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

基本信息

批准号：
10478015
负责人：
Sarat Chandarlapaty
金额：
$ 42.28万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-13 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478015
关键词：
Affect Aromatase Inhibitors Benchmarking Biochemistry Bioinformatics Biological Assay Biological Markers Biological Models Breast Cancer Model Breast Cancer cell line Breast Cancer therapy CDK4 gene CRISPR/Cas technology Cancer Model Caring Cause of Death Cell Cycle Inhibition Cell Line Cells Cessation of life Characteristics Clinic Clinical Clinical Trials Comparative Genomic Analysis DNA Repair DNA Sequence Alteration Data Data Set Dependence Detection Development Diagnosis Disease Disease Resistance Disseminated Malignant Neoplasm Drug Combinations Drug resistance ERBB2 gene ESR1 gene Endocrine Enzymes Estrogen Antagonists Estrogen Receptors Estrogen receptor positive Estrogens FAT gene Family Genes Genetic Genetic Transcription Genomic Instability Genomics Glare Immune response Immunohistochemistry Immunologics Individual Kinetics Knock-out Large-Scale Sequencing Link Malignant Neoplasms Mediating Medical Metastatic breast cancer Methods Minority Modeling Mutagenesis Mutation NF1 gene Neoplasm Metastasis Newly Diagnosed Pathogenesis Pathogenicity Patients Pattern Phenotype Positioning Attribute Prevalence Primary Neoplasm Process RB1 gene Recurrence Regimen Resistance Resistance development Sampling Series Shapes Systemic Therapy Tamoxifen Testing Therapeutic Time Translating United States Woman acquired drug resistance antagonist base breast cancer diagnosis cancer cell cancer genome cancer therapy cell free DNA chromatin remodeling curative treatments deprivation genomic profiles hormone therapy immune checkpoint blockade inhibitor innovation insight knock-down malignant breast neoplasm mortality multimodality neoplastic cell novel strategies overexpression patient derived xenograft model prevent refractory cancer resistance allele resistance mutation therapeutic target transcription factor tumor tumor DNA tumor progression

项目摘要

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.

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) 阳性乳腺癌都可以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肿瘤和转移性肿瘤进行比较基因组分析得出了差异。我们和其他人已经确定了影响转移性癌症中更常见的特定基因的几种突变高于其主要对应物，包括 ESR1、ERBB2 和 NF1。这些突变会导致耐药性一线内分泌治疗是 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某些“突变特征”的发现与原发性乳腺癌相比，转移性疾病较多。这些突变特征代表了塑造癌症基因组的 DNA 损伤和修复过程，并可引起此类癌症突变及其所传达的转化表型。来自多个大型研究机构的明显而一致的发现规模测序研究表明 APOBEC 突变特征既丰富又高度普遍存在于 ER 阳性转移性疾病中，包括这些药物的显性突变特征耐药且最终致命的癌症。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与特征相关 APOBEC-许多耐药等位基因的突变变化。这些结果共同表明 APOBEC 突变过程是 ER 阳性转移性乳腺发育和发病机制的关键驱动因素癌症和内分泌治疗耐药性。在这个高度协作和创新的项目中，我们提出了三个具体目标是推进 APOBEC 突变过程作为乳腺生物标志物和治疗靶点癌症。 (1) 我们将开发并利用强大的生物信息学方法来检测来自肿瘤和无细胞 DNA 的临床 NGS 数据集的 APOBEC 突变特征的出现（cfDNA）。我们将进一步确定一种有前途的 A3B 酶 IHC 检测是否可以识别那些 ER 阳性的患者随后可能出现 APOBEC 突变特征的癌症。 (2) 我们将确定 APOBEC 对内分泌抵抗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来剖析由 APOBEC 引起的耐药模式类型以及它们的时机以及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学和合成致死方法，其中 APOBEC 诱导活性并确定其杀死 APOBEC 阳性癌症的能力。我们预计我们的研究结果将使我们的团队处于独特的地位，可以启动临床试验来测试特定的诊断方法 APOBEC 阳性肿瘤，防止对内分泌治疗产生耐药性，并针对 ER 阳性内分泌耐药性转移性乳腺癌的最大子集。