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

描述(申请人提供)：在美国，每年有超过200,000个新的肺癌病例和160,000个死亡病例，大多数是非小细胞肺癌(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。新的治疗方法针对生长因子(EGF、VEGF)、基因易位(EML4-ALK)和癌基因(RAS)，但最常见的仅适用于非鳞状细胞肺癌亚型。最有希望的鳞状组织学靶向治疗最近遇到了重大挫折，因为与单独化疗相比，IGF单抗的试验未能改善结果，并与治疗臂中过多的毒性死亡有关。由于鳞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。我们证实了非典型PKC同工酶PKCi是非小细胞肺癌的癌基因。PKCi在NSCLC细胞系和原发肿瘤中高表达，PKCi表达可能预示NSCLC患者预后不良。PKCi基因PRKCI在70%的鳞癌组织中扩增，PRKCI基因的扩增导致PKCi在这些肿瘤中的表达增加。在体内外，PKCi信号通路的基因中断阻断了SCC细胞的转化生长。我们最近发现了一种小分子PKCI抑制剂，金硫马酸(ATM)，它在NSCLC细胞中表现出强大的抗肿瘤活性，特别是由于PRKCI扩增而导致PKCi表达升高的SCC细胞。ATM干扰PKCi和Par6之间的蛋白质-蛋白质相互作用，从而抑制致癌的PKCi信号转导。ATM是FDA批准用于类风湿性关节炎的药物，使其成为作为抗肿瘤药物进行临床开发的有吸引力的候选药物。在晚期NSCLC患者的I期剂量递增临床试验中，我们已经确定了ATM的安全剂量。在临床前研究中，当ATM与mTOR抑制剂雷帕霉素联合使用时，显示出协同抗肿瘤活性。基于这些结果，我们推测，ATM与mTOR抑制剂RAD001联合使用将是一种安全有效的治疗晚期SCC表达升高的PKCi的方法。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IB/II期临床试验，以评估ATM和RAD001联合治疗晚期NSCLC患者的安全性和有效性。在目标2中，我们将评估肿瘤和循环血液中PKCi和mTOR信号的生物标记物作为ATM/mTOR联合治疗反应的预测因子。这些目标的成功完成将为在肺癌中使用PKCi和mTOR联合靶向治疗提供原则证据，并确定可能有助于识别最有可能对这种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，五年存活率约为15%。蛋白激酶C9(PKC9)是肺癌的癌基因和治疗靶点，一种新的小分子PKC9抑制剂金硫马酸(ATM)具有很强的抗肺癌活性，特别是与mTOR抑制剂联合使用时。本项目将评估联合抑制PKC9和ATM以及mTOR和RAD001在晚期肺鳞癌患者维持治疗中的安全性和有效性，并评估PKC9和mTOR信号转导的替代标记物预测治疗反应的能力。

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.