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Neal Rosen, MD, PhD
Director, Center for Mechanism-Based Cancer Therapies
Enid A. Haupt Chair in Medical Oncology
Member, Medicine & Molecular Pharmacology & Chemistry
Director, Center for Mechanism-Based Cancer Therapeutics
Memorial Sloan Kettering Cancer Center
New York, New York
- Seeking to improve response to targeted therapies.
- Laboratory studies are ongoing to test rational combination strategies to prevent resistance to targeted therapies.
- Targeted therapies are at the heart of precision medicine. These studies will lead to more effective combination approaches to improve patient response to these therapies.
Drug resistance is a persistent challenge in the management of breast cancer. The success of emerging targeted therapies that block specific proteins in tumor cells is hampered by the ability of the tumor cells to adapt and resist the killing effect of the drug. Dr. Rosen is conducting laboratory studies focused on developing rational combination approaches that not only target the cancer cell, but also prevent the development of drug resistance.
Full Research Summary
Cancer growth is fueled by mutated or defective proteins that regulate important cellular pathways. In a way, tumor cells become "addicted" to the growth-promoting benefits caused by the defects. For this reason, targeted therapies have been developed in hopes of preventing tumor growth by blocking the activity of the mutated protein in the pathway. This approach, however, has not resulted in substantial clinical benefit in clinical trials.
The focus of Dr. Rosen's BCRF research is to understand tumor response to targeted therapies and to develop combination treatments to improve response to these therapies. His current work focuses on a class of drugs that inhibit a protein called PI3K.
Research by Dr. Rosen and colleagues has shown that while inhibition of proteins in the PI3K signaling pathway and other oncogenic pathways with targeted drugs slows tumor growth, it also results in the activation of compensatory pathways, reducing the anti-tumor effect of the drug. His team pioneered the approach of inhibiting cancer targets while also blocking pathways of drug resistance.
They recently discovered two potent inhibitors of PI3K signaling pathway that target other proteins that work with PI3K to promote tumor growth.
This year, the team will apply this information to develop rational combination therapies for breast cancer. This multi-pronged approach represents a rational route to the development of more effective therapies.
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.