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A Novel Treatment Strategy for Metastatic Breast Cancer

转移性乳腺癌的新治疗策略

基本信息

批准号：
10356596
负责人：
Andrei V. Bakin
金额：
$ 23.59万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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：
2021-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356596
关键词：
Adjuvant Therapy Amplifiers Animals Base Excision Repairs Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Carcinoma Carcinoma Cell Line Cells Clinic Clinical Clinical Trials Combined Modality Therapy Comet Assay DNA Damage DNA Repair DNA Repair Pathway DNA amplification DNA biosynthesis Data Deoxyuridine Development Disease Drug Combinations Excision FDA approved Flow Cytometry Floxuridine Future Goals Hand Hot Spot Human Immune Immunocompetent Injections Lead Malignant Neoplasms Measures Mediating Metastatic breast cancer Methodology Modeling Molecular Abnormality Mus Mutation Neoadjuvant Therapy Neoplasm Metastasis Patients Pharmaceutical Preparations Phase I Clinical Trials Poly(ADP-ribose) Polymerases Pre-Clinical Model Primary Neoplasm Process Recurrence Regimen Research Role Safety Speed TP53 gene Tail Testing Therapeutic Therapeutic Intervention Toxic effect Translating Tumor Suppressor Genes United States Veins Work analog base cancer cell cell type clinical application clinical practice clinically relevant cytotoxicity defined contribution design driver mutation drug efficacy effective therapy efficacy testing efficacy validation gene repair genomic data improved in vivo Model inhibitor insight malignant breast neoplasm mortality mouse model mutant new combination therapies novel novel drug combination novel strategies novel therapeutic intervention novel therapeutics nucleotide analog patient derived xenograft model patient population pre-clinical repaired response synergism tool treatment planning treatment response treatment strategy triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

Project Summary/Abstract Metastatic breast cancer (MBC) is a deadly disease and novel therapeutic approaches are urgently needed. The proposal aims to test and characterize a novel therapeutic strategy for selectively damaging breast cancer cells with a genetic abnormality in the tumor suppressor p53 gene that commonly occurs in MBC. Genetic alteration in p53 drives cancer development and speeds metastatic progression. We found that p53-mutant cancer cells accumulate DNA damage in response to treatment with nucleotide analogues in part due to dysregulation in the DNA repair process. We further discovered that poly(ADP-ribose) polymerase (PARP) inhibitors selectively amplify DNA damage and increase toxicity induced by nucleotide analogues in p53- mutant cancer cells. We developed a novel methodology evaluating this response by flow cytometry. The proposed novel combination strategy was further validated in animal MBC models. Thus, unlike all prior approaches that depend upon mutant p53 as a target, our novel strategy exploits vulnerability of the identified dysregulation of DNA repair in p53-mutant cancer cells. We hypothesize that a combination therapy of nucleotide analogues with PARP inhibitors will selectively eliminate p53-mutant MBC. The proposal will examine in clinically relevant models of MBC a combination of two drugs that have never been tested together. We will assess the contribution of various hot-spot mutants of p53 in the observed response. Successful completion of the project will support a Phase I clinical trial testing the novel drug combination. This research has a strong potential to transform breast cancer treatment and significantly reduce the mortality associated with metastatic disease.

项目总结/文摘