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

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。

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.