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

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $93,163

## Abstract

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 transcriptio...

## Key facts

- **NIH application ID:** 10272823
- **Project number:** 1R01CA261925-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Josep Maria Domingo-Domenech
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $93,163
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-01-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10272823

## Citation

> US National Institutes of Health, RePORTER application 10272823, Determine the Microphthalmia Transcription Factor (MITF)-regulated cell rewiring mechanisms in lethal prostate cancer (1R01CA261925-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10272823. Licensed CC0.

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