BIOLOGIC EFFECTS OF 17AA GELDANAMYCIN

拟议的研究涉及前列腺癌进展审查小组确定的两个高度优先的领域：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来监测临床反应。拟议的研究将在17- n -烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG）的I期临床试验背景下进行，17-AAG是第一种进入临床试验的安纳霉素抗生素。安霉素类抗生素是一类新的化合物，可诱导结合热休克蛋白90家族伴侣蛋白的选择性降解。应激后的蛋白质重折叠、核类固醇受体、某些蛋白激酶和其他细胞周期调控因子的构象成熟都需要Hsp90。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）、HER2和过度表达周期蛋白D1的恶性细胞对这些药物敏感，这使得前列腺癌、乳腺癌和结肠癌具有特殊的治疗意义。已获得使用加速滴定设计的17-AAG进行I期临床试验的批准（LOI-98-355，批准日期为1999年4月15日），并由MSKCC机构审查委员会批准（方案编号99-37，批准日期为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，我们建议进行临床和实验室调查，以了解哪些肿瘤可能最敏感，哪些靶蛋白在体内受到影响。我们将重点关注治疗前后肿瘤活检中AR（前列腺）、ER（乳腺）、HER2和cyclin D1的表达，我们已经证明，这些蛋白被体外化合物降低，并标志着对该化合物的敏感性。这些相同的蛋白质将在从外周血中分离出来的循环肿瘤细胞中进行评估。为了评估反应，我们将使用正电子发射断层扫描研究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记。初步数据表明，脂滴（前列腺癌）或脂肪（乳腺癌）的积聚可能标志着该药物的分化作用。

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.