This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.OBJECTIVES:Primary - To determine the antitumor activity of SAHA in patients with advanced renal cell carcinoma (RCC) who have failed up to 2 lines of prior immunotherapy and/or bilogical therapy or in previously untreated patients who are not appropriate candidates to receive IL-2 based treatment, as determined by objective response and progression rates.Secondary - To further evaluate the safety and tolerability of SAHA given at a dose of 300mg twice daily for 3 consecutive days every week in this patient population as determined by toxicity profile, incidence and rating according to NCI/CTC v3.0 criteria- To further evaluate the biologic activity of SAHA as determined by progression free survival, survival rate at 12 months after initiation of treatment and overall survival.- To characterize the pharmacodynamic relationships between the plasma steady state concentration of SAHA and the drug effect on expression of acetylated histones in peripheral blood mononuclear cells (PBMC) and tumor tissue where the tumor is accessible for biopsy.- To analyze the biologic effects of SAHA on apoptosis, angiogenesis and downstream targets and gene transcription.- To correlate changes in these biological measurements with indices of patient outcome.RESEARCH PLAN:Adult male and female patients with advanced renal cell carcinoma, metastatic or inoperable, are expected to participate in the study.METHODS:Potential patients eligible for care at the VA/GCRC will be treated with SAHA.Enrollment of about 5 patients is anticipated at the GCRC, located at the South Texas Veterans Health Care System, Audie Murphy Division.CLINICAL
SAHA is a potent inhibitor of HDAC activity and binds directly to the catalytic pocket of HDAC enzymes. SAHA causes G1 or G2 phase cell-cycle arrest, apoptosis, or differentiation in cultured transformed cells. Intraperitoneal administration of SAHA causes significant tumor growth inhibition in human prostate cancer xenografts in mice; tumor regressions were observed at SAHA doses (50 mg/kg/day) that did not produce toxic side effects. Intraperitoneal administration of SAHA in combination with retinoic acid induced leukemic remission and prolonged survival in a therapy-resistant transgenic mouse model of acute promyelocytic leukemia (APL). Intraperitoneal administration of SAHA causes significant tumor growth inhibition in both human breast carcinoma and human colon carcinoma cancer xenografts in mice. Tumor growth inhibition was observed at SAHA doses (100 mg/kg/day) that do not produce toxic side effects.
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