Titles and Affiliations
Director, Center for Mechanism-Based Therapy
Enid A. Haupt Chair in Medical Oncology
Member, Sloan Kettering Institute Molecular Pharmacology Program
Research area
Developing novel therapeutic combinations to inhibit tumor growth and treat advanced breast and endometrial cancers.
Impact
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.
Progress Thus Far
Over the past year, Dr. Rosen and his team have made progress in understanding how to target estrogen receptor ER-positive breast cancers by focusing on a protein called eIF4A, which helps cells make proteins needed for growth. They discovered that production of the ER protein itself depends on eIF4A, and blocking eIF4A slows cancer cell growth. Building on this, they combined an eIF4A inhibitor called zotatifin with fulvestrant, an ER degrader drug, in a phase 1clinical trial for patients whose cancers had become resistant to multiple treatments. This combination produced strong and long-lasting responses in several patients, and tumor samples confirmed a large reduction in ER protein levels. Adding a third drug, a CDK4/6 inhibitor that blocks cancer cell division, further improved results. In parallel, the team studied endometrial cancers and found that tumors with both PI3K mutations and loss of a related gene called PTEN did not respond to current drugs. To overcome this, they developed a new compound that specifically targets TORC1, which is activated by PI3K, successfully blocking tumor growth.
What’s next
In the upcoming year, Dr. Rosen will continue the translational work on both projects. The team will further improve the combination therapy for the treatment of refractory breast cancer and extend the clinical studies to determine whether an ER antagonist synergizes with the TORC1 inhibitor. In addition, the team will continue clinical studies of their regiment for endometrial cancers as well as employ this regimen for breast cancers with acquired resistance to ER/PI3K-targeted combinations.
Biography
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.
