Memorial Sloan Kettering Cancer Center New York, New York
Director, Center for Mechanism-Based Therapy Enid A. Haupt Chair in Medical Oncology Member, Sloan Kettering Institute Molecular Pharmacology Program
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 and continue to spread. Understanding the drivers of metastasis and inhibiting those processes is essential to stopping metastatic spread. Dr. Rosen’s work is centered around finding new ways to more powerfully inhibit proteins that are necessary for the growth or spread of those tumors. He and his team are focused on two mechanisms that lead to metastasis: resistance to hormone therapies in estrogen receptor (ER)-positive breast cancers and endometrial cancers in which TORC1 kinase, a growth-promoting protein, is hyper-activated. Dr. Rosen aims to understand why resistance occurs after an initial response, called adaptive resistance, and to develop novel therapies for endometrial and breast cancers.
Dr. Rosen and his team found that hormone-dependent breast cancers are dependent on the eIF4A helicase, a regulator of gene expression, and that inhibiting elF4A reduces ER levels. Additionally, Dr. Rosen found that combining elF4A with a selective estrogen receptor degrader (SERD) drug has a synergistic effect reducing ER levels and suppressing tumor growth in breast cancer models. A phase 1 trial of this combination is in progress in patients with adaptive resistance to hormone therapy. In contrast, the majority of endometrial cancers have both PI3K mutations and PTEN loss, both of which are cancer-promoting, along with hyper-activated TORC1. No currently available TORC1 inhibitor has been successful in impeding the growth of endometrial cancers. Dr. Rosen and his team have developed a TORC1 selective inhibitor and found that it effectively inhibits tumor growth. A phase 1 trial of this drug is in progress. Thus far, the drug has been well-tolerated. Dr. Rosen and his team have begun to focus on understanding which patients are most likely to respond to TORCI-directed therapy and on developing combination therapies with enhanced anti-tumor activity that prevent drug resistance.
The antitumor activity observed in both phase 1 trials is promising. Dr. Rosen will now focus on identifying biomarkers that determine sensitivity or resistance to these agents, and from these data, development of new, more effective combination strategies that enhance toxicity to tumors. Targeting eIF4A helicase represents a novel, and difficult, strategy that prevents ER synthesis. Dr. Rosen anticipates the studies will be very informative about the effects of regulating ER expression and the effects of eIF4A regulation.
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.
2003
The Joseph and Arlene Taub Foundation Award
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