Translational studies of Hsp90 inhibitors in NSCLC

肺癌是美国和世界范围内癌症死亡的主要原因。Hsp90的监护人是 多个致癌激酶的稳定性所必需的，这些激酶驱动信号、增殖和非小细胞肺癌的生存 细胞肺癌(NSCLC)，包括突变的EGFR、Her2、B-Raf、c-Met和CDK4。抗肿瘤药物 将研究HspQO，包括格尔达那霉素，如17-AAG，水溶性衍生物IPI-504和 17-DMAG和STA-11-9090，比较它们的相对效价，确定 药效学终点，并在分子定义的患者亚组中进行临床试验。在 首先，这些化合物将在EGFR突变的NSCLC细胞中进行研究，包括那些表达 突变的EGFR含有T790M继发突变，导致厄洛替尼耐药。热休克蛋白90的能力 耗尽突变的EGFR并抑制PI3K-Akt-mTOR-p70S6K下游信号转导的抑制剂 将对路径进行评估。17-DMAG和STA-11-9090的相对效力将与17-DMAG和STA-11-9090进行比较。 AAG在体外等基因细胞系模型和体内EGFR突变体/T790M NCI-H1975异种移植瘤中的表达。这个 这些化合物的活性也将在突变的EGFR驱动的肺腺癌模型中进行评估。 在第二个特定目标中，hsp90抑制剂的活性将在由 其他Hsp90客户端。此外，Hsp90抑制剂介导的IGF-1R的耗竭将在细胞中进行评估 表达EGFR：IGF-1R异源二聚体以确定与厄洛替尼是否有细胞毒协同作用。在第三节 17-AAG与其他破坏伴侣功能或Hsp70诱导的药物的特定靶点、协同作用将 被探索，包括HDAC6、蛋白酶体或细胞周期蛋白依赖性激酶9的抑制剂。 具体地说，将进行IPI-504IPI-504的L/11期试验；在确定最大耐受量后 剂量(MTD)，初步的抗肿瘤活性将被定义在携带EGFR突变的非小细胞肺癌患者中 或者是野生型肿瘤。还将进行STA-11-9090的第一阶段试验，以确定MTD和安全性 将在肿瘤活检样本和外周血中评估Hsp90客户耗尽情况 非核细胞。 总而言之，晚期非小细胞肺癌的存活率仍然很低。许多推动肺癌生长的蛋白质 依赖于一种名为Hsp90的伴侣来获得它们的稳定性和功能。这项工作将探索化合物 在临床前模型和临床试验中抑制Hsp90作为肺癌的潜在治疗方法。

Lung cancer Is the leading cause of cancer death in the U.S. and worldwide. The Hsp90 chaperone is required for the stability of multiple oncogenic kinases that drive signaling, proliferation and survival of nonsmall cell lung cancers (NSCLCs), including mutant EGFR, Her2, B-Raf, c-Met and cdk4. Inhibitors of HspQO will be studied including geldanamcyins such as 17-AAG, the water-soluble derivatives IPI-504 and 17-DMAG, and STA-11-9090, a novel non-geldanamycin, to compare their relative potencies, to define pharmacodynamic endpoints and to conduct clinical trials in molecularly defined patient subgroups. In the first specific aim, these compounds will be studied in EGFR mutant NSCLC cells, including those expressing mutant EGFR harboring the T790M secondary mutation conferring erlotinib resistance. The ability of Hsp90 inhibitors to deplete mutant EGFR and to suppress downstream signaling of the PI3K-Akt-mTOR-p70S6K pathway will be assessed. The relative potencies of 17-DMAG and STA-11 -9090 will be compared to 17- AAG in isogenic cell line models in vitro, and in EGFR mutant/T790M NCI-H1975 xenografts in vivo. The activity of these compounds will also be evaluated in mutant EGFR-driven models of lung adenocarcinoma. In the second specific aim, the activity of Hsp90 inhibitors will be assessed in EGFR wild-type cells driven by other Hsp90 clients. Additionally, Hsp90 inhibitor-mediated depletion of IGF-1R will be evaluated in cells expressing EGFR: IGF-1R heterodimers to determine if there is cytotoxic synergy with erlotinib. In the third specific aim, synerglsm of 17-AAG with other agents that disrupt chaperone function or Hsp70 induction will be explored, including inhibitors of HDAC6, the proteasome or cyclin-dependent kinase 9. In the fourth specific aim, a Phase l/ll Trial of IPI-504 will be conducted; after establishment of the maximum tolerated dose (MTD), preliminary antitumor activity will be defined in NSCLC patients harboring either EGFR mutant or wild-type tumors. A Phase I trial of STA-11-9090 will also be performed to establish the MTD .and safety profile, Hsp90 client depletion will be evaluated in tumor biopsy specimens and peripheral blood nononuclear cells. In summary, survival for advanced NSCLC remains poor. Many proteins that drive lung cancer growth depend on a chaperone called Hsp90 for their stability and function. This work will explore compounds that inhibit Hsp90 in preclinical models and clinical trials as potential treatments for lung cancer.