Neal Rosen, MD, PhD
New York, New York
Director, Center for Mechanism-Based Therapy
Enid A. Haupt Chair in Medical Oncology
Member, Sloan Kettering Institute Molecular Pharmacology Program
Memorial Sloan Kettering Cancer Center
New York, New York
Developing novel therapeutic combinations to inhibit tumor growth and treat advanced breast and endometrial cancers.
Metastatic breast and endometrial cancers may respond to initial treatment but eventually become resistant to conventional therapies. Abnormal estrogen receptors and a mutated cancer gene, PIK3CA, and the protein it codes phosphatidylinositol kinase-3 (PI3K), generate unregulated signals that drive the growth of many of these tumors. However, inhibitors of estrogen receptors and PI3K have been mostly unsuccessful in clinical trials because cancer cells adapt by activating alternative growth pathways and are able to survive the treatment. Dr. Rosen is working to understand why this is and to develop improved therapies for advanced breast and endometrial cancers.
Dr. Rosen and his team have discovered and tested two novel drugs. The first blocks a protein called eIF4A, which can promote cancer progression. In experimental systems, the combination of the eIF4A inhibitor with the anti-estrogen drug Fulvestrant effectively eradicated tumors that have become resistant to endocrine therapy. The second drug blocks a protein called TORC1, a component of the PI3K pathway, and laboratory studies have shown it to reverse drug resistance and prevent tumor growth. Clinical trials of these drugs are ongoing.
In the coming award year, Dr. Rosen plans to continue studies on the mechanism and biologic effects of eIF4A inhibition in breast cancer models. The synergistic effect seen in combination with Fulvestrant strongly suggests that the major effects of the combination are due to inhibition of estrogen receptor function. They will develop laboratory models of drug resistant tumors treated with eIF4A or Fulvestrant alone or in combination to determine the mechanism of action. Finally, Dr. Rosen will determine the effects of the TORC1 inhibitor in endometrial and breast cancer models that also have mutations in the PIK3CA gene, as this is common in both cancers.
Neal Rosen, MD, PhD, is the Director of the Center for Mechanism-Based Therapeutics at Memorial Sloan Kettering Cancer Center and a Member in the Program in Molecular Pharmacology and Chemistry. His major interests include the study of the key molecular events and growth signaling pathways responsible for human cancers, and the use of this information for developing effective therapies. Dr. Rosen has played a leading role in the development of inhibitors of tyrosine kinase and RAS-mediated signaling and has pioneered the concept that feedback reactivation of parallel signaling pathways is a common cause of adaptive resistance to selective pathway inhibitors. Recent work includes the elucidation of the biochemical and biologic mechanisms of action of RAF inhibitors, the mechanisms underlying resistance to these compounds, and studies on the role of ERK-dependent feedback in tumors with RAF or RAS mutation. This research has led to many international clinical trials with promising early results.
The Joseph and Arlene Taub Foundation Award
When you give to BCRF, you're funding critical hours in the lab. More time for research means longer, healthier lives for the ones we love.