Credentialing Models of Invasive Lobular Breast Cancer for Translational Research

用于转化研究的侵袭性小叶乳腺癌模型认证

基本信息

批准号：
10589777
负责人：
Adrian V Lee
金额：
$ 57.03万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589777
关键词：
Advocate Affect Bioinformatics Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis CRISPR screen Cancer Advocacy Cancer Biology Cancer cell line Cell Culture Techniques Cell Line Cells Characteristics Clinical Clinical Trials Collaborations Communities Credentialing Data Dependence Development Disease Drug Screening Duct (organ) structure E-Cadherin Encyclopedias Endocrine Estrogen receptor positive Future Gastrointestinal tract structure Generations Genetic Engineering Genetically Engineered Mouse Genomics Genotype Goals Growth Guidelines Histologic Histopathology Human Human Biology Immune checkpoint inhibitor Immune system Immunology Immunotherapy In Vitro Infiltration Invaded Isogenic transplantation Lobular Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Maps Medical Oncology Modeling Molecular Molecular Profiling Mus Neoplasm Metastasis Oncology Organoids Ovarian Ovary Pathology Patient-Focused Outcomes Patient-derived xenograft models of breast cancer Patients Pattern Peritoneum Phenotype Quality of life Recurrence Reporting Resistance Resources Rodent Rodent Model Site Testing Treatment Efficacy Validation Voice Woman Work Xenograft procedure cancer clinical trial clinically relevant cohort drug sensitivity efficacy study epigenomics gastrointestinal homograft hormone therapy human disease immune cell infiltrate immune checkpoint blockade improved improved outcome in vivo innovation malignant breast neoplasm member model development molecular phenotype mortality multidisciplinary novel patient derived xenograft model response targeted treatment transcriptomics translational applications translational cancer research treatment response tumor growth urogenital tract

项目摘要

Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after the more common invasive ductal breast cancer (IDC). In 2020, ILC will affect up to 40,000 patients in the US, and if considered an independent malignancy is the 6th most frequent cancer in women. Loss of E-cadherin (CDH1) is the pathognomonic feature of ILC, which leads to a single-file pattern infiltration of small discohesive cells into the stroma. Patients with ILC suffer from late recurrences and metastasis to unique sites such as the urogenital tract (e.g. ovary) and the gastrointestinal (GI) tract (e.g. peritoneum). Despite numerous studies showing unique clinical, histopathological, and molecular features of ILC, clinical trials and guidelines mostly ignore the unique aspects of ILC, and treat IDC and ILC as a single disease. Our long-term goal is to improve outcome for patients with ILC, a disease associated with limited understanding and representing a great unmet clinical need. ILC is currently understudied at least in part due to a lack of credentialed models and it is currently unclear which ILC models are most appropriate to test clinically meaningful questions. We will collaborate with the Cancer Dependency Map Project (DepMap - CCLE) and members of PDXNet to comprehensively credential ILC models. We have established a team with complementary expertise in ILC biology, rodent modeling, bioinformatics, immunology, pathology, medical oncology, and breast cancer advocacy and will use innovative validation strategies to cross-compare in vitro and in vivo translational ILC models. Our goal is to create a robust set of well-curated models that are credentialed to provide translationally reliable information for evaluating targeted therapies in primary and metastatic ILC. In Aim 1 we will molecularly characterize ILC models and compare them to human ILC. This will include 19 ILC or ‘ILC-like’ cell lines, 20 primary ILC organoids, 8 patient derived xenografts, 2 homograft rodent models and 3 genetically engineered mouse models (GEMM). We will assess histopathology and perform comprehensive genomic, epigenomic and transcriptomic analyses. In Aim 2 we will focus on in vitro growth phenotypes and in vivo metastasis to determine which models recapitulate the unique growth pattern seen in human ILC. Since we have recently sequenced unique sites of ILC metastasis (ovary, GI) in the human disease, we will compare the molecular profile of our metastasis models to human ILC metastasis. Finally, Aim 3 will focus on therapeutic efficacy. We will work with the Broad Institute to perform CRISPR and drug screening on ILC cell lines and organoids and make all data available in the DepMap portal. In vivo we will assess endocrine therapy response in homografts and compare the results to an ongoing ILC clinical trial led by our group. We will also characterize the immune cell infiltrate and response to checkpoint inhibitors in homograft rodent ILC models in order to assess their suitability for the study of therapies targeting the immune system.

侵入性小叶乳腺癌（ILC）是仅次于乳腺癌的第二常见组织学亚型更常见的浸润性导管乳腺癌（IDC）。在2020年，ILC将影响美国多达40,000名患者，以及如果被认为是独立的恶性肿瘤，则是女性中最常见的癌症。 E-钙粘蛋白的丧失（CDH1）是ILC的病理特征，它导致小脱粘的单文件模式浸润细胞进入基质。 ILC患者遭受迟到的回报和转移到独特场所的转移泌尿生殖道（例如卵巢）和胃肠道（GI）道（例如腹膜）。尽管进行了许多研究显示ILC的独特临床，组织病理学和分子特征，临床试验和准则主要是忽略ILC的独特方面，而将IDC和ILC视为一种疾病。我们的长期目标是改善 ILC患者的结局，这种疾病与有限的理解有关，代表了良好的未得到的疾病临床需求。目前，ILC至少部分是由于缺乏证书模型而被理解的，这是目前尚不清楚哪种ILC模型最适合测试临床上有意义的问题。我们将与癌症依赖图项目（DEPMAP -CCL）和PDXNET成员合作全面的ILC模型。我们已经建立了一个具有ILC完善专业知识的团队生物学，啮齿动物建模，生物信息学，免疫学，病理学，医学肿瘤学和乳腺癌倡导，并将使用创新验证策略在体外和体内翻译ILC交叉跨能力型号。我们的目标是创建一组强大的策划模型，这些模型具有符合认证的方式，可以翻译可靠的信息，用于评估原发性和转移性ILC中的靶向疗法。在AIM 1中，我们将分子表征ILC模型并将其与人类ILC进行比较。这将包括19 ILC 或“ ILC样”细胞系，20个主要ILC类器官，8例患者衍生Xenographictics，2个同源啮齿动物模型和3个基因工程的小鼠模型（GEMM）。我们将评估组织病理学并进行全面基因组，表观基因组和转录组分析。在AIM 2中，我们将专注于体外生长表型和体内转移确定哪些模型概括了人ILC中看到的独特生长模式。自从我们最近对人类疾病中ILC转移（卵巢，GI）的独特部位进行了测序，我们将比较我们转移模型对人ILC转移的分子谱。最后，AIM 3将重点放在治疗效率。我们将与Broad Institute合作，对ILC细胞进行CRISPR和药物筛查线条和器官，使所有数据在DepMap门户网站中可用。在体内我们将评估内分泌疗法同种移植物的反应，并将结果与我们小组领导的正在进行的ILC临床试验进行了比较。我们也会表征免疫球浸润和对同种体啮齿动物ILC模型中检查点抑制剂的响应为了评估他们对针对免疫系统的疗法研究的适用性。