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Full Project 2

完整项目2

基本信息

批准号：
10762291
负责人：
Maurizio Pellecchia
金额：
$ 22.43万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
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 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762291
关键词：
African American population Animal Model Apoptosis Attention Award Basic Science Biotechnology California Cancer Etiology Cell Line Cell model Cells Cessation of life Chemoresistance Cities City of Hope Comprehensive Cancer Center Clinic Clinical Trials Collaborations Comprehensive Cancer Center Core Facility County Cytotoxic Chemotherapy Data Development Doctor of Philosophy Drug Kinetics Economic Development Ethnic Origin Event Fibroblasts Genetic Goals 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 Oncology 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 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 X-Ray Crystallography biophysical techniques cancer cell chemotherapy clinical translation design drug development drug discovery efficacy study first-in-human gemcitabine inhibitor innovation lead optimization neoplastic cell novel overexpression pancreatic cancer cells pancreatic cancer model pancreatic cancer patients 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.

PIN 1是一种顺-反脯氨酰异构酶，控制脯氨酸介导的磷酸化信号传导事件，在胰腺癌细胞和癌症相关的成纤维细胞中过表达。PIN 1过表达是一个主要的促进肿瘤发生，激活几种癌蛋白，包括KRAS途径中的蛋白，同时使几种肿瘤抑制剂失活最近的研究使用遗传和药理学 PIN 1抑制剂显示PIN 1调节关键的致癌途径。重要的是，PIN 1促进了免疫抑制/治疗抵抗性TME，通过上调PD-L1（程序性细胞死亡受体-1）化疗药物吉西他滨经常用于胰腺癌的一线治疗。PIN 1还驱动通过降解吉西他滨摄取转运蛋白ENT 1（等研磨性核转运蛋白）转运蛋白-1）。因此，PIN 1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（加州滨江; UCR）已经开发了初始的PIN 1抑制剂，药代动力学特性为此，Pellecchia博士使用了一种基于组合的药物发现策略。生物物理学方法，包括1）药物化学2）NMR光谱学，3）X射线晶体学（博士。 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创新的共价PIN 1靶向剂，导致胰腺细胞系中PIN 1的降解。指导根据我们的资源和初步数据，我们建议UCR和CoH进行合作，以1）优化和2）开发一种有效的和选择性的PIN 1抑制剂用于治疗胰腺癌。目标1将设计，合成，并迭代优化新型药物样PIN 1靶向剂。目标2将研究作用机制，在胰腺癌的细胞和动物模型中最有前途的药物的功效。我们将评估药物动力学特性（Dr. Horne和CoHCCC共享资源），并测试其胰腺癌动物模型（Dr. Horne、Dr. Raoof、CoH）中的疗效，包括原位、患者来源异种移植物和胰腺癌的转基因小鼠模型。