Breast Cancer, Estrogen, and HDAC inhibitors

The FDA recently designated Syndax Pharmaceutical’s lead product, entinostat, as a Breakthrough Therapy for advanced estrogen receptor (ER)-positive breast cancer (Schull).  Entinostat is considered a class I histone deacetylase inhibitor (Syndax). 

As an overview, chromatin is formed by winding double-stranded DNA around proteins called histones, which regulate transcription by providing access to certain genes.  Histones can be modified in several ways, one of which is the addition of acetyl groups, called acetylation (Horobin).  Histone acetylation induces conformational changes that increase the access of transcription factors to DNA, which allows DNA to be transcribed for protein production.  Histone deacetylases (HDACs) are enzymes that remove acetyl groups from the histones and thus prevent availability of the transcription factors (Camolotto). There are five classes of HDACs (Horobin), and alterations in these enzymes have been identified in malignant cells (Secrist).

ER+ breast cancer is a type of breast cancer that has cells sensitive to the female hormone estrogen, meaning that the growth of these malignant cells is dependent on the binding of the estrogen to their receptors (Mayo). Approximately 80% of all breast cancers are considered ER+ (Breastcancer.org).  Treatment of ER+ breast cancers often involves blocking the estrogen receptors with drugs such as tamoxifen, or utilizing aromatase inhibitors, such as exemestane, which block the enzyme aromatase from synthesizing estrogen in the ovaries (American).  Both treatments reduce the estrogen fuel source to the cancer cells, thus preventing further growth.  Unfortunately, the cells can undergo modifications, such as the histone modifications previously mentioned, and become less dependent on estrogen (Horobin).  As a result these cancer cells become resistant to the endocrine therapies like tamoxifen and exemestane.

Drugs, such as entinostat, have shown potential in reversing this resistance, by targeting HDACs, and restoring the cancer cells’ sensitivity to estrogen (Horobin).  In a recent, Phase II study, entinostat in combination with exemestane was shown to improve both progression free survival and overall survival.  The combination treatment was also well tolerated with fatigue, nausea, and neutropenia as the most frequent adverse events (Yardley).  As cancers continue to evolve, these combination therapies show promise in not only treating resistant cancers, but eliminating some of the high grade side-effects seen with chemotherapy and radiation.

REFERENCES:

American Cancer Society [2013 Jul 7]. Aromatase inhibitors: What are aromatase inhibitors? [Internet]. ACS website. [cited 2013 Nov 29]. Available from: http://www.cancer.org/cancer/breastcancer/moreinformation/medicinestoreducebreastcancer/medicines-to-reduce-breast-cancer-risk-aromatase-inhibitors.

Breastcancer.org [2013 Nov 13]. How to read hormone receptor test results [Internet]. Breastcancer.org Symptoms & Diagnosis website. [cited 2013 Nov 29]. Available from: http://www.breastcancer.org/symptoms/diagnosis/hormone_status/read_results.

Camolotto SA, Racca AC, Ridano ME, Genti-Raimondi S, Panzetta-Dutari GM. 2013 Feb. PSG gene expression is up-regulated by lysine acetylation involving histone and nonhistone proteins. PLOS ONE. 8(2):1-12.

Horobin J. 2011. The case for epigenetic oncology therapy. Vital Signs. 4:18-19.

Mayo Clinic. [2013 Jul 13]. Breast cancer types: What your type means [Internet]. Mayo Clinic Diseases and Conditions website. [cited 2013 Nov 29]. Available from: http://www.mayoclinic.com/health/breast-cancer/HQ00348/NSECTIONGROUP=2.

Secrist JP, Zhou X, Richon VM. 2003 Dec. HDAC inhibitors for the treatment of cancer. Curr Opin Investig Drugs. 4(12):1422-1427.

Schull D, Middleman M. 2013 Sep 11. Syndax’s entinostat receives breakthrough therapy designation from FDA for treatment of advanced breast cancer. Syndax Pharmaceuticals [Internet]. [cited 2013 Nov 29]. Available from: http://www.syndax.com/news.aspx. Syndax Pharmaceuticals. 2013. Entinostat [Internet]. [cited 2013 Nov 29]. Available from: http://www.syndax.com/dev-entinostat.aspx.

Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, Cruickshank S, Miller KD, Lee MJ, Trepel JB. 2013 Jun. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J CLIN ONCOL. 31(17): 2128-2135.