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：
10704108
负责人：
Sarat Chandarlapaty
金额：
$ 43.65万
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/10704108
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 Damage 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 Eligibility Determination Endocrine Enzymes Estrogen Antagonists Estrogen Receptors Estrogen receptor positive Estrogens FAT gene Family Genes Genetic Genomic Instability Genomics Immune response Immunohistochemistry Immunologics Individual Kinetics Knock-out Large-Scale Sequencing Link Malignant Neoplasms Mediating Medical Metastatic breast cancer Methods Minority Modeling Mutagenesis Mutagens 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 Viral Woman acquired drug resistance antagonist breast cancer diagnosis cancer cell cancer genome cancer therapy cell free DNA chromatin remodeling curative treatments deprivation dominant genetic mutation genomic profiles hormone therapy immune checkpoint blockade inhibitor innovation insight knock-down malignant breast neoplasm mortality multimodality next generation sequence data 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.

转移性乳腺癌中APOBEC诱变的诊断和治疗摘要：尽管大多数早期雌激素受体（ER） - 阳性乳腺癌均已治愈通过多模式护理，转移性ER阳性乳腺癌仍然是致命的疾病。对此有所了解差异是通过对原发性和转移性肿瘤的比较基因组分析得出的。我们和其他人已经确定了几个影响特定基因的突变，这些突变在转移性癌症中更为普遍比在其主要对应物中，包括ESR1，ERBB2和NF1。这些突变导致对前线内分泌疗法是ER阳性乳腺癌的主要系统治疗。甚至然而，比某些“突变签名”的发现更加惊人与原发性乳腺癌相比，在转移性疾病中富集。这些突变标志表示塑造癌症基因组的DNA损伤和修复过程，并可能引起这种情况它们传达的突变及其转变的表型。从多个大的比例测序研究是APOBEC突变特征既丰富又高度在ER阳性转移性疾病中普遍存在，包括这些药物的主要突变特征抗性，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耐药性的发展，与特征有关许多药物抗性等位基因的APOBEC突破性变化。这些结果在一起指向Apobec 突变过程是ER阳性转移性乳房发育和发病机理的关键驱动力癌症和内分泌疗法耐药性。在这个高度协作和创新的项目中，我们提出了三个具体旨在将APOBEC突变过程作为乳腺癌的生物标志物和治疗靶标发展癌症。（1）我们将开发并利用强大的生物信息学方法来检测存在和时间来自肿瘤和无细胞DNA的临床NGS数据集的APOBEC突变特征的发作（CFDNA）。我们将进一步确定A3B酶的有希望的IHC分析是否可以识别那些ER阳性随后可能会开发APOBEC突变签名的癌症。（2）我们将确定 Apobec对内分泌抗性的贡献的机制和动力学。我们将使用同源细胞系模型和患者衍生的异种移植物，以剖析由APOBEC引起的电阻模式的类型他们的时间以及内分泌疗法本身是否有助于诱导APOBEC活性。（3）我们将评估靶向肿瘤的免疫学和合成致命方法诱导活动并确定其杀死Apobec阳性癌症的能力。我们预计我们的调查结果将独特地定位我们的团队启动临床试验测试特定诊断方法 APOBEC阳性肿瘤，以防止对内分泌疗法的抗性发展，并针对 ER阳性内分泌抗性转移性乳腺癌的最大子集。