Neal Rosen, MD, PhD
Director, Center for Mechanism-Based Cancer Therapies
Head, Development Therapeutics
Memorial Sloan-Kettering Cancer Center
New York, New York
2013-2014 BCRF Project(s):
(The Joseph and Arlene Taub Foundation Award)
The abnormal growth of many breast cancers is dependent on activation by mutation of a key pathway in the cell, the PI3K signaling pathway. Drugs that inhibit specific components of this pathway have been developed, but they have limited efficacy in patients. Dr. Rosen’s group has determined that inhibition of the PI3K pathway by these drugs reactivates other pathways that rescue the tumor. Combined therapy with inhibitors of the reactivated pathways causes profound death of the tumor cells. In particular, inhibitors PI3Kalpha, a commonly mutated protein in breast cancer, have significant therapeutic activity in breast cancer, but these effects in patients are incomplete and temporary. Over the last year, Dr. Rosen has shown that tumors treated with this drug compensate by activating HER kinase receptors and an enzyme related to the target, PI3Kbeta. This work has led to the preclinical and clinical development of these combinations, which he believes will provide significantly enhanced therapeutic benefit.
The new paradigm for the development of rational combination therapy consists of inhibiting the mutated signaling pathway in the tumor cell, determining how the tumor compensates for this inhibition by reactivating specific pathways that allow it to survive, and the developing treatments that combine inhibition of the mutant oncoprotein and the compensatory pathways. In this funding period Dr. Rosen’s team has concentrated on defining the PI3K signaling and feedback networks in PI3K mutant, HER2, and triple negative breast cancer. They have made three discoveries of potential translational significance. First, inhibition of PI3K inhibits AKT and mTor but also transiently inhibits RAS/ERK signaling. Both are required for induction of tumor cell death. Second, only transient inhibition of signaling is required, and pulsatile intermittent inhibition of PI3K maximizes antitumor activity and will likely reduce toxicity in patients. Third, in triple negative breast cancers in which the function of the PTEN gene is defective, PI3K beta is the dominant driver of the pathway. However, the antitumor effects of PI3K beta inhibition are reduced by feedback reactivation of PI3K alpha. Combined inhibition of both enzymes has profound antitumor activity and is predicted to have acceptable toxicity because of the selectivity of these agents. Dr. Rosen’s current goal is the accelerated preclinical development of these ideas so they can be rapidly translated to clinic.
Dr. Rosen is a Member in the Department of Medicine and in the Molecular Pharmacology and Chemistry Program at Memorial Sloan-Kettering Cancer Center, where he serves as Head of Developmental Therapeutics. He is also a Professor of Pharmacology, Cell Biology and Medicine at Cornell University Medical School.
His major interests are the identification and study of key molecular events and growth signaling pathways responsible for the development of human cancer and the use of this information for developing mechanism-based therapeutic strategies. He has played an important role in the development of tyrosine kinase-mediated signaling inhibitors and has pioneered the concept that cancer cells are dependent on cellular machinery for protein folding.
In the course of this work his laboratory has developed inhibitors of the Hsp90 protein chaperone and validated their anticancer activity in animal models and clinical trials. These inhibitors have now shown significant activity in patients with breast cancer, myelogenous leukemia and multiple myeloma. Currently his laboratory work focuses on using pharmacologic and genetic approaches to develop a detailed understanding of feedback and cross-talk among oncogene-activated pathways in order to develop rational combination therapy for refractory breast and lung cancer, melanoma and other tumors. Multiple novel clinical trials based on the work of the Rosen laboratory are being tested at Memorial Sloan-Kettering and other cancer centers in the United States and internationally.
Dr. Rosen received his undergraduate degree in Chemistry from Columbia College and an MD, PhD in Molecular Biology from the Albert Einstein College of Medicine. He completed a residency in Internal Medicine at the Brigham and Women's Hospital and post-doctoral training and a fellowship in Medical Oncology at the National Cancer Institute. He was on the senior staff of the Medicine Branch at the NCI prior to joining the faculty of Memorial Sloan-Kettering Cancer Center.