have shown that tumors that form in the breast send signals to white blood cells which arm them with the ability to inhibit the growth of metastatic tumor cells in the lung. Unfortunately, in many cases, the metastatic tumor cells win this battle leading to the appearance of life-threatening lung metastases. The researchers have identified the chemical signals which induce these white blood cells to fight lung metastatic cells in laboratory models and have shown that re-infusion of these treated white blood cells profoundly reduces lung cancer metastasis in models. Such an approach can lead to the utilization of a patient’s own cells to prevent metastasis in what promises to be an effective, non-toxic rational strategy to reducing breast cancer mortality.

Bio:
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. Before he joined Sloan-Kettering, Benezra worked at Fred Hutchinson Cancer Center in Seattle where 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 dergulation 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 and is currently developing molecular and cellular tools to inhibit these processes in patients.