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Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in glioma

神经胶质瘤对单功能烷化剂与双功能烷化剂的不同耐药机制

基本信息

批准号：
10374792
负责人：
Simona Dalin
金额：
$ 6.76万
依托单位：
BROAD INSTITUTE, INC.
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：
2021-04-01 至 2024-07-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374792
关键词：
Alkylating Agents Alkylation BRCA mutations Bar Codes Biological Assay Biology Carmustine Cells Characteristics Chemicals Chemoresistance Clinical Clinical Trials Computer Analysis DNA Damage DNA Interstrand Crosslinking DNA Probes DNA Repair Dana-Farber Cancer Institute Data Evaluation Faculty Gene Activation Genomic Instability Genomics Glioma Guanine Human Institutes Knowledge Lesion Light Lomustine Malignant Glioma Mediating Methylation Mismatch Repair Mismatch Repair Deficiency Modeling Modernization Molecular Mutation Nitrosourea Compounds Nucleotides Outcome Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phenotype Prognosis Proteins Radiation Regimen Resistance Techniques Technology Testing Therapeutic Toxic effect Training Transcriptional Activation Transferase Ursidae Family Variant Work adduct algorithm development biomarker-driven chemotherapeutic agent clinical biomarkers clinical implementation crosslink design detection method effective therapy functional genomics genomic data genomic signature improved improved outcome inhibitor member patient population phase III trial prevent promoter rational design repaired resistance mechanism response biomarker skills student mentoring targeted treatment temozolomide therapy development treatment optimization treatment strategy tumor

项目摘要

Project Summary Resistance to alkylating agents, including monofunctional temozolomide (TMZ) and bifunctional CCNU, remains a major obstacle to improving outcomes for patients with glioma. An important difference between these therapies is that monofunctional alkylators form several types of alkylated nucleotides, while bifunctional alkylators form highly toxic interstrand crosslinks (ICLs). We hypothesize that CCNU and TMZ kill glioma cells through different mechanisms, leading in some instances to different patterns of resistance and independent effects on outcome that may be leveraged for therapeutic benefit. Resistance to both agents can result from expression of the methyl guanine methyl transferase (MGMT) protein. TMZ resistance can also result from mismatch repair deficiency (MMR-d). Resistance to CCNU has not been systematically characterized but involves members of several DNA damage repair (DDR) pathways. We will extend previous work by systematically probing DDR pathways using varied and representative models and state-of-the-art genomic and functional genomic technologies to test the following hypotheses: Aim 1: TMZ resistance via MMR-d predicts sensitivity to CCNU. Our recent work suggests that MMR-d does not cause CCNU resistance. Using isogenic and patient derived models, we will determine which TMZ resistance mechanisms also result in resistance to CCNU and assess changes in mutational signatures after CCNU treatment. We will then use competition assays and barcoding assays to test the hypothesis that the combination of TMZ and CCNU may provide therapeutic benefit over monotherapy in some contexts. Aim 2: Repair proteins that engage CCNU-induced ICLs determine sensitivity to CCNU. We will test the effect of transcriptional activation of genes known to contribute to ICL repair on CCNU resistance. We will then determine if chemical inhibitors of those proteins can improve CCNU efficacy. Finally, we will perform complete genomic characterization of gliomas pre- and post- CCNU treatment to characterize mutational and SV profiles of CCNU resistance as well as the effect of CCNU treatment on genomic instability. This proposal will shed light on differences in resistance to mono- and bi-functional alkylating agents that may be clinically exploitable to improve outcomes for patients with glioma. This training at the Broad Institute and Dana Farber Cancer Institute will provide Dr. Simona Dalin skills of a faculty member, including systematic and genomic techniques, computational analysis of genomic datasets, algorithm development, and DDR biology. She will also mentor students in aspects of the project.

项目总结