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: hormone-dependent breast cancers that have become resistant to the drugs that inhibit estrogen receptors (ER) 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’s work on both treatment strategies now involves the identification of biomarkers that determine sensitivity and mechanisms of adaptive resistance.
Dr. Rosen has now begun to focus on understanding the exact way to use these drugs in individual tumors that have different genetic characteristics and on developing combination therapies with enhanced anti-tumor activity that can overcome drug resistance. He and his team are continuing to determine the effects of inhibiting both eIF4A and TORC1 and will continue their preclinical and clinical studies. In the next year, Dr. Rosen will focus on understanding the mechanisms of anti-tumor activity of their drugs and adaptive resistance with the goal of developing drug combinations that enhance tumor cytotoxicity. The team will test whether the combination of an eIF4A inhibitor plus fulvestrant is effective in tumors that are resistant to CDK4 inhibitors, which are used to treat advanced hormone receptor-positive breast cancer.
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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