Targeting Histone Acetyltransferase in Triple Negative BC

Institution: Torrey Pines Institute for Molecular Studies
Investigator(s): Ruth Gjerset, Ph.D. -
Award Cycle: 2011 (Cycle 17) Grant #: 17IB-0023 Award: $272,995
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2011)

Triple negative breast cancer (TNBC) is very aggressive and poses a challenge for treatment. Because it lacks expression of the estrogen, progesterone, and Her-2 receptors, TNBC is not a candidate for targeted anti-estrogen, aromatase inhibitor, or anti-HER-2 therapy. An important unmet challenge in breast cancer research is to identify a therapeutic target for TNBC. We believe histone acetyltransferase (HAT) would represent such a therapeutic target for TNBC, because it plays a central role in DNA metabolism and DNA repair functions that are critical for TNBC cell survival. Histone acetyltransferases (HAT) are enzymes that acetylate conserved lysine amino acids on histone (chromosomal DNA-associated) proteins to regulate DNA activity. Our specific approach will employ a class of cancer-specific polyamine-CoA-based inhibitors of HAT that suppress multiple mechanisms of DNA repair, thereby exploiting the unique susceptibility of TNBC.

For our studies, we will use cultured breast cancer cells derived from TNBC and other types of breast cancer as well as mouse models for human breast cancer to evaluate the mechanism by which our polyamine-CoA-based inhibitors suppress TBNC cell growth and to evaluate their anti-tumor efficacy. We will use cell-based methodologies to determine the effects of our inhibitors on the growth and viability of TNBC and other breast cancer cell types in cell culture. We will use biochemical methodologies to evaluate the uptake and stability of our inhibitors in breast cancer cells, and to measure their effects on HAT, DNA synthesis and DNA repair. We will use mouse models for localized and metastatic human breast cancer to determine the anti-tumor effects of our inhibitors, and to evaluate any potential toxicity.

TNBC affects some 170,000 women worldwide each year, and constitutes a disproportionate percentage of breast cancer deaths. There is a critical need to identify new therapeutic targets for TNBC and to use them to develop targeted, more effective and less toxic therapies as alternatives when conventional chemotherapy fails. The histone acetyltransferase-targeted compounds investigated here could offer a targeted, non-toxic alternative to chemotherapy, and provide long term control or cures for TNBC while preserving quality of life.

Final Report (2014)

Overview of topic: This project focused on a novel therapeutic target for triple negative (TNBC) and advanced breast cancers, namely histone acetyltransferase (HAT), an enzyme central to biological regulation. Inhibition of this enzyme with a novel class of small molecules inhibitors based on a polyamine-CoA structure was found to be highly suppressive of breast cancer cell growth in cell culture and tumor growth in a mouse model for TNBC. The inhibitors were well-tolerated in mice and therefore hold promise as the starting point for a novel, less toxic approach to TNBC. The study addressed the unmet need for improved therapies for these aggressive forms of breast cancer, which are not treatable with currently available targeted breast cancer therapeutics.

Degree to which stated Aims have been completed. The goals of Aim I were accomplished through cell based assays that characterized the mechanism of action of the HAT inhibitors and identified the most promising inhibitor for further study. The goals of Aim II were accomplished by validating the anti-tumor properties of this inhibitor in a mouse model for triple negative breast cancer.

Barriers that were overcome. One of the inhibitors we had originally studied displayed poor cellular uptake. We therefore focused on a second inhibitor, with a shortened chemical structure, that was efficiently internalized into breast cancer cells.

Major accomplishments. (a) We established histone acetyltransferase (HAT) as a target for drug discovery in breast cancer, and we identified a potential lead compound for further optimization; (b) We established an underlying molecular mechanism to understand the anti-tumor effects of the lead compound, namely, suppression of DNA metabolism; We provided evidence that HAT inhibition suppressed breast cancer cell viability in culture and tumor growth in a mouse model for TNBC; (d) We provided evidence that the combined effects of HAT inhibition and irinotecan provided greater suppression of breast cancer cell growth than did either treatment individually.

Plans for continuation. Future studies will focus on the design additional polyamine-CoA-based compounds with greater in vivo stability, and on testing combination therapeutic approaches that incorporate HAT inhibition.