Combating Resistance of Pancreatic Cancer with a First-in-Class Dual Targeted PI3K/EGFR Inhibitor

胰腺癌是最致命的癌症之一，5年生存率中位数低于10%。 这种疾病对化疗方法是不利的，最近批准的治疗方法只能提供 生存率略有提高。KRAS是胰腺肿瘤中最常见的突变基因， 发病率超过90%。尽管进行了大量的努力，突变型KRAS（KRASmt）仍然是不可治疗的， 因此，RAS信号级联的上游和下游都起作用的激酶继续被利用， 用于开发新的药剂以减弱通过该关键致癌基因的信号传导。MTX-211是一种 类PI 3 K和EGFR激酶的双重和选择性抑制剂，具有有前途的药物特性和能力 与目前批准的MEK抑制剂单一疗法相比， 提出研究以优化MTX-211（我们的临床候选药物（目的1））的单药活性，然后 平行研究两种合理的联合治疗策略，以进一步建立在治疗 MTX-211的功效也就是说，初步数据支持的实验原理支持进一步的研究 基于MTX-211的联合方案，包括MEK抑制剂（Aim 2）或免疫检查点 抑制剂（目的3）。我们的总体目标是提供证据支持MTX-211的临床开发， KRASmt胰腺癌的治疗拟议的研究整合了分子成像的使用 报告员和临床相关的胰腺癌模型进行小鼠试验，将告知未来 临床试验设计的方式，这是最有可能影响胰腺癌患者的管理 癌

Pancreatic cancer is one of the deadliest forms of cancer, with median 5-year survival rates less than 10%. This disease is recalcitrant to chemotherapeutic approaches and recently approved therapies afford only modest improvements in survival. KRAS is the most commonly mutated gene in pancreatic tumors with an incidence rate exceeding 90%. Despite intensive efforts, mutant KRAS (KRASmt) has remained undruggable, hence kinases acting both upstream and downstream of the RAS signaling cascade continue to be exploited for the development of novel agents to attenuate signaling through this critical oncogene. MTX-211 is a first-in- class dual and selective inhibitor of PI3K and EGFR kinase with a promising pharmaceutical profile and ability to prevent reactivation of ERK signaling than ensues from currently approved MEK inhibitor monotherapies. Studies are proposed to optimize single agent activity of MTX-211, our clinical candidate (Aim 1), followed by parallel investigation of two rational combination treatment strategies to further build upon the therapeutic efficacy of MTX-211. Namely, experimental rationale backed by preliminary data support further investigation of MTX-211-based combination regimens that incorporate a MEK inhibitor (Aim 2) or an immune checkpoint inhibitor (Aim 3). Our overall objective is to provide evidence to support clinical development of MTX-211 for the treatment of KRASmt pancreatic cancer. The proposed studies integrate the use of molecular imaging reporters and clinically relevant models of pancreatic cancer to conduct mouse trials that will inform future clinical trial design in a manner which is most likely to impact the management of patients with pancreatic cancer.