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

• 批准号: 10560334
• 负责人: Josep Maria Domingo-Domenech
• 金额: $ 34.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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/10560334
• 关键词: Determine; Microphthalmia; Transcription; Factor; MITF

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.

一旦前列腺癌发展到晚期去势抵抗阶段， 疾病到目前为止，了解内在的肿瘤细胞生物学过程中涉及的病理生物学， 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前列腺 癌症模型。我们实验室和其他人的工作表明，主调节转录因子 调节可操作的机制，通过调节关键基因的表达来动态地重编程癌细胞， 前列腺癌的核生长因子受体，如雄激素受体。通过综合 包括原发性和转移性组织的人类转录组前列腺癌公共数据库的分析 样品，再加上在体外和体内患者衍生的实验模型，我们已经确定 转录调控机制与致命的前列腺癌的病理生物学。最相关 对于这一提议，我们的研究指出了小眼症转录因子（MITF）在晚期糖尿病中的关键作用。 致命的前列腺癌低MITF水平与原发性前列腺癌的致死性和疾病复发相关 前列腺癌患者。值得注意的是，功能研究表明，在前列腺癌中，MITF调节前列腺癌细胞的生长， 并通过控制不同的临床相关基因网络赋予对雄激素剥夺疗法的抗性。 事实上，计算研究表明，MITF调节特定的关键癌蛋白的蛋白质合成 和前列腺特异性生长因子，如MYC和AR。因此，基于这些结果，我们假设， MITF通过调节转录和翻译参与致死性前列腺癌的发病机制 将癌细胞重新编程为耐药致死状态的机制。我们会调查的 假设如下：在目标1中，我们将探索MITF调控的转录机制， 致命的前列腺癌，重点是不同的MITF亚型，以描绘他们的个人功能，以及 确定临床相关的MITF调控的下游效应基因。在目标2中，我们将研究MITF如何 调节蛋白质合成，重点是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 目的3：我们将研究这些发现在致死性前列腺癌循环肿瘤细胞中的临床相关性。 沿着在靶向蛋白质合成的临床前模型中测试体内功效， 雄激素剥夺疗法作为延缓去势发展的联合治疗策略 低MITF前列腺肿瘤的耐药性。最终，这些研究有望扩大我们对 主调节转录因子如何控制一个错综复杂的信号网络， 细胞，在这种情况下，通过调节翻译，这可能提供新的药物治疗的机会， 前列腺癌患者。