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Evolving Role Of Vorinostat Combined With Radiation Therapy In The Treatment Of Brain Tumors, From The Lab To The Clinic, Y. R. Lawrence, P. Wachsberger, Y. Liu, B. Andersen, A. P. Dicker

Bodine Journal

Purpose/Objective(s): Radiation therapy (RT) is a critical element in the treatment of both brain metastases and glioblastoma (GBM). Temozolomide (TMZ) has an established role in the upfront treatment of GBM. Down-regulated mismatch repair (MMR) is a known mechanism of resistance to TMZ. Vorinostat (SAHA), an HDAC inhibitor, has successfully been combined with a number of cytotoxic agents, including ionizing radiation (IR). We performed a series of preclinical and clinical studies to examine the role of SAHA in the treatment of brain tumors.

American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, CA

Combination Of Vorinostat With Whole-Brain Radiotherapy In The Treatment Of Brain Metastases, Y. R. Lawrence, R. M. Pfeffer, M. Werner-Wasik, H. Choy, A. Dicker

Bodine Journal

Background: A third of patients with solid malignancies develop brain metastases. Expected overall survival is 4-7 months depending on age, performance status, and extracranial disease. Standard treatment is controversial; however, the majority of patients receive wholebrain radiation therapy at some point. Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved HDAC inhibitor, has been demonstrated to radiosensitize tumor cells in vitro, as assessed by both radiation-induced DNA damage and clonogenic cell survival (Munshi et al. Molecular Cancer Therapeutics 5, 1967-1974, 2006). We have shown that vorinostat downregulates key genes involved in double-strand DNA repair (Rad50, Rad51, XRCC2, XRCC3, XRCC6), as assessed by …

Functional Antagonism Between Vorinostat And Temozolomide When Combined With Ionizing Radiation (Ir) In Glioblastoma, Y. R. Lawrence, Y. Liu, B. Andersen, X. Xia, A. P. Dicker, P. Wachsberger

Bodine Journal

Background: Glioblastoma is the most common primary adult brain tumor. Surgery followed by radiation therapy in combination with temozolomide (Tmz) produces a median survival of 14.6 months. Tmz is a DNA akylating agent that leads to the mispairing of guanine residues with thymine. An intact mismatch-repair mechanism (MMR) converts the mispaired thymine into a lethal double-strand DNA break. Vorinostat (SAHA), an HDAC inhibitor, has been shown to act as a radiosensitizer, possibly through inhibition of DNA repair. SAHA has successfully been combined with a number of cytotoxic agents. We hypothesized that SAHA would further potentiate the radiosensitizing properties of Tmz …