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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：
10432048
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/10432048
关键词：
1-Phosphatidylinositol 3-Kinase Address Antibodies Attenuated Back 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 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 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 Tumor-Derived anti-PD1 antibodies base biomarker signature candidate marker 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，中位5年生存率不到10%。这种疾病对化疗方法是顽固性的，最近批准的治疗方法只能存活率略有提高。KRAS是胰腺肿瘤中最常见的突变基因发病率超过90%。尽管进行了密集的努力，突变的KRAS(KRASmt)仍然无法下药，因此，作用于RAS信号级联上游和下游的激酶继续被利用用于开发新的药物以通过这种关键的癌基因来减弱信号。MTX-211是第一款一类双重和选择性的PI3K和EGFR激酶抑制剂，具有良好的药用前景和能力以防止ERK信号的重新激活，而不是目前批准的MEK抑制剂单一疗法。建议进行研究以优化我们的临床候选药物MTX-211的单剂活性(目标1)，其次是两种合理联合治疗策略的平行研究，以进一步建立在治疗的基础上甲氨喋呤-211的疗效。也就是说，有初步数据支持的实验原理支持进一步的研究加入MEK抑制剂(AIM 2)或免疫检查点的基于MTX-211的联合方案抑制物(目标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。建议的研究综合了分子成像的使用。记者和临床相关胰腺癌模型进行小鼠试验，将为未来提供信息以最有可能影响胰腺癌患者治疗的方式进行临床试验设计癌症。