Defining the roles of PPARgamma and TGFbeta in regulating NECTIN4 and resistance to NECTIN4-targeting therapies

定义 PPARgamma 和 TGFbeta 在调节 NECTIN4 和 NECTIN4 靶向治疗耐药性中的作用

基本信息

批准号：
10507722
负责人：
Jonathan Chou
金额：
$ 26.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10507722
关键词：
Agonist Antibody-drug conjugates Area Award Binding Binding Sites Biological Biological Assay Biopsy Specimen Cancer Biology Cancer Center Cancer Model Career Choice Cell Line Cell surface Cells Cessation of life Chemicals Clinic Clinical Data Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collection Complement Data Diet Diet Modification Down-Regulation Drug Combinations Drug resistance Educational workshop Effectiveness Experimental Models FDA approved Fatty Acids Foundations Funding Genitourinary system Genomic approach Genomics Goals High Fat Diet Immunohistochemistry In Vitro Knock-out Laboratories Lead Luciferases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mediating Mediator of activation protein Medicine Membrane Proteins Mentors Mentorship Methods Microtubules National Comprehensive Cancer Network PPAR gamma PPARG gene Pathway interactions Patient Selection Patients Pharmaceutical Preparations Pharmacology Pre-Clinical Model Radiation Oncology Recording of previous events Regulatory Pathway Research Research Personnel Resistance Resources Role Sampling Signal Transduction Small Interfering RNA Structure Surface T cell therapy Technology Testing Therapeutic Therapeutic Uses Thiazolidinediones Training Transforming Growth Factor beta Transitional Cell Carcinoma Translational Research Urothelium Work antagonist bladder transitional cell carcinoma cancer cell cancer drug resistance checkpoint therapy chemotherapy chimeric antigen receptor chimeric antigen receptor T cells chromatin immunoprecipitation clinically relevant experience hands on research improved in vivo instructor knock-down malignant breast neoplasm minority patient mouse model next generation sequencing novel drug combination overexpression patient derived xenograft model professor promoter resistance mechanism response rosiglitazone skills targeted treatment therapeutic target transcription factor transcriptome transcriptomics translational cancer research tumor tumor metabolism

项目摘要

PROJECT SUMMARY The goal of this K08 application is to provide Dr. Jonathan Chou, an Instructor of Medicine at UCSF, with the skills he will need to become an independently-funded laboratory investigator. Dr. Chou proposes to elucidate the regulatory mechanisms of NECTIN4, the target of a newly approved antibody-drug conjugate (ADC) in metastatic urothelial cancer called enfortumab vedotin (EV) and identify mechanisms of resistance using PDX and metastatic biopsy samples. The proposal builds on Dr. Chou’s recent work, which showed that NECTIN4 expression is enriched in luminal subtypes of bladder cancer, and that increasing and decreasing NECTIN4 can enhance EV sensitivity or lead to resistance, respectively. Dr. Chou hypothesizes that the transcription factor PPARG, which regulates luminal bladder cancer cell identity and integrates fatty acid signaling, is a direct regulator of NECTIN4 and that transiently augmenting NECTIN4 expression in urothelial cancer cells will enhance the efficacy of NECTIN4-targeting therapies. In Aims 1 and 2, Dr. Chou will elucidate the mechanism underlying this regulatory pathway and determine whether sensitivity to NECTIN4-targeted therapies can be enhanced by directly modulating the PPARg pathway using pharmacologic approaches, biological modifiers and dietary alterations. In Aim 3, Dr. Chou will determine whether loss of PPARg or alternatively, activation of the EMT-associated TGFb pathway downregulates NECTIN4, thus leading to resistance. He will leverage EV- resistant cell lines that he has generated, patient-derived xenograft (PDX) models (established from minority patients treated at UCSF), as well as metastatic biopsy samples from UCSF patients treated on EV, to accomplish this Aim. Dr. Chou’s training and research plan includes a combination of structured coursework and workshops, one-on-one tutorials, and hands-on research experience that will all take place at UCSF, a world- renowned NCCN Cancer Center with a history of excellence in basic and translational cancer research. Dr. Chou’s training plan will complement his existing expertise to build a strong foundation in the following areas: 1) bladder cancer biology; 2) preclinical modeling of ADCs and adoptive T cell therapies; 3) cancer metabolism and drug resistance; and 4) genomics and next-generation sequencing methods and analysis. The project will be conducted under the mentorship of Dr. Felix Feng, Professor of Radiation Oncology and Associate Director for Translational Sciences, and co-mentored by Dr. Alan Ashworth, Professor of Medicine and President of the UCSF Cancer Center. He has assembled a distinguished advisory panel with complementary expertise to guide his research and career path. At the completion of this award, Dr. Chou will have the relevant didactic and research experience to become a leader in bladder cancer models, therapeutic targeting strategies and genomic approaches to investigate drug resistance, including to ADCs. If successful, this project will also provide a translational opportunity from the laboratory to the clinic, to utilize dietary modifications and thiazolidinedione drug combinations to augment responses and potentially reverse resistance to NECTIN4-targeting therapies.

