Project 2

项目2

基本信息

批准号：
10762161
负责人：
Maurizio Pellecchia
金额：
$ 14.61万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762161
关键词：
African American African American population Animal Model Apoptosis Attention Award Basic Science Biotechnology California Cancer Etiology Cell Line Cell model Cells Cessation of life Chemoresistance City of Hope Comprehensive Cancer Center Clinic Collaborations Comprehensive Cancer Center Core Facility County Cytotoxic Chemotherapy Data Development Doctor of Philosophy Drug Kinetics Economic Development Ethnic Origin Event Fibroblasts Genetic Immunotherapy In Vitro Incidence Incubators Individual Infrastructure Institution KRAS2 gene Laboratories Link Malignant Neoplasms Malignant neoplasm of pancreas Measurement Mediating Medicine Mus NMR Spectroscopy Nuclear Oncogenic Oncoproteins Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Penetration Peptidylprolyl Isomerase Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phosphorylation Proline Property Proteins Resistance Resource Sharing Resources Signal Transduction Small Business Innovation Research Grant Structure Survival Rate Synthesis Chemistry Testing Tissues Transgenic Mice Translating Translations Tumor Suppressor Proteins United States United States Food and Drug Administration United States National Institutes of Health Universities Up-Regulation Woman X-Ray Crystallography biophysical techniques cancer cell chemotherapy clinical translation design drug development drug discovery efficacy study first-in-human gemcitabine improved inhibitor innovation lead optimization malignant breast neoplasm neoplastic cell novel overexpression pancreatic cancer cells pancreatic cancer model pancreatic cell line patient derived xenograft model pharmacologic phase 1 testing programmed cell death protein 1 racial population receptor rural counties small molecule targeted agent targeted treatment therapeutic development therapy resistant tumor heterogeneity tumor microenvironment tumor-immune system interactions tumorigenesis uptake

项目摘要

PIN1 is a cis-trans prolyl isomerase that controls proline-mediated phosphorylation signaling events that is overexpressed both in pancreatic cancer cells and cancer-associated fibroblasts. PIN1 overexpression is a major contributor to tumorigenesis, activating several oncoproteins, including proteins in the KRAS pathway, and simultaneously inactivating several tumor suppressors. Recent studies using genetic and pharmacological inhibitors show that PIN1 regulates key oncogenic pathways. Importantly, PIN1 promotes an immunosuppressive/treatment-resistant TME, by up-regulating PD-L1 (programmed cell-death receptor-1) The chemotherapy drug, gemcitabine, is frequently used in front-line treatment of pancreatic cancer. PIN1 also drives chemotherapy-resistance by degrading the gemcitabine uptake-transporter, ENT1 (equillabrative nuclear transporter-1) both in tumor cells and cancer-associated fibroblasts. Hence, the development of PIN1 inhibitors could increase sensitivity of pancreatic cancer to both chemotherapy and immunotherapy. The laboratory of Dr. Pellecchia (University of California Riverside; UCR) has developed initial PIN1 inhibitors that have promising pharmacokinetic properties. To do this, Dr. Pellecchia used a drug discovery strategy based on a combination of biophysical methods including 1) medicinal chemistry 2) NMR spectroscopy, 3) X-ray crystallography (Dr. Blaha, UCR) and 4) denaturation thermal shift measurements. This structure-based design approach used to derive innovative covalent PIN1 targeting agents that cause degradation of PIN1 in pancreatic cell lines. Guided by our resources and preliminary data, we propose a collaboration between UCR and CoH to 1) optimize and 2) develop a potent and selective PIN1 inhibitor for treatment of pancreatic cancer. Aim 1 will design, synthetize, and iteratively optimize novel, drug-like PIN1 targeting agents. Aim 2 will study the mechanism of action and efficacy of most promising agents in cellular and animal models of pancreatic cancer. We will assess the pharmacokinetics properties (Dr. Horne and CoHCCC shared resources) of refined agents in mice and test their efficacy in animal models of pancreatic cancer (Dr. Horne, Dr. Raoof, CoH) including orthotopic, patient derived xenografts, and transgenic mouse models of pancreatic cancer.

PIN1 是一种顺反脯氨酰异构酶，控制脯氨酸介导的磷酸化信号事件，即在胰腺癌细胞和癌症相关成纤维细胞中过度表达。 PIN1 过度表达是一个主要的促进肿瘤发生，激活多种癌蛋白，包括 KRAS 通路中的蛋白，以及同时灭活多种肿瘤抑制因子。最近的研究利用遗传和药理学抑制剂表明 PIN1 调节关键的致癌途径。重要的是，PIN1 促进了通过上调 PD-L1（程序性细胞死亡受体-1）来治疗免疫抑制/耐药性 TME 化疗药物吉西他滨经常用于胰腺癌的一线治疗。 PIN1 也驱动通过降解吉西他滨摄取转运蛋白 ENT1（平衡核转运蛋白-1) 均存在于肿瘤细胞和癌症相关成纤维细胞中。因此，PIN1抑制剂的开发可以增加胰腺癌对化疗和免疫治疗的敏感性。博士的实验室 Pellecchia（加州大学河滨分校；UCR）开发了初步的 PIN1 抑制剂，具有良好的前景药代动力学特性。为此，Pellecchia 博士使用了基于组合的药物发现策略生物物理方法，包括 1) 药物化学 2) NMR 光谱学，3) X 射线晶体学（Dr. Blaha，UCR）和 4）变性热位移测量。这种基于结构的设计方法用于衍生出创新的共价 PIN1 靶向剂，可导致胰腺细胞系中 PIN1 降解。引导根据我们的资源和初步数据，我们建议 UCR 和 CoH 之间进行合作，以 1) 优化和 2) 开发一种有效的、选择性的 PIN1 抑制剂来治疗胰腺癌。目标 1 将设计、综合、并迭代优化新型药物样 PIN1 靶向药物。目标2将研究作用机制和最有前途的药物在胰腺癌细胞和动物模型中的功效。我们将评估精制药物在小鼠体内的药代动力学特性（Dr. Horne 和 CoHCCC 共享资源）并测试其效果在胰腺癌动物模型（Dr. Horne、Dr. Raoof、CoH）中的疗效，包括原位、患者来源异种移植和胰腺癌转基因小鼠模型。