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

使用一流的双靶向 PI3K/EGFR 抑制剂对抗胰腺癌耐药性

基本信息

批准号：
10652462
负责人：
Judith S Leopold
金额：
$ 47.47万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652462
关键词：
Address Antibodies Attenuated Caspase Cells Clinical Trials Clinical Trials Design Colorectal Cancer Combined Modality Therapy Data Development Diagnosis Disease Disease Outcome Dose Effectiveness Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evaluation FRAP1 gene Future Gene Expression Profiling Genes Genomics Goals Human Immune Immune checkpoint inhibitor Immune system Immunotherapy Impairment Implant In Vitro Incidence Individual Investigation KRAS2 gene Lead Lipids MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of pancreas Microsatellite Instability Microsatellite Repeats Mismatch Repair Modeling Molecular Profiling Mus Mutate Mutation Oncogenes Organoids PIK3CG gene Pancreas Pathway interactions Patients Pharmacodynamics Pharmacologic Substance Phosphotransferases Public Health Regimen Reporter Reporting Resistance Schedule Signal Transduction Signaling Molecule Survival Rate Therapeutic Transgenic Organisms Treatment Efficacy Tumor Subtype anti-PD1 antibodies biomarker signature candidate identification checkpoint inhibition chemotherapy clinical candidate clinical development clinical translation clinically relevant comparative design disease prognosis effective therapy efficacy study exome sequencing genomic signature humanized mouse improved improved outcome in vivo inhibitor knock-down molecular imaging monocyte mouse model mutant neoplastic cell novel pancreatic PDX models pancreatic cancer model pancreatic cancer patients pancreatic neoplasm patient derived xenograft model patient population patient stratification patient subsets pembrolizumab peripheral blood phosphoproteomics pre-clinical prevent programmed cell death protein 1 resistance mechanism response small hairpin RNA synergism targeted treatment therapy outcome treatment strategy tumor

项目摘要

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.

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