MSK SPORE in Genomic Instability in Breast Cancer

摘要 本 SPORE 中提出的研究项目解决了乳腺癌的基因组不稳定性问题。三个区域是 研究重点：同源重组缺陷、染色体不稳定和APOBEC突变。 我们的最终计划是利用肿瘤潜在的基因组不稳定性的特定漏洞。 这些基因组不稳定性特征为乳腺癌发展的驱动因素提供了新的见解 和进展。乳腺癌治疗有机会取得进展，这些进展已经出现 基于最初的成功，例如，通过治疗利用同源重组缺陷 PARP 抑制剂。该计划是确定这些药物的最佳用途并为这些药物开发新药物 肿瘤。染色体不稳定性不一定具有独特的突变模式，与 预后较差，但目前尚无特效治疗策略。染色体之间的联系 不稳定和先天免疫信号传导已经建立，目标是利用这种联系进行治疗。 对于 APOBEC，我们知道观察到 SNV 的特征模式，但在本应用中，我们是 强调 APOBEC 在获得耐药性中的作用，并介绍新的方法 通过主动 APOBEC 诱变过程可靠地识别乳腺癌并进行治疗。 总之，目标是承担基因组不稳定的风险（预后不良、疾病快速发展） 耐药性）并将基因组不稳定性转化为治疗靶向的优势，从而改善 高风险乳腺癌的预后。

ABSTRACT The research projects proposed in this SPORE address genomic instability in breast cancer. Three areas are the focus of study: homologous recombination deficiency, chromosomal instability and APOBEC mutagenesis. Our ultimate plan is to exploit tumor specific vulnerabilities by virtue of their underlying genomic instability. These profiles of genomic instability have offered novel insights about the drivers breast cancer development and progression. There are opportunities for therapeutic advances in breast cancer, which have emerged based on the initial successes, for example, in utilizing homologous recombination deficiency by treatment with a PARP inhibitor. The plan is to determine the optimal use of these agents and develop novel agents for these tumors. Chromosomal instability, which does not necessarily have a unique pattern of mutations, is associated with a poor prognosis, but no specific therapeutic strategy at present. The link between chromosomal instability and innate immune signaling has been made, and the goal is to exploit this connection for therapy. For APOBEC, we know that a characteristic pattern of SNVs are observed, but in this application, we are highlighting the role of APOBEC in the acquisition of drug resistance, and introducing novel approaches for reliably identifying and therapeutically targeting breast cancers with an active APOBEC mutagenesis process. In summary, the goals are to take the risks of genomic instability (poor prognosis, rapid development of resistance) and turn genomic instability into an advantage for therapeutic targeting, thereby improving the prognosis for high risk breast cancers.