# Investigating the molecular mechanism that mediates the addiction of inflammatory breast cancer cells to HDAC6 function

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $383,386

## Abstract

SUMMARY
 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 the half of the non-IBC patients. Furthermore, its mortality
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 depend on histone deacetylase 6 (HDAC6) function while non-IBC cells are mainly independent.
Importantly, we have demonstrated that the leading HDAC6 inhibitor (Rocilinostat/ACY1215, Acetylon Inc),
which is currently being tested in clinical trials for other tumors presents anticancer activity in IBC cells in
preclinical models. Our findings represent an opportunity to develop novel targeted therapies for IBC patients.
Hypothesis and Objective: We hypothesize that key biological processes regulated by HDAC6 are essential to
maintain the homeostasis of IBC cells. In this proposal our goal is to characterize the mechanisms involved in the
addiction of IBC cells to HDAC6 function in order to be able to transition our finding to the clinic.
Specific Aim1. Uncover the molecular mechanisms by which HDAC6 regulate the homeostasis of IBC cells.
HDAC6 is a class-IIB histone deacetylase with a critical function on the cell's response to accumulation of
misfolded proteins and damaged mitochondria due to its role in formation of aggresome, mito-aggresome and
autophagy. We will study if the lethality seen in IBC cells is due to loss of canonical functions or a different one.
-Aim 1.a) Evaluate the function of HDAC6 in the metabolism of toxic bioproducts.
-Aim 1.b) Evaluate the function of HDAC6 in basal autophagy.
-Aim 1.b) Investigate novel putative HDAC6 substrates.
Specific Aim2. Design and evaluation of combination therapy with HDAC6 inhibition for IBC treatment.
Systemic therapy combining different anticancer agents is generally needed in epithelial cancer to achieve
maximum therapeutic benefit. Here, we hypothesize that combinatorial therapy will circumvent resistance to
monotherapy based on HDAC6 inhibition. We will perform both candidate based and unbiased studies to
optimize the anticancer activity of regimens containing HDAC6 inhibitors.
-Aim 2.a) Candidate based therapy using chemotherapy plus HDAC6 inhibition.
-Aim 2.b) Unbiased system biology studies for the identification of Master Regulators (MR) associated with the
 response to HDAC6 inhibition.
Significance. This proposal represents the preclinical studies necessary to translate our findings into targeted
therapy for IBC patients. The importance of our proposal is that it could lead to a decrease in mortality from the
most lethal and one the less characterized group of breast cancers.

## Key facts

- **NIH application ID:** 9952342
- **Project number:** 5R01CA201162-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jose M Silva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,386
- **Award type:** 5
- **Project period:** 2016-07-29 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952342

## Citation

> US National Institutes of Health, RePORTER application 9952342, Investigating the molecular mechanism that mediates the addiction of inflammatory breast cancer cells to HDAC6 function (5R01CA201162-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9952342. Licensed CC0.

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