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

• 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
• 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

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.

浸润性小叶乳腺癌（ILC）是继乳腺癌之后的第二种最常见的乳腺癌组织学亚型。 更常见的浸润性导管乳腺癌（IDC）。到2020年，ILC将影响美国多达40，000名患者， 如果被认为是一种独立的恶性肿瘤，则是女性中第六常见的癌症。E-钙粘蛋白丢失 （CDH 1）是ILC的特征性特征，其导致小的不粘聚物的单行模式渗透 细胞进入基质。ILC患者患有晚期复发和转移到独特部位，如 泌尿生殖道（例如卵巢）和胃肠道（GI）（例如腹膜）。尽