A Novel Treatment Strategy for Metastatic Breast Cancer

项目摘要/摘要 转移性乳腺癌是一种致命的疾病，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损伤乳腺癌的新治疗策略。 在肿瘤抑制基因P53基因中有遗传异常的细胞，这种异常通常发生在MBC中。遗传 P53基因的改变推动了癌症的发展，并加速了转移进展。我们发现P53基因突变 癌细胞对核苷酸类似物治疗的反应导致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核苷酸类似物对P53的DNA损伤并增加其毒性 突变的癌细胞。我们开发了一种新的方法，通过流式细胞术来评估这种反应。这个 提出的新组合策略在动物MBC模型中得到了进一步的验证。因此，与以前的所有 以突变型p53为靶点的方法，我们的新策略利用了已识别的 P53突变癌细胞中DNA修复的失调。我们假设一种综合疗法 与PARP抑制剂的核苷酸类似物将选择性地消除P53突变的MBC。这项提议将 在临床相关的MBC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P53的各种热点突变在观察到的反应中的作用。成功 该项目的完成将支持测试这种新型药物组合的第一阶段临床试验。这项研究 有很强的潜力改变乳腺癌的治疗方法，显著降低相关死亡率 患有转移性疾病。

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.