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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：
10272823
负责人：
Josep Maria Domingo-Domenech
金额：
$ 9.32万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10272823
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 Databases Development Disease 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 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 Property Prostate Prostatic Diseases Prostatic Neoplasms Protein Biosynthesis Protein Isoforms 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 Translations Tumor Biology Tumor Cell Biology Tumor Suppressor Proteins Work Xenograft Model androgen deprivation therapy base cancer cell clinical efficacy clinically relevant clinically significant computer studies efficacy evaluation falls functional genomics genomic platform improved in vivo in vivo evaluation insight male melanocyte melanoma microphthalmia-associated transcription factor novel novel drug combination programs promoter prostate cancer model protein expression therapy resistant transcription factor transcriptomics 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.

一旦前列腺癌发展到晚期去势抵抗阶段，它就成为一种无法治愈的致命疾病