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

描述（由申请人提供）：在美国，每年有超过20万例肺癌新病例和16万例肺癌死亡，其中大多数来自非小细胞肺癌（NSCLC）。晚期非小细胞肺癌患者的惨淡前景促使人们寻求更有效的治疗策略。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），但通常只适用于非鳞状亚型的NSCLC。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毒性死亡相关，这是最有希望的鳞状组织学靶向治疗最近遭遇重大挫折。由于SCC患者约占所有NSCLC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的致癌基因。PKCi在非小细胞肺癌细胞系和原发肿瘤中过表达，PKCi的表达可能预示着非小细胞肺癌患者的低生存率。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信号的遗传破坏阻断了体外和体内SCC细胞的生长。我们最近发现了一种小分子PKCi抑制剂，金硫硫酸盐（ATM），它在非小细胞肺癌细胞中表现出强大的抗肿瘤活性，特别是由于PRKCI扩增导致PKCi表达升高的SCC细胞。ATM破坏PKCi和Par6之间的蛋白相互作用，从而抑制致癌PKCi信号传导。ATM已获fda批准用于类风湿性关节炎，这使其成为抗肿瘤药物临床开发的一个有吸引力的候选药物。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抑制剂雷帕霉素联合使用时，ATM显示出协同抗NSCLC肿瘤生长的抗肿瘤活性。基于这些结果，我们假设当与mTOR抑制剂RAD001联合使用时，ATM将是一种安全有效的治疗表达PKCi升高的晚期SCC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Aim 1中，我们将进行一项IB/II期临床试验，以评估ATM和RAD001联合治疗维持晚期NSCLC患者的安全性和有效性。在Aim 2中，我们将评估PKCi和mTOR信号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在肺癌中使用PKCi和mTOR联合靶向治疗提供原理证明，并表征候选生物标志物，这些生物标志物可能有助于识别最有可能对这种治疗有反应的患者。

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.