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Identification of Druggable Targets to Complement Melanoma Therapy

确定可补充黑色素瘤治疗的药物靶点

基本信息

批准号：
10630160
负责人：
Alan Tackett
金额：
$ 34.1万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630160
关键词：
Animal Model Antitumor Response Autoimmunity Bioinformatics Biology Biometry Biopsy CTLA4 gene Centers of Research Excellence Combined Modality Therapy Complement Coupled Cutaneous Data Analyses Dermatopathology Disease Drug Design Epigenetic Process Genetic Transcription Goals Histones Homeostasis Immune checkpoint inhibitor Immune system Immunotherapy Intelligence Investigation Laboratories Malignant Neoplasms Mass Spectrum Analysis Molecular Monoclonal Antibodies Nivolumab Oncology Operative Surgical Procedures Pathway interactions Patients Positioning Attribute Post-Translational Protein Processing Proteins Proteomics Reporting Resistance Resolution Resources Survival Rate Systems Biology Tissues United States National Institutes of Health cell type checkpoint therapy computer cluster druggable target histone modification ipilimumab mass spectrometer melanoma neoplastic cell patient response patient subsets pembrolizumab pre-clinical prevent programmed cell death protein 1 relapse patients responders and non-responders response standard of care success tumor immunology

项目摘要

Abstract Historically, treatment options for melanoma were limited, and 5-year survival rates were <10% for patients with advanced-stage disease. Recently, immune checkpoint inhibitors (ICIs) have shown encouraging success for treatment of melanoma. However, approximately 40% of patients with advanced melanoma have primary ICI resistance and sub-populations of initially responding patients develop secondary resistance. Can we identify druggable molecular pathways in these non-responders to increase their ICI responsiveness and potentially save lives? We have performed the only reported proteomics investigation of pre-ICI treatment melanoma biopsies from responders and non-responders (6). In this preliminary study, we were able to identify a panel of protein and histone epigenetic signatures that provided evidence for dysregulated molecular pathways correlated to ICI responsiveness – providing the scientific premise for the outlined studies. This preliminary study will be expanded to include 1) a larger number of patients, 2) patients with primary and secondary ICI therapy resistance, and 3) tumor cell-type analyses. The overall goal of this proposal is to combine state-of-the-art proteomics of patient tissues with pre-clinical animal models of ICI responsiveness to create a functional proteomics pipeline for uncovering cellular protein and histone epigenetic pathways functionally dysregulated in melanoma ICI non-responders. We will use a rigorous strategy to target gene transcription and histone modifying proteins as these are upstream pathway effectors that can be druggable. We hypothesize that certain proteins involved in gene transcription and posttranslational modification of histones will be dysregulated in ICI non-responders and functionally coupled to molecular mechanisms of ICI responsiveness, which will identify these proteins as high-priority, druggable candidates for complementing existing ICI therapy. The aims of this study are: 1) perform functional proteomics to identify dysregulated gene transcription protein pathways in melanoma ICI non-responders, 2) use high-resolution mass spectrometry to identify dysregulated histone modifying protein pathways in melanoma ICI non-responders, and 3) determine the functional significance in antitumor responses to ICI therapy for gene transcription and histone modifying proteins dysregulated in melanoma ICI non-responders.

摘要