Translational studies of Hsp90 inhibitors in NSCLC

Hsp90 抑制剂在 NSCLC 中的转化研究

• 批准号: 7450274
• 负责人: GEOFFREY I SHAPIRO
• 金额: $ 15.91万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-19 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450274
• 关键词: 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin; 70-kDa Ribosomal Protein S6 Kinases; Apoptosis; Apoptotic; Biopsy Specimen; CDK9 Protein Kinase; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Cessation of life; Client; Clinical; Clinical Trials; Complex; Conduct Clinical Trials; Data; Disruption; End Point; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evaluation; Exons; Experimental Neoplasms; Geldanamycin; Genetic Transcription; Growth; HDAC6 gene; In Vitro; Interleukin-3; Investigation; Lung Adenocarcinoma; Malignant neoplasm of lung; Maximum Tolerated Dose; Mediating; Modeling; Molecular; Molecular Chaperones; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phosphotransferases; Point Mutation; Pre-Clinical Model; Principal Investigator; Proteasome Inhibitor; Proteins; Receptor Inhibition; Receptor Signaling; Relative (related person); Resistance; Safety; Signal Transduction; Somatomedins; Stress; Subgroup; Variant; Water; Work; Xenograft procedure; base; cancer cell; cell transformation; cell type; cytotoxic; human FRAP1 protein; in vitro Model; in vivo; inhibitor/antagonist; interest; multicatalytic endopeptidase complex; mutant; novel; peripheral blood; programs; research study; response; synergism; translational study; tumor

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.

肺癌是美国和全世界癌症死亡的主要原因。Hsp 90分子伴侣是 对于驱动非小细胞肺癌细胞信号传导、增殖和存活的多种致癌激酶的稳定性是必需的。 细胞肺癌（NSCLC），包括突变型EGFR、Her 2、B-Raf、c-Met和cdk 4。的抑制剂 将研究HspQO，包括格尔德霉素如17-AAG、水溶性衍生物IPI-504和HspQO。 17-DMAG和STA-11-9090（一种新型非格尔德霉素），以比较它们的相对效力， 药效学终点，并在分子定义的患者亚组中进行临床试验。在 第一个具体目标是，将在EGFR突变NSCLC细胞中研究这些化合物，包括表达EGFR突变NSCLC细胞的那些细胞。 携带T790 M二级突变的突变型EGFR，其赋予埃罗替尼抗性。Hsp 90的能力 耗尽突变型EGFR并抑制PI 3 K-Akt-mTOR-p70 S6 K下游信号传导的抑制剂 路将进行评估。将17-DMAG和STA-11 - 9090的相对效力与17-DMAG和STA-11 - 9090的相对效力进行比较。 AAG在体外同基因细胞系模型中，以及在体内EGFR突变体/T790 M NCI-H1975异种移植物中。的 还将在突变EGFR驱动的肺腺癌模型中评价这些化合物的活性。 在第二个具体目的中，将在EGFR野生型细胞中评估Hsp 90抑制剂的活性，所述EGFR野生型细胞由以下驱动： HSP 90客户端此外，将在细胞中评价Hsp 90介导的IGF-1 R耗竭 表达EGFR：IGF-1 R异二聚体，以确定是否存在与厄洛替尼的细胞毒性协同作用。第三 具体目的是，17-AAG与其它破坏分子伴侣功能或Hsp 70诱导的试剂的协同作用将 包括HDAC 6、蛋白酶体或细胞周期蛋白依赖性激酶9的抑制剂。第四 为了达到特定目的，将进行IPI-504的I/II期试验;在建立最大耐受剂量后， 剂量（MTD），将在携带EGFR突变体或EGFR突变体的NSCLC患者中定义初步抗肿瘤活性 或野生型肿瘤。还将进行STA-11-9090的I期试验，以确定MTD和安全性 在肿瘤活检标本和外周血中评估Hsp 90客户端耗竭 非增殖细胞。 总之，晚期NSCLC的生存率仍然很低。许多蛋白质驱动肺癌生长 它们的稳定性和功能依赖于一种叫做HSP 90的分子伴侣。这项工作将探索化合物， 在临床前模型和临床试验中抑制Hsp 90作为肺癌的潜在治疗。