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.

项目概要/摘要转移性乳腺癌（MBC）是一种致命的疾病，迫切需要新的治疗方法。该提案旨在测试和表征一种选择性破坏乳腺癌的新治疗策略肿瘤抑制 p53 基因存在遗传异常的细胞，这种情况常见于 MBC。遗传 p53 的改变会促进癌症的发展并加速转移进展。我们发现p53突变体癌细胞因核苷酸类似物治疗而积累 DNA 损伤，部分原因是 DNA 修复过程中的失调。我们进一步发现聚（ADP-核糖）聚合酶（PARP）抑制剂选择性地放大 DNA 损伤并增加 p53- 中核苷酸类似物诱导的毒性突变的癌细胞。我们开发了一种通过流式细胞术评估这种反应的新颖方法。这所提出的新型组合策略在动物 MBC 模型中得到了进一步验证。因此，与之前所有的依赖突变体 p53 作为目标的方法，我们的新策略利用了已识别的脆弱性 p53 突变癌细胞中 DNA 修复失调。我们假设联合疗法核苷酸类似物与 PARP 抑制剂将选择性消除 p53 突变体 MBC。该提案将在 MBC 的临床相关模型中检查两种从未一起测试过的药物的组合。我们将评估 p53 的各种热点突变体在观察到的反应中的贡献。成功的该项目的完成将支持测试新型药物组合的一期临床试验。这项研究具有改变乳腺癌治疗并显着降低相关死亡率的巨大潜力患有转移性疾病。