Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc

联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌

基本信息

批准号：
8299006
负责人：
Alan P. Fields
金额：
$ 32.77万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299006
关键词：
Accounting Aurothiomalate Back Biological Assay Biological Markers Blood Cancer Etiology Cancer Patient Cancer cell line Cells Cessation of life Clinical Clinical Research Clinical Trials Development Dose EGF gene Effectiveness Exhibits FDA approved Gene Amplification Genes Genetic Growth Growth Factor Histology In Vitro Isoenzymes Lung Lymphocyte Maintenance Maintenance Therapy Malignant neoplasm of lung Monitor Monoclonal Antibodies Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Outcome Patients Phase Primary Neoplasm Progression-Free Survivals Protein Kinase Rheumatoid Arthritis Safety Signal Transduction Sirolimus Squamous Cell Lung Carcinoma Staging Surrogate Markers Survival Rate Testing Therapeutic United States Vascular Endothelial Growth Factors antitumor agent arm base cancer cell chemotherapy effective therapy human FRAP1 protein improved in vivo inhibitor/antagonist mTOR Inhibitor mTOR inhibition novel novel strategies preclinical study protein protein interaction response small molecule therapeutic target treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): More than 200,000 new cases and 160,000 deaths occur from lung cancer annually in the US, most from non-small cell lung cancer (NSCLC). The dismal outlook for patients with advanced NSCLC has prompted a search for more effective treatment strategies. New approaches are targeted against growth factors (EGF, VEGF), gene translocations (EML4-ALK), and oncogenes (RAS), but are applicable most commonly only to non-squamous subtypes of NSCLC. The most promising targeted therapy for squamous histology has had recent significant setbacks when trials of the IGF monoclonal antibody figitumumab failed to improve outcomes compared to chemotherapy alone and was associated with excess toxic deaths in the treatment arm. Since SCC patients account for ~40% of all NSCLC patients, there is a pressing need for more effective treatments. We demonstrated that the atypical PKC isozyme, PKCi, is an oncogene in NSCLC. PKCi is over-expressed in NSCLC cell lines and primary tumors, and PKCi expression may predict poor survival in NSCLC patients. The PKCi gene PRKCI is amplified in ~70% of SCC and PRKCI amplification drives elevated PKCi expression in these tumors. Genetic disruption of PKCi signaling blocks transformed growth of SCC cells in vitro and in vivo. We recently identified a small molecule PKCi inhibitor, aurothiomalate (ATM), which exhibits potent anti-tumor activity in NSCLC cells, particularly SCC cells harboring elevated PKCi expression as a result of PRKCI amplification. ATM disrupts the protein-protein interaction between PKCi and Par6, thereby inhibiting oncogenic PKCi signaling. ATM is FDA-approved for rheumatoid arthritis making it an attractive candidate for clinical development as an anti-tumor agent. We have established a safe dose for ATM in a phase I dose escalation clinical trial in advanced NSCLC patients. In preclinical studies, ATM exhibits synergistic anti-tumor activity against NSCLC tumor growth when combined with the mTOR inhibitor rapamycin. Based on these results, we hypothesize that ATM will be a safe and effective treatment for advanced SCC expressing elevated PKCi when used in combination with the mTOR inhibitor RAD001. This hypothesis will be tested in two interrelated specific aims. In Aim 1 we will conduct a phase IB/II clinical trial to assess the safety and efficacy of combined therapy with ATM and RAD001 in the maintenance of advanced NSCLC patients. In Aim 2 we will assess tumor and circulating blood biomarkers of PKCi and mTOR signaling as predictors of response to combined ATM/mTOR therapy. Successful completion of these aims will provide proof of principle for use of combined PKCi and mTOR targeted therapy in lung cancer and characterize candidate biomarkers that may be useful in identifying patients most likely to respond to this therapy.

描述（由申请人提供）：美国每年有超过 200,000 例新发肺癌病例和 160,000 例死亡病例，其中大部分来自非小细胞肺癌 (NSCLC)。晚期非小细胞肺癌患者的悲观前景促使人们寻找更有效的治疗策略。新方法针对生长因子（EGF、VEGF）、基因易位（EML4-ALK）和癌基因（RAS），但最常仅适用于非鳞状非小细胞肺癌亚型。最有前途的鳞状组织学靶向治疗最近遭遇了重大挫折，因为与单独化疗相比，IGF 单克隆抗体 Figitumumab 的试验未能改善结果，并且与治疗组中过量的中毒性死亡有关。由于鳞状细胞癌患者约占所有非小细胞肺癌患者的 40%，因此迫切需要更有效的治疗方法。我们证明非典型 PKC 同工酶 PKCi 是 NSCLC 中的癌基因。 PKCi 在 NSCLC 细胞系和原发性肿瘤中过度表达，PKCi 表达可能预示 NSCLC 患者的生存率较差。 PKCi 基因 PRKCI 在约 70% 的 SCC 中扩增，PRKCI 扩增导致这些肿瘤中 PKCi 表达升高。 PKCi 信号传导的基因破坏可阻止 SCC 细胞在体外和体内的转化生长。我们最近发现了一种小分子 PKCi 抑制剂金硫苹果酸 (ATM)，它在 NSCLC 细胞中表现出有效的抗肿瘤活性，特别是由于 PRKCI 扩增而导致 PKCi 表达升高的 SCC 细胞。 ATM 破坏 PKCi 和 Par6 之间的蛋白质-蛋白质相互作用，从而抑制致癌 PKCi 信号传导。 ATM 已获得 FDA 批准用于治疗类风湿性关节炎，使其成为抗肿瘤药物临床开发的有吸引力的候选药物。我们在晚期 NSCLC 患者的 I 期剂量递增临床试验中确定了 ATM 的安全剂量。在临床前研究中，ATM 与 mTOR 抑制剂雷帕霉素联合使用时，对 NSCLC 肿瘤生长表现出协同抗肿瘤活性。基于这些结果，我们假设，当与 mTOR 抑制剂 RAD001 联合使用时，ATM 将成为表达升高 PKCi 的晚期 SCC 的安全有效的治疗方法。该假设将在两个相互关联的具体目标中得到检验。在目标1中，我们将进行一项IB/II期临床试验，以评估ATM和RAD001联合治疗在维持晚期NSCLC患者中的安全性和有效性。在目标 2 中，我们将评估 PKCi 和 mTOR 信号传导的肿瘤和循环血液生物标志物，作为 ATM/mTOR 联合治疗反应的预测因子。这些目标的成功完成将为肺癌联合 PKCi 和 mTOR 靶向治疗提供原理证明，并确定候选生物标志物的特征，这些生物标志物可能有助于识别最有可能对该治疗产生反应的患者。