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Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target

将 MAGE-A4/RAD18 确立为新型癌症特异性化疗靶点

基本信息

批准号：
9905492
负责人：
Kenneth Hugh Pearce
金额：
$ 40.39万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-04-02 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905492
关键词：
Affect Affinity Antigens Antineoplastic Agents Binding Biological Testing Cancer Model Carcinogenesis Mechanism Cause of Death Cell Survival Cells Cellular Assay Chemicals Complex DNA Damage DNA Repair DNA Repair Gene DNA biosynthesis Engineering Environmental Risk Factor Genes Genomic Instability Germ Cells Goals Knowledge Libraries Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mission Mitotic Mitotic spindle Molecular Mutagens Normal Cell Nude Mice Oncogenes Oncogenic Pathologic Pathway interactions Patients Peptide Phage Display Library Peptides Permeability Phenotype Physiological Platinum Poison Problem Solving Process Proteins Public Health Research Resistance Role Signal Pathway Signal Transduction Somatic Cell Stress Structure Testing Therapeutic Therapeutic Agents Tissues Topoisomerase II Toxic effect Transgenic Mice Ubiquitin United States National Institutes of Health Work base cancer cell cancer testis antigen cancer therapy carcinogenesis chemotherapeutic agent chemotherapy defined contribution drug discovery druggable target environmental agent experience experimental study improved in vivo inhibitor/antagonist innovation melanoma mortality neoplastic cell new therapeutic target novel outcome forecast preclinical study preneoplastic cell pressure prevent replication stress response screening side effect small molecule targeted treatment taxane therapeutic target therapy resistant tumor tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

SUMMARY There are fundamental gaps in our understanding of how cancer cells acquire DNA damage-tolerance and evade chemotherapy (termed ‘chemoresistance’). The gaps in our knowledge of DNA damage tolerance (and how it differs between normal and neoplastic cells), limit our ability to kill tumors without causing side effect toxicities to normal healthy tissues. Our long-term goals are to solve the problem of how neoplastic cells tolerate therapy, and identify new molecular vulnerabilities that can be specifically targeted for improved treatment. The objective here is to define a novel tumor-specific mechanism of chemoresistance and to establish its tractability as a therapeutic target. Remarkably, we discovered that Melanoma Antigen-A4 (MAGE-A4, a Cancer/Testes Antigen or 'CTA') is an activating binding partner of the DNA repair protein RAD18 (an E3 ubiquitin ligase). MAGE-A4 is absent from all normal somatic cells but pathologically activates DNA repair in cancer cells. MAGE-A4 also activates the E3 ligase TRIM69 which confers resistance to mitotic spindle poisons. MAGE-A4 expression is associated with poor patient prognosis yet its potential impact on the responsiveness of tumors to chemotherapy in a physiological setting is untested. Based on exciting and compelling preliminary studies, we will test the central hypothesis that MAGE-A4 pathologically reprograms ubiquitin signaling in tumors to confer chemoresistance to genotoxins and spindle poisons. The rationale is that defining the contribution of MAGE-A4 to chemoresistance will allow extraordinarily specific therapeutic strategies that target a unique molecular vulnerability of neoplastic cells. The Specific Aims are: SA1 Define contribution of pathologically-activated DNA repair to chemoresistance in vivo. SA2 Establish chemical tractability of MAGE-A4/RAD18 as a therapeutic target. SA3 Mechanistically define MAGE-A4/TRIM69 functions in mitotic progression and resistance to spindle poisons. In SA1 We will use a new transgenic mouse and orthotopic lung cancer models to determine how MAGE-A4/RAD18 impacts responses to chemotherapy in vivo. In SA2 we will screen peptide phage display libraries to identify sequence motifs that bind MAGE-A4 and disrupt the MAGE-A4/RAD18 interaction. Bioactive MAGE-A4 inhibitor peptides will be tested for anti-neoplastic activity. In SA3 we will define a novel role of MAGE-A4 in regulating TRIM69 and conferring resistance to spindle poisons. We will mechanistically define the MAGE-A4/TRIM69 signaling pathway and establish its role in tolerance of therapeutic taxanes. These experiments will likely establish MAGE-A4 as a druggable target for ameliorating chemoresistance in cancer cells, serving as a crucial gateway in the drug discovery process. The proposed ideas and research are innovative because they are the first studies to test how biological activities of CTAs affect cancer therapy. The proposed work is significant because it will provide new paradigms for chemoresistance due to pathological ubiquitin signaling leading directly to novel targeted therapies for chemoresistant cancer.

总结