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）：每年在美国肺癌发生了200,000多例新病例和160,000例死亡，其中大多数来自非小细胞肺癌（NSCLC）。患有晚期NSCLC患者的惨淡前景促使人们寻求更有效的治疗策略。新方法是针对生长因子（EGF，VEGF），基因易位（EML4-ALK）和ONCEGONES（RAS）的针对性，但最常用于NSCLC的非Quamous子类型。当IGF单克隆抗体figitumumab的试验与单独的化学疗法相比，最有前途的针对性治疗对鳞状组织学的靶向疗法最近发生了重大挫折，并且与单独的化学疗法相比未能改善结局，并且与治疗组中的毒性死亡过多有关。由于SCC患者占所有NSCLC患者的约40％，因此需要更有效的治疗。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，PKCI表达可能预测NSCLC患者的存活率不佳。 pKCI基因PRKCI在〜70％的SCC和PRKCI扩增中得到扩增，这些肿瘤中的PKCI表达升高。 PKCI信号传导的遗传破坏阻滞了体外和体内SCC细胞的生长。我们最近确定了一个小分子PKCI抑制剂Aurothiomalate（ATM），该抑制剂在NSCLC细胞中表现出有效的抗肿瘤活性，尤其是由于PRKCI扩增而产生的PKCI表达升高的SCC细胞。 ATM会破坏PKCI和PAR6之间的蛋白质 - 蛋白质相互作用，从而抑制致癌性PKCI信号。 ATM已被FDA批准用于类风湿关节炎，使其成为抗肿瘤剂的临床发育的有吸引力的候选者。我们已经在晚期NSCLC患者的I期剂量升级临床试验中为ATM建立了安全剂量。在临床前研究中，当与MTOR抑制剂雷帕霉素结合使用时，ATM对NSCLC肿瘤的生长表现出协同抗肿瘤活性。基于这些结果，我们假设ATM将是与MTOR抑制剂RAD001结合使用时，对高级SCC的安全有效治疗，表达PKCI升高。该假设将以两个相互关联的特定目的进行检验。在AIM 1中，我们将进行IB/II期临床试验，以评估与ATM和RAD001合并治疗在维持晚期NSCLC患者中的安全性和功效。在AIM 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，以预测对ATM/MTOR疗法组合的反应。这些目标的成功完成将提供原则证明，用于使用PKCI和MTOR靶向治疗中的肺癌中的靶向疗法，并表征候选生物标志物，这些候选生物标志物可能有助于确定最有可能对此疗法反应的患者。 公共卫生相关性：肺癌是美国癌症死亡的第一大原因，五年生存率约为15％。蛋白激酶C9（PKC9）是肺癌中的癌基因和治疗靶标，而新型的小型小分子PKC9抑制剂极光（ATM）表现出对肺癌的有效抗肿瘤活性，尤其是当与MTOR抑制剂结合时。该项目将评估PKC9与ATM和MTOR与RAD001联合抑制的安全性和有效性，用于在肺的晚期鳞状细胞癌的维持治疗中，并评估PKC9和MTOR信号的替代标记以预测治疗反应的能力。