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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：
10540805
负责人：
Andrei V. Bakin
金额：
$ 19.27万
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540805
关键词：
Acceleration 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 Genes Goals Hand Human Immune Immunocompetent Immunologic Deficiency Syndromes Injections 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) Polymerase Inhibitor 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 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 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/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。该提案旨在测试和描述一种选择性破坏乳腺癌的新治疗策略肿瘤抑制基因p53基因异常的细胞，通常发生在MBC中。遗传 p53的改变驱动癌症发展并加速转移进展。我们发现p53突变体癌细胞对核苷酸类似物治疗的反应是积累DNA损伤，部分原因是 DNA修复过程中的异常我们进一步发现聚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新的方法，通过流式细胞术评估这种反应。的在动物MBC模型中进一步验证了所提出的新组合策略。因此，与所有先前的依赖于突变型p53作为靶点的方法，我们的新策略利用了鉴定的p53的脆弱性。 p53突变癌细胞中DNA修复的失调。我们假设，具有PARP抑制剂的核苷酸类似物将选择性地消除p53突变MBC。该提案将在MBC的临床相关模型中检查从未一起测试过的两种药物的组合。我们将评估各种热点突变体的p53在所观察到的反应的贡献。成功该项目的完成将支持对该新型药物组合进行I期临床试验。本研究具有改变乳腺癌治疗并显著降低相关死亡率的强大潜力转移性疾病