Determine the Microphthalmia Transcription Factor (MITF)-regulated cell rewiring mechanisms in lethal prostate cancer

确定致死性前列腺癌中小眼转录因子 (MITF) 调节的细胞重连机制

基本信息

批准号：
10407636
负责人：
Josep Maria Domingo-Domenech
金额：
$ 45.28万
依托单位：
MAYO CLINIC ROCHESTER
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：
2022-02-03 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407636
关键词：
AR gene Androgen Receptor Automobile Driving Biological Biological Assay Cancer Patient Candidate Disease Gene Castration Categories Cells Clinical Combination Drug Therapy Complex Coupled Data Data Set Development Disease Disease Progression Dissection Epigenetic Process Eukaryotic Initiation Factors Experimental Models Genes Genetic Transcription Genetic study Genomic approach Growth Growth Factor Growth Factor Receptors Human In Vitro Individual Laboratories Link Luciferases MYC gene Male Castration Malignant Neoplasms Malignant neoplasm of prostate Messenger RNA Modeling Molecular Molecular Abnormality Mus Mutagenesis Neoplasm Circulating Cells Nuclear Oncogenes Oncogenic Oncoproteins Organ Organoids Outcome PTEN gene Pathogenesis Patient-Focused Outcomes Patients Pharmaceutical Preparations Play Pre-Clinical Model Process Prokaryotic Initiation Factor-3 Proliferating Property Prostate Prostatic Diseases Prostatic Neoplasms Protein Biosynthesis Protein Isoforms Protein Synthesis Inhibition Proteomics RB1 gene Recurrent disease Regulation Reporter Research Proposals Resistance Ribavirin Ribosomes Role SOX12 gene Signal Pathway Signal Transduction TP53 gene Testing Therapeutic Tissue Sample Transcriptional Regulation Translating Translation Initiation Translational Regulation Translations Tumor Biology Tumor Cell Biology Tumor Suppressor Proteins Work Xenograft Model androgen deprivation therapy cancer cell clinical efficacy clinically relevant clinically significant computer studies efficacy evaluation enzalutamide falls functional genomics gene network gene repression genomic platform improved in vivo in vivo evaluation insight melanocyte melanoma microphthalmia-associated transcription factor neoplastic cell novel novel drug combination programs promoter prostate cancer model prostate cancer progression protein expression public database therapy resistant transcription factor transcriptomics translational impact tumor

项目摘要

Once prostate cancer progresses to an advanced castration resistant stage it becomes an incurable deadly disease. To date the understanding of the intrinsic tumor cell biology processes involved in the pathobiology of lethal prostate cancer remains limited. Our research proposal aims to elucidate actionable molecular mechanisms that sustain the aggressiveness of lethal tumors by using clinically significant human prostate cancer models. Work from our laboratory and others have revealed that master regulator transcription factors regulate actionable mechanisms that dynamically reprogram the cancer cell by regulating the expression of key nuclear growth factor receptors of prostate cancer such as the Androgen receptor. Through the comprehensive analysis of human transcriptomic prostate cancer public databases that include primary and metastatic tissue samples, coupled with in vitro and in vivo patient derived experimental models, we have identified transcriptionally regulating mechanisms associated with the pathobiology of lethal prostate cancer. Most relevant to this proposal, our studies point to a key role of the Microphthalmia Transcription Factor (MITF) in advanced lethal prostate cancer. Low MITF levels are associated with lethal prostate cancer and disease relapse in primary prostate cancer patients. Notably, functional studies suggest that in prostate cancer MITF regulates the growth and confers resistance to androgen deprivation therapy by controlling a distinct clinically relevant gene network. Indeed, computational studies suggest that MITF regulates the protein synthesis of specific key oncoproteins and prostate specific growth factors, such as MYC and AR. Thus, based on these results, we hypothesize that MITF contributes to the pathogenesis of lethal prostate cancer by regulating both transcriptional and translational mechanisms that reprogram the cancer cell into a therapy resistant lethal state. We will investigate this hypothesis as follows: In aim 1 we will explore the MITF regulated transcriptional mechanisms associated with lethal prostate cancer, focusing on distinct MITF isoforms to delineate their individual functions, as well as determine the clinically relevant MITF regulated downstream effector genes. In aim 2 we will examine how MITF regulates protein synthesis, focusing on specific translation initiation subunits to determine their function in regulating the translation of specific mRNAs, as well as regulatory crosstalk between MITF and MYC. Finally, in aim 3 we will study the clinical relevance of these findings in circulating tumor cells from lethal prostate cancer patients along with testing the in vivo efficacy in preclinical models of targeting protein synthesis together with androgen deprivation therapy as a combined therapeutic strategy to delay the development of castration resistance in low MITF prostate tumors. Ultimately, these studies are poised to broaden our understanding of how master regulator transcription factors govern an intricate complex signaling network that rewires the cancer cell, in this case through regulation of translation, which may offer novel druggable therapeutic opportunities for prostate cancer patients.

一旦前列腺癌进展到晚期去势抵抗阶段，它就会成为无法治愈的致命疾病疾病。迄今为止，人们对涉及肿瘤病理学的内在肿瘤细胞生物学过程的了解致命的前列腺癌仍然有限。我们的研究计划旨在阐明可操作的分子通过使用具有临床意义的人类前列腺来维持致命肿瘤的侵袭性的机制癌症模型。我们实验室和其他实验室的工作表明，主调节转录因子通过调节关键的表达来调节可操作的机制，动态地重新编程癌细胞前列腺癌的核生长因子受体，例如雄激素受体。通过综合对包括原发组织和转移组织的人类转录组前列腺癌公共数据库进行分析样本，加上体外和体内患者衍生的实验模型，我们已经确定与致死性前列腺癌病理学相关的转录调节机制。最相关的针对这一提议，我们的研究指出了小眼转录因子 (MITF) 在高级疾病中的关键作用致命的前列腺癌。低 MITF 水平与致命性前列腺癌和原发性前列腺癌疾病复发有关前列腺癌患者。值得注意的是，功能研究表明，MITF 在前列腺癌中调节生长并通过控制独特的临床相关基因网络赋予对雄激素剥夺疗法的抵抗力。事实上，计算研究表明 MITF 调节特定关键癌蛋白的蛋白质合成以及前列腺特异性生长因子，例如 MYC 和 AR。因此，根据这些结果，我们假设 MITF 通过调节转录和翻译促进致命性前列腺癌的发病机制将癌细胞重新编程为治疗抵抗性致死状态的机制。我们将对此进行调查假设如下：在目标 1 中，我们将探索 MITF 调节的转录机制致命的前列腺癌，重点关注不同的 MITF 同工型来描述其各自的功能，以及确定临床相关的 MITF 调节的下游效应基因。在目标 2 中，我们将研究 MITF 如何调节蛋白质合成，重点关注特定的翻译起始亚基以确定其功能调节特定 mRNA 的翻译，以及 MITF 和 MYC 之间的调节串扰。最后，在目标 3 我们将研究这些发现在致命性前列腺癌循环肿瘤细胞中的临床相关性患者并测试靶向蛋白质合成的临床前模型的体内功效雄激素剥夺疗法作为延缓去势发展的综合治疗策略低 MITF 前列腺肿瘤的耐药性。最终，这些研究将拓宽我们对主调节转录因子如何控制错综复杂的信号网络，从而重新连接癌症细胞，在这种情况下通过翻译调节，这可能为以下疾病提供新的药物治疗机会：前列腺癌患者。