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Dissecting Early Tumor Evolution to Uncover Mechanisms of Tumor Initiation and Drug Resistance

剖析早期肿瘤演化，揭示肿瘤发生和耐药机制

基本信息

批准号：
10607859
负责人：
Matthew James Ryan
金额：
$ 3.98万
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：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607859
关键词：
Acceleration Alanine Androgen Receptor Automobile Driving Binding Binding Sites Bypass CDK4 gene CDKN2A gene Cancer Biology Cancer cell line Cell Cycle Cell Cycle Progression Cells Clinical Complement Comprehensive Cancer Center Cyclin-Dependent Kinase Inhibitor 2A DNA Binding DNA Mismatch Repair Protein MSH2 Data Detection Disease Disease Progression Doctor of Philosophy Drug resistance EDN2 gene Engineering Event Evolution Family Fellowship Fostering Foundations G1/S Checkpoint Pathway Gene Expression Genes Genetic Genetic Drift Genetic Models Genetic Transcription Genetically Engineered Mouse Genomic approach Genomics Growth Human IRS4 gene In Vitro Knock-out Knockout Mice Lesion MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Medical Oncologist Mentorship Mismatch Repair Missense Mutation Mus Mutagenesis Mutation Oncogenes Organoids PIK3CG gene PTEN gene Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacotherapy Phase I Clinical Trials Phenotype Phosphorylation Phosphotyrosine Point Mutation Preceptorship Prevalence Proliferating Prostate Prostatic Neoplasms Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Reporting Research Personnel Resistance Role Sampling Secure Signal Transduction System Testing Training Transcription Alteration Tumor Suppressor Proteins Variant Work advanced prostate cancer burden of illness cancer drug resistance cancer genetics cancer genomics cancer initiation career exome sequencing experience functional genomics gain of function gain of function mutation gene function gene repair genetic corepressor genetic variant health disparity improved in vivo inhibitor insertion/deletion mutation insight men multiple omics overexpression pre-clinical preclinical study premalignant prevent programs response standard of care therapeutic target transcription factor tumor tumor growth tumor initiation tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Despite the prevalence of prostate cancer worldwide, we lack an understanding of the genetic events that drive tumor initiation or drug resistance. Only a few genetic models exist, leaving hundreds of recurrent mutations unaccounted for, and most studies interrogate gene function by overexpression or knockout rather than studying the mutational variants present in disease. Better understanding of the mutations driving tumor initiation and drug resistance could allow us to screen for precancerous lesions or prevent fatal disease progression, greatly relieving the global burden of disease. Therefore, there is an urgent need for a new functional genomic approach to enable the functional study of multiple genetic variants per cell to identify mechanisms of tumor initiation and drug resistance. We have developed such a system in mouse prostate organoids by knocking out the tumor suppressor Pten and the mismatch repair gene Msh2 to induce the accumulation of point mutations and indels. This system has allowed us to interrogate which mutations complement PTEN loss to drive tumor initiation and drug resistance in vivo. We have discovered that hotspot mutations in IRS4 and CDK4 are uniquely enriched during tumor initiation and drug resistance, respectively. Thus, I propose to determine the mechanisms by which IRS4 and CDK4 gain of function mutations complement PTEN loss to drive prostate cancer initiation and drug resistance, respectively. In my first aim, I will test the necessity and sufficiency of IRS4 gain of function to drive tumor initiation through MAPK activation and downstream transcriptional alterations. For my second aim, I will test the necessity and sufficiency of CDK4 gain of function to drive drug resistance through cell cycle dysregulation and investigate the reversibility of this phenotype in patient-derived organoids. My sponsor Rohit Bose, MD, PhD, has extensive experience in genetic and transcriptional network alterations underlying prostate tumor initiation. My co-sponsor Kevin Shannon, MD, has renowned experience studying MAPK circuitry and drug resistance in cancer. Additionally, I have secured scientific support and career mentorship from a respected and prolific cadre of investigators with complementary expertise, Dr. Felix Feng (prostate cancer genomics), Dr. Rahul Aggarwal (drug-resistant tumor samples), Dr. Catherine Smith (cell cycle dysregulation and tumor evolution), Dr. Franklin Huang (prostate cancer genomics and health disparities), and Dr. Hani Goodarzi (multi-omics and tumor evolution). Concurrently, I will continue bimonthly clinical preceptorships with Drs. Aggarwal, Bose, and Feng at the UCSF Helen Diller Family Comprehensive Cancer Center. Overall, the proposed work will further our understanding of tumor initiation and drug resistance in prostate cancer, laying the groundwork for improved detection and treatment. Moreover, this fellowship will foster my training in cancer biology and genetics, supporting me through combined MD/PhD training towards a career as an academic medical oncologist studying tumor evolution and drug resistance in prostate cancer.

项目总结/摘要尽管前列腺癌在世界范围内普遍存在，但我们对导致前列腺癌的遗传事件缺乏了解。肿瘤起始或耐药性。只有少数遗传模型存在，留下数百个重复突变大多数研究通过过度表达或敲除来询问基因功能，而不是研究疾病中存在的突变变体。更好地理解驱动肿瘤发生的突变，耐药性可以让我们筛查癌前病变或预防致命的疾病进展，减轻全球疾病负担。因此，迫切需要一种新的功能基因组学方法能够对每个细胞的多种遗传变异进行功能研究，以确定肿瘤发生的机制，耐药性我们已经在小鼠前列腺类器官中开发了这样一个系统，抑制基因Pten和错配修复基因Msh 2诱导点突变和插入缺失的积累。该系统使我们能够询问哪些突变补充了PTEN缺失以驱动肿瘤起始，体内耐药性。我们已经发现IRS 4和CDK 4中的热点突变是独特富集的，在肿瘤发生和耐药期间。因此，我建议通过以下方式确定机制： IRS 4和CDK 4功能突变的获得补充了PTEN的缺失，从而导致前列腺癌启动和耐药性。在我的第一个目标中，我将测试IRS 4的必要性和充分性获得通过MAPK激活和下游转录改变驱动肿瘤起始的功能。为我的第二个目标是，我将测试CDK 4功能获得驱动耐药性的必要性和充分性。细胞周期失调，并研究这种表型在患者来源的类器官中的可逆性。我发起人Rohit Bose，医学博士，博士，在遗传和转录网络改变方面具有丰富的经验潜在的前列腺肿瘤发生。我的共同赞助人凯文·香农，医学博士，有着著名的研究经验， MAPK通路与癌症耐药性此外，我还获得了科学支持和职业生涯来自一个受人尊敬的和多产的研究人员与互补的专业知识，博士费利克斯冯（前列腺癌基因组学），Rahul Aggarwal博士（耐药肿瘤样本），Catherine Smith博士（细胞周期失调和肿瘤演变），富兰克林黄博士（前列腺癌基因组学和健康差异），和博士哈尼·古德兹（多组学和肿瘤演变）。同时，我将继续每两个月的临床 Aggarwal博士，Bose博士和Feng博士在UCSF Helen Diller Family Comprehensive Cancer 中心总的来说，这项工作将进一步加深我们对肿瘤发生和耐药的理解。前列腺癌，为改善检测和治疗奠定了基础。此外，该奖学金将促进我在癌症生物学和遗传学方面的培训，支持我通过MD/PhD联合培训走向职业生涯作为一名学术医学肿瘤学家，研究前列腺癌的肿瘤演变和耐药性。