Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer

转移性乳腺癌APOBEC突变的诊断和治疗 摘要：尽管大多数早期雌激素受体（ER）阳性乳腺癌都能治愈， 通过多模式护理，转移性ER阳性乳腺癌仍然是一种致命疾病。对此的见解 通过对原发性和转移性肿瘤的比较基因组分析，已经发现了差异。我们和 其他人已经确定了几个影响特定基因的突变，这些基因在转移性癌症中更普遍 包括ESR 1、ERBB 2和NF 1。这些突变导致对 一线内分泌治疗是ER阳性乳腺癌的主要全身治疗。甚至 然而，比这些个体突变更引人注目的是， 与原发性乳腺癌相比，在转移性疾病中富集。这些变异的特征 代表了DNA损伤和修复过程，这些过程塑造了癌症基因组， 突变和它们传递的转化表型。从多个大的- 大规模测序研究表明，APOBEC突变特征是富集的，并且高度依赖于DNA序列。 在ER阳性转移性疾病中普遍存在，包括这些药物的显性突变特征， 耐药并最终致命的癌症。我们的初步数据证实，APOBEC激活可以促进 ER阳性癌症模型中内分泌抵抗的发展，并与特征性 APOBEC-许多耐药等位基因的突变变化。总之，这些结果指向APOBEC 突变过程作为ER阳性转移性乳腺癌发生和发病机制的关键驱动因素 癌症和内分泌治疗抗性。在这个高度合作和创新的项目中，我们提出三个 具体目标是推进APOBEC突变过程作为乳腺癌的生物标志物和治疗靶点。 癌(1)我们将开发和利用强大的生物信息学方法来检测的存在和时间， 来自肿瘤和细胞游离DNA的临床NGS数据集的APOBEC突变特征的开始 （cfDNA）。我们将进一步确定一种有前途的A3 B酶免疫组化检测方法是否能鉴别出ER阳性的细胞。 癌症可能随后产生APOBEC突变标签。(2)康贝特人将以 APOBEC对内分泌抗性的作用机制和动力学。我们将使用同基因细胞系 模型和患者来源的异种移植物，以剖析由APOBEC引起的耐药模式的类型 以及它们的时机和内分泌治疗本身是否有助于诱导APOBEC活性。 (3)我们将评估针对肿瘤的免疫和合成致死方法，其中APOBEC 活性被诱导，并决定其杀死APOBEC阳性癌症的能力。我们预计， 研究结果将使我们的团队能够启动临床试验，测试特定的诊断方法， APOBEC阳性肿瘤，以防止对内分泌治疗产生耐药性，并靶向 ER阳性内分泌耐药转移性乳腺癌的最大子集。

Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer Summary: Although the majority of early stage estrogen receptor (ER)-positive breast cancers are cured through multimodality care, metastatic ER-positive breast cancer remains a lethal disease. Insights into this discrepancy have come through comparative genomic analyses of primary and metastatic tumors. We and others have identified several mutations affecting specific genes that are more prevalent in metastatic cancers than in their primary counterparts, including ESR1, ERBB2, and NF1. These mutations result in resistance to front-line endocrine treatments that are the mainstay systemic therapy in ER-positive breast cancer. Even more striking than such individual mutations, however, has been the finding that certain `mutational signatures' are enriched in metastatic disease as compared to primary breast cancers. These mutational signatures represent the DNA damage and repair processes that shape the cancer genome and can give rise to such mutations and the transformed phenotypes they convey. A glaring and consistent finding from multiple large- scale sequencing studies has been that the APOBEC mutational signature is both enriched and highly prevalent in ER-positive metastatic disease, comprising the dominant mutational signature for these drug- resistant and ultimately lethal cancers. Our preliminary data confirm that APOBEC activation can promote the development of endocrine resistance in ER-positive cancer models and is associated with characteristic APOBEC-mutational changes in many drug resistance alleles. Together, these results point to the APOBEC mutational process as a key driver in the development and pathogenesis of ER-positive metastatic breast cancer and endocrine therapy resistance. In this highly collaborative and innovative project, we propose three specific aims to advance the APOBEC mutational process as a biomarker and therapeutic target in breast cancer. (1) We will develop and utilize robust bioinformatic methods to detect the presence and the timing of onset of the APOBEC mutational signature from clinical NGS datasets of both tumor and cell free DNA (cfDNA). We will further ascertain if a promising IHC assay for the A3B enzyme can identify those ER-positive cancers likely to subsequently develop an APOBEC mutational signature. (2) We will determine the mechanisms and kinetics of APOBEC's contribution to endocrine resistance. We will use isogenic cell line models and patient derived xenografts to dissect the types of resistance patterns that are caused by APOBEC as well their timing and whether the endocrine therapy itself contributes to the induction of APOBEC activity. (3) We will assess both immunologic and synthetic lethal approaches to targeting tumors in which APOBEC activity is induced and determine their capabilities in killing APOBEC-positive cancers. We anticipate that our findings will uniquely position our team to launch clinical trials testing specific approaches to diagnose APOBEC-positive tumors, to prevent the development of resistance to endocrine therapies, and to target the largest subset of ER-positive endocrine-resistant metastatic breast cancers.