CLINICAL TRIAL: PK AND BIOL STUDY OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) IN P

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 目的： 初级 - 通过客观缓解率和进展率确定SAHA在既往免疫治疗和/或生物治疗失败达2线的晚期肾细胞癌（RCC）患者中或在既往未经治疗但不适合接受IL-2治疗的患者中的抗肿瘤活性。 二次 - 根据NCI/CTC v3.0标准，通过毒性特征、发生率和评级，进一步评价SAHA 300 mg每日两次每周连续3天给药在该患者人群中的安全性和耐受性 - 通过无进展生存期、治疗开始后12个月的生存率和总生存期，进一步评价SAHA的生物活性。 - 表征SAHA血浆稳态浓度与药物对外周血单核细胞（PBMC）和肿瘤组织（肿瘤可进行活检）中乙酰化组蛋白表达的影响之间的药效学关系。 - 分析SAHA对细胞凋亡、血管生成及下游靶点和基因转录的生物学效应。 - 将这些生物学测量结果的变化与患者结局指标相关联。 研究报告： 预计患有晚期肾细胞癌（转移性或不可手术）的成年男性和女性患者将参加本研究。 方法： 符合VA/GCRC治疗条件的潜在患者将接受SAHA治疗。 位于南德克萨斯退伍军人医疗保健系统Audie Murphy分部的GCRC预计将招募约5名患者。 临床相关性： SAHA是HDAC活性的有效抑制剂，并直接结合HDAC酶的催化口袋。 SAHA导致G1或G2期细胞周期停滞，细胞凋亡，或在培养的转化细胞分化。 腹腔内给予SAHA可显著抑制小鼠人前列腺癌异种移植物的肿瘤生长;在SAHA剂量（50 mg/kg/天）下观察到肿瘤消退，未产生毒副作用。 在急性早幼粒细胞白血病（APL）的治疗抗性转基因小鼠模型中，SAHA与维甲酸联合腹腔给药可诱导白血病缓解并延长生存期。 腹膜内施用SAHA在小鼠中的人乳腺癌和人结肠癌癌症异种移植物中引起显著的肿瘤生长抑制。 在不产生毒副作用的SAHA剂量（100 mg/kg/天）下观察到肿瘤生长抑制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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 RELEVANCE: 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.