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

• 批准号: 10237883
• 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
• 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/10237883
• 关键词: Affect; Antiviral Agents; Aromatase Inhibitors; Benchmarking; Biochemistry; Bioinformatics; Biological Assay; Biological Markers; Biological Models; Breast Cancer Model; Breast Cancer cell line; Breast Cancer therapy; CDK4 gene; Cancer Model; Caring; Cause of Death; Cell Cycle Inhibition; Cell Line; Cells; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; 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; 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/antagonist; 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

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)阳性的乳腺癌已经治愈 通过多模式的护理，转移性ER阳性乳腺癌仍然是一种致命的疾病。对此的洞察 差异来自于对原发肿瘤和转移肿瘤的比较基因组分析。我们和 其他人已经发现了几个影响转移性癌症中更常见的特定基因的突变 包括ESR1、ERBB2和NF1在内的主要对应基因。这些突变导致对 一线内分泌治疗是ER阳性乳腺癌的主要系统治疗。连 然而，比这些个体突变更令人震惊的是，发现某些“突变特征” 与原发乳腺癌相比，转移性疾病更容易发生。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，并可能导致 突变和它们所传达的转化的表型。从多个大型- 规模测序研究表明，APOBEC突变特征既丰富又高度 在ER阳性的转移性疾病中普遍存在，构成了这些药物的显性突变特征- 耐药并最终致死的癌症。我们的初步数据证实，APOBEC的激活可以促进 内分泌抵抗在ER阳性肿瘤模型中的发展及其与肿瘤特征的关系 APOBEC-许多耐药等位基因的突变改变。总而言之，这些结果指向APOBEC 突变过程是ER阳性转移性乳腺发生和发病的关键驱动因素 癌症与内分泌治疗的抗药性。在这个高度协作和创新的项目中，我们提出了三个 特异性靶向推进APOBEC突变过程作为乳房生物标志物和治疗靶点 癌症。(1)我们将开发和利用稳健的生物信息学方法来检测病毒的存在和时机 从临床NGS肿瘤和游离DNA数据集中发现APOBEC突变特征 (CfDNA)。我们将进一步确定一种有前景的A3B酶的IHC检测方法是否能识别出那些ER阳性的人 癌症可能随后发展为APOBEC突变特征。(2)我们会决定 APOBEC促进内分泌抵抗的机制和动力学。我们将使用等基因细胞系 分析APOBEC引起的耐药类型的模型和患者来源的异种移植 以及它们的时机和内分泌治疗本身是否有助于诱导APOBEC活动。 (3)我们将评估针对APOBEC的肿瘤的免疫学和合成致死方法 活性是被诱导的，并决定它们杀死APOBEC阳性癌症的能力。我们预计我们的 这些发现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，以防止内分泌治疗耐药性的发展，并针对 ER阳性、内分泌耐药转移性乳腺癌的最大亚群。