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Androgen receptor function in melanoma

雄激素受体在黑色素瘤中的功能

基本信息

批准号：
10709864
负责人：
GIAN-PAOLO DOTTO
金额：
$ 44.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2022-09-23 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709864
关键词：
AR gene Address Age Androgen Receptor Androgen Suppression Androgens BRAF gene Biochemical Cell Aging Cells Collection Cytoplasm Cytotoxic T-Lymphocytes DNA DNA Damage DNA Repair Data Development Epigenetic Process Estrogens Extravasation Female Gene Expression Profile Gene Silencing Genes Genetic Genetic Transcription Genome Stability Gonadal Steroid Hormones Immunocompetent Incidence Infiltration Inflammatory Lamin Type A Lamins Ligands Link Macrophage Maintenance Malignant Neoplasms Melanoma Cell Modeling Mutation Nuclear Envelope Nuclear Lamin Nuclear Receptor Coactivator 4 Organ Pathway interactions Patients Phosphorylation Play Population Predisposition Process Proliferating Protein phosphatase Proteins RNA Helicase Receptor Inhibition Receptor Signaling Resistance Resources Role Sex Differences Signal Transduction T-Cell Activation Testing Up-Regulation Validation Work cancer type clinically significant ds-DNA genome integrity hormonal signals in vivo inhibitor male melanoma mouse model overexpression patient derived xenograft model patient response pharmacologic prevent prognostic significance receptor expression receptor function response self-renewal sex sexual dimorphism transcriptomics treatment response tumor tumorigenesis

项目摘要

Abstract Malignant melanoma is an example of primary clinical significance for investigating sex-related differences in cancer arising in organs with non-reproductive functions. Differences in sex hormone levels and in downstream pathways are likely to play a key role, which is however still poorly understood. Our main working hypothesis is that androgen receptor (AR) and associated proteins converge on control of melanoma development and response to treatment. In recent work, we have found that genetic and pharmacological suppression of AR activity in a large panel of melanoma cells reduces self-renewal potential and tumorigenesis, inducing double strand DNA damage and cytoplasmic leakage, a STING-dependent pro-inflammatory cascade and a gene expression signature associated with better patients' survival. Based on further preliminary data, we will test two specific hypotheses: 1) AR signaling plays a key role in melanoma cells at the intersection between gene transcription and DNA repair / genomic stability with nuclear lamins as co-determinants. We will probe into the biochemical and functional significance of endogenous AR-lamin interactions and AR-dependent lamin A/C association with the PPP1 protein phosphatase, impinging on lamin phosphorylation at critical residues, and with the DDX3X and DDX3Y RNA helicases, encoded by X- and Y-linked genes and with expression of prognostic significance for female and male patients, respectively. 2) Targeting AR is of translational significance for preventing / counteracting resistance of melanomas with BRAFv600 mutations to BRAF inhibitors (BRAFi). In preliminary work, we found striking up-regulation of AR expression in response to BRAFi, proliferation and tumorigenesis of BRAFi resistant melanoma cells are suppressed by AR inhibition, AR overexpression is by itself sufficient to confer BRAFi resistance. In further studies we will assess to what extent suppression of AR expression and activity has an impact on melanoma cell subpopulations with intrinsic BRAFi resistance and/or BRAFi-induced epigenetic reprogramming. We will analyze a collection of freshly derived cells from Patient- Derived Xenografts (PDX) of BRAFi sensitive and resistant melanomas and assess to what extent the beneficial effects of suppression of AR signalling occur in vivo, restoring one or more aspects of the BRAFi response of the corresponding PDXs.

摘要