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

• 批准号: 8110919
• 负责人: Alan P. Fields
• 金额: $ 34.2万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110919
• 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

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. PUBLIC HEALTH RELEVANCE: Lung cancer is the number one cause of cancer death in the United States with a five year survival rate of approximately 15%. Protein kinase C9 (PKC9) is an oncogene and therapeutic target in lung cancer and a novel small molecule PKC9 inhibitor aurothiomalate (ATM) exhibits potent anti-tumor activity against lung cancer, especially when combined with an mTOR inhibitor. This project will assess the safety and efficacy of combined inhibition of PKC9 with ATM and mTOR with RAD001 in the maintenance therapy of patients with advanced squamous cell carcinoma of the lung, and assess the ability of surrogate markers of PKC9 and mTOR signaling to predict response to therapy.

描述（由申请人提供）：在美国，每年有超过200，000例新发病例和160，000例死亡来自肺癌，其中大部分来自非小细胞肺癌（NSCLC）。晚期NSCLC患者的暗淡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（EML 4-ALK）和癌基因（RAS），但最常仅适用于NSCLC的非鳞状亚型。最有希望的鳞状组织学靶向治疗最近出现了重大挫折，IGF单克隆抗体figitumumab的试验与单独化疗相比未能改善结局，并且与治疗组中过量的毒性死亡相关。由于SCC患者占所有NSCLC患者的约40%，因此迫切需要更有效的治疗方法。我们证明了非典型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表达，并且PKCi表达可预测NSCLC患者的不良生存。PKCi基因PRKCI在约70%的SCC中扩增，并且PRKCI扩增驱动这些肿瘤中PKCi表达升高。PKCi信号传导的遗传破坏阻断了体外和体内SCC细胞的转化生长。我们最近鉴定了一种小分子PKCi抑制剂硫代苹果酸金酯（ATM），其在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Par 6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是FDA批准的类风湿性关节炎，使其成为一个有吸引力的候选人的临床开发作为一种抗肿瘤剂。我们已经在晚期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，当与mTOR抑制剂雷帕霉素组合时，ATM表现出针对NSCLC肿瘤生长的协同抗肿瘤活性。基于这些结果，我们假设当ATM与mTOR抑制剂RAD 001联合使用时，ATM将是表达升高的PKCi的晚期SCC的安全有效的治疗。这一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RAD 001联合治疗在晚期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对联合ATM/mTOR疗法的响应的预测因子。这些目标的成功完成将为在肺癌中使用PKCi和mTOR联合靶向治疗提供原则证据，并表征可能有助于识别最有可能对该治疗有反应的患者的候选生物标志物。 公共卫生相关性：肺癌是美国癌症死亡的头号原因，五年生存率约为15%。蛋白激酶C9（PKC 9）是肺癌的致癌基因和治疗靶点，新型小分子PKC 9抑制剂金硫苹果酸酯（ATM）对肺癌表现出有效的抗肿瘤活性，特别是当与mTOR抑制剂组合时。本项目将评估联合抑制PKC 9与ATM和mTOR与RAD 001在晚期肺鳞状细胞癌患者维持治疗中的安全性和有效性，并评估PKC 9和mTOR信号传导的替代标志物预测治疗反应的能力。