Brain metastases-Drug (w/ WBRT) prolongs survival

Fallleaves

Patients who received valproic acid in addition to radiotherapy survived for 11 months, compared to 5 months for those who just got radiotherapy.

http://www.ncbi.nlm.nih.gov/pubmed/26482599

JohnSmith

Yes, the Anti-epileptic drug Valproic Acid is a powerful HDAC inhibitor (HDACi). In general, HDACi's are emerging as promising anticancer drugs. They interfere with HDAC activity and regulate biological events, such as cell cycle arrest, differentiation, modulation of immune response, angiogenesis and apoptosis in cancer cells. The exact mechanisms of how they work against cancer is unclear, which makes it challenging when developing drugs as well as designing the best clinical trials to test them.
As of March 2015, the FDA has approved three HDAC inhibitors for T-cell Lymphoma and more are in different stages of clinical development. They have shown promising activity in reversing therapy resistance in other tumor types. For example, UCSF researchers discovered one of the mechanisms for Tamoxifen resistance and how an HDACi could reverse that resistance mechanism, as described in this article.

A couple breast cancer clinical trials have been launched to explore this resistance issue.

1. "Phase II Trial of SAHA & Tamoxifen for Patients With Breast Cancer".
That trial ended a few years ago and resulted in this report: "A phase II study of the histone deacetylase inhibitor Vorinostat combined with Tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer".
It concluded that "the combination of Vorinostat and Tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance".

2. "Reversing Hormone Therapy Resistance With Epigenetic-Immune Modification"
Estimated Enrollment: 58
Study Start Date: March 2015
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Beyond the resistance issue, a New Zealand based researcher focused on gastric cancer (HDGC) believes HDACi's might be a potential therapy (based on cell line observations) against Lobular. HDGC and Lobular are similar since they often share CDH1 gene mutations. The CDH1 gene, which encodes the cell adhesion protein E-cadherin (Ecad), is frequently mutated. The lack of Ecad is the hallmark of Lobular.

Anyway, there's a number of HDACi including:
Entinostat (Other names: SNDX-275, MS 27-275, MS-275, SNDX-275)
Vorinostat (Brand name: Zolinza)

2014 research by the University of Pittsburgh generated an Abstract "HDAC7 is a putative therapeutic target in ILC".
2007 research by Sloan-Kettering generated this Abstract "HDACi selectively suppress expression of HDAC7" and found that Vorinostat selectively down-regulates HDAC7.
* Perhaps Vorinostat would be useful for ILC patients? This needs to be explored.

There's a flurry of HDACi Abstracts being presented next month at the 2015 SABCS.
Here's some that are specifically focused on Entinostat:

P2-04-02
Immunomodulatory effects of Entinostat on PD-L1 and MHC class I and II in different subtypes of breast cancer
Chumsri S, Necela B, Ordentlich P, Advani P, Moreno-Aspitia A, McLaughlin S, Geiger X, McDonough M, Vallow L, Perez E, Thompson E.
Mayo Clinic, Jacksonville, FL; Syndax Pharmaceuticals, Inc., Waltham, MA.

P2-11-10
Epigenetic immune modulation by Entinostat in breast cancer: Correlative analysis of ENCORE 301 trial
Chumsri S, Lee M-J, Tomita Y, Lee S, Tomita S, Cruickshank S, Ordentlich P, Trepel J.
Mayo Clinic, Jacksonville, FL; National Cancer Institute, Bethesda, MD; Syndax Pharmaceuticals, Inc., Waltham, MA.

P4-14-22
A single-center, open-label phase 1b study of Entinostat, and lapatinib alone, and in combination with and trastuzumab in patients with HER2+ metastatic breast cancer after progression on trastuzumab
Lim B, Jackson S, Alvarez R, Ibrahim N, Willey J, Murthy R, Booser D, Giordano S, Barcenas C, Brewster A, Walters R, Brown P, Tripathy D, Valero V, Ueno N.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX.

P5-03-05
Genomic analysis and efficacy of Entinostat in basal-like and HER2-overexpressing models
Tanioka M, Usary J, Darr D, Harrell C, Perou C.
University of North Carolina at Chapel Hill, Chapel Hill, NC.

P5-04-02
The histone deacetylase inhibitor Entinostat enhances the efficacy of the MEK inhibitor pimasertib against aggressive types of breast cancer through Noxa-mediated myeloid cell leukemia 1 degradation
Torres-Adorno A, Lee J, Kogawa T, Bartholomeusz C, Pitner MK, Ordentlich P, Lim B, Tripathy D, Ueno N. University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX;
Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Syndax Pharmaceuticals, Inc., Waltham, MA.

OT2-01-04
E2112: Randomized phase III trial of endocrine therapy plus Entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group
Connolly R, Zhao F, Miller K, Tevaarwerk A, Wagner L, Lee M, Murray J, Gray R, Piekarz R, Zujewski JA, Sparano J. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD;
Dana-Farber Cancer Institute, Boston, MA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; University of Wisconsin Carbone Cancer Center, Madison, WI; Wake Forest University Health Services, Winston-Salem, NC; National Cancer Institute, Bethesda, MD; Cancer Therapy Evaluation Program (CTEP) National Cancer Institute, Bethesda, MD; Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY.

Fallleaves

Wow, I had no idea there was so much going on with HDAC inhibitors! Thanks for sharing all the information.