BIOLOGIC EFFECTS OF 17AA GELDANAMYCIN

拟议的研究解决了前列腺癌进展审查小组确定的两个高度优先领域：针对新靶点的新型治疗药物的作用和使用相关生物标志物监测临床反应。 这些研究将在17-N-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）的I期临床试验中进行，17-AAG是第一个进入临床试验的安莎霉素抗生素。 安莎霉素抗生素是一类新的化合物，其诱导与Hsp 90分子伴侣家族结合的蛋白质的选择性降解。 热休克蛋白90是必需的蛋白质重折叠后的压力，并为构象成熟的核类固醇受体，某些蛋白激酶和其他调节细胞周期的控制。 我们和其他人的临床前工作表明，表达雄激素受体（AR）、雌激素受体（ER）、HER 2和过表达细胞周期蛋白D1的恶性细胞对这些药物敏感，使前列腺癌、乳腺癌和结肠癌具有特别的治疗意义。 已获得使用加速滴定设计进行17-AAG I期临床试验的批准（LOI-98-355，批准日期：1999年4月15日），并获得MSKCC机构审查委员会的批准（方案编号：99-37，批准日期：1999年5月25日）。 除了作为I期研究常规部分的安全性评估和药代动力学研究外，我们还建议进行临床和实验室研究，以了解哪些肿瘤可能最敏感，以及哪些靶蛋白在体内受到影响。 我们将重点关注AR（前列腺），ER（乳腺），HER 2和细胞周期蛋白D1在治疗前和治疗后获得的肿瘤活检组织中的表达，我们已经证明这些蛋白质在体外对化合物的敏感性降低。 将在从外周血分离的循环肿瘤细胞中评价这些相同的蛋白质。 为了评估反应，我们将使用正电子发射断层扫描探索FDG摄取的一系列变化。 还将对已建立的细胞系进行体外研究，以探索对特定蛋白质的作用时间以及药物作用的其他标志物。 初步数据表明，脂滴（前列腺癌）或脂肪（乳腺癌）的积累可能标志着药物的分化效应。

The proposed research addresses two high priority areas identified by the Prostate Cancer Progress Review Group: the role of novel therapeutic agents directed at new targets and the use of relevant biomarkers to monitor clinical response. The studies proposed will be performed in the context of phase I a clinical trial of 17-N-allylamino-17-demethoxy geldanamycin (17-AAG), the first ansamycin antibiotic to enter clinical testing. Ansamycin antibiotics are a new class of compounds that induce the selective degradation of proteins which bind to the Hsp 90 family of chaperones. Hsp90 is required for protein refolding after stress, and for the conformational maturation of nuclear steroid receptors, certain protein kinases and other regulators of cell cycle control. Preclinical work by us and others has shown that malignant cells that express the androgen receptor (AR), the estrogen receptor (ER), HER2 and which overexpress cyclin D1 are sensitive to these agents, making prostate, breast and colon cancers of particular therapeutic interest. Approval to conduct a phase I clinical trial using of 17-AAG using an accelerated titration design has been obtained (LOI-98-355, Approval Date 4/15/99) and approved by the MSKCC Institutional Review Board (Protocol No. 99-37, Approved 5/25/99). In addition to the safety assessments and pharmacokinetic studies that are a routine part of the phase I study, we propose to conduct clinical and laboratory investigations to understand which tumors may be most sensitive, and which target proteins are affected in vivo. We will focus on the expression of the AR (prostate), ER (breast), HER2 and cyclin D1 in tumor biopsies obtained prior to and following treatment, proteins we have shown to be decreased by and which mark for sensitivity to the compound in vitro. These same proteins will be evaluated in circulating tumor cells isolated from the peripheral blood. To assess response, we will explore serial changes in FDG uptake using positron emission tomography. In vitro studies of established cell lines will also be conducted to explore the timing of the effects on specific proteins, and for other markers of drug effect. Preliminary data suggest that the accumulation of lipid droplets (prostate cancers) or fat (breast cancer) may mark for a differentiation effect of the drug.