Novel Targeted Therapies for Inflammatory Breast Cancer
Abstract
Overarching Challenge: This proposal will address two main challenges: (1) Revolutionize treatments regimens with safer and more efficient options. (2) Eliminate the mortality associated with metastatic cancers. Background: Inflammatory breast cancer (IBC, ~5% of all breast cancers) is the most lethal form of breast cancer, presenting a 5-year survival rate that is less than half of the non-IBC patients and a mortality rate that has continued to increase during the last 20 years. Despite these facts, IBC remains poorly understood, and systemic disease management relies exclusively on chemotherapy. Remarkably, we have found that survival of IBC cells depends on histone deacetylase 6 (HDAC6) function while this is mainly dispensable in non-IBCs. Importantly, we have demonstrated that the leading HDAC6 inhibitor (Rocilinostat/ACY1215, Acetylon, Inc.), which is being tested in clinical trials for other tumor types, inhibits the growth of IBC cells in vitro and in vivo. Our findings represent an exciting opportunity to develop novel targeted therapies for IBC patients. Hypothesis and Objectives: We hypothesize that key biological processes regulated by HDAC6 are essential to maintain the homeostasis of IBC cells. Our goals are to characterize the mechanisms involved in the dependency of IBC cells on HDAC6 function and to develop targeted therapy regimens based on HDAC6 inhibition for IBC patients. Specific Aim 1: Uncover the molecular mechanisms by which HDAC6 regulate the homeostasis of IBC cells. Specific Aim 2: Design and evaluation of combination therapy with HDAC6 inhibition for IBC treatment. Clinical Impact: Current treatments for IBC patients mainly rely on their response to chemotherapy. We have discovered that IBC cells are sensitive to inhibition of HDAC6 function. Importantly, small molecule inhibitors in advanced clinical trials (Phase II) already exist. This proposal represents the preclinical work necessary to translate our findings into targeted therapy for IBC patients. If successful, our findings could lead to a decrease in mortality from the most lethal type of breast cancers. Importantly, in our proposal we will study the molecular determinants that define the therapeutic response to HDAC6 inhibition. This may allow us to rationally apply targeted HDAC6 therapy not only to IBCs but also to other cancer subtypes. Importantly, our partnership with Acetylon will greatly facilitate the transition of our research to the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610461
Entities
People
- Jose Silva
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army