项目概要此 K08 应用程序的目标是为 UCSF 医学讲师 Jonathan Chou 博士提供周博士建议阐明他成为一名独立资助的实验室研究员所需的技能。 NECTIN4 的调节机制，NECTIN4 是新批准的抗体药物偶联物 (ADC) 的靶标称为 enfortumab vedotin (EV) 的转移性尿路上皮癌，并使用 PDX 确定耐药机制该提案以 Chou 博士最近的工作为基础，该工作表明 NECTIN4。 NECTIN4 的表达在膀胱癌的管腔亚型中丰富，增加和减少 NECTIN4 可以周博士领导者认为转录因子分别增强EV敏感性或导致耐药性。 PPARG 调节管腔膀胱癌细胞身份并整合脂肪酸信号传导，是一种直接的 NECTIN4 的调节因子，并且短暂增加尿路上皮癌细胞中的 NECTIN4 表达将增强 NECTIN4 靶向治疗的疗效在目标 1 和 2 中，Chou 博士将阐明其机制。揭示这一调控途径的基础，并确定是否可以改变对 NECTIN4 靶向疗法的敏感性通过使用药理学方法、生物修饰剂和直接调节 PPARg 途径来增强在目标 3 中，Chou 博士将确定 PPARg 是否丢失或激活。 EMT 相关的 TGFb 通路下调 NECTIN4，从而导致耐药性。他生成的耐药细胞系、患者来源的异种移植（PDX）模型（由少数人建立）在 UCSF 接受治疗的患者），以及接受 EV 治疗的 UCSF 患者的转移性活检样本，以实现这一目标周博士的培训和研究计划包括结构化课程和研讨会、一对一教程和实践研究经验都将在加州大学旧金山分校（UCSF）举行，这是一个世界性的著名的 NCCN 癌症中心，在基础和转化癌症研究方面拥有卓越的历史。周的培训计划将补充他现有的专业知识，在以下领域打下坚实的基础：1) 膀胱癌生物学；2) ADC 和过继性 T 细胞疗法的临床前建模；3) 癌症代谢和耐药性；4）基因组学和下一代测序方法和分析。在放射肿瘤学教授兼副主任 Felix Feng 博士的指导下进行转化科学，由医学教授兼主席 Alan Ashworth 博士共同指导他组建了一个具有互补专业知识的杰出顾问小组来提供指导。完成该奖项后，周博士将获得相关的教学和职业道路。成为膀胱癌模型、治疗靶向策略和基因组领域领导者的研究经验调查耐药性的方法，包括 ADC。如果成功，该项目还将提供一种方法。从实验室到临床的转化机会，利用饮食调整和噻唑烷二酮药物组合可增强反应并可能逆转对 NECTIN4 靶向疗法的耐药性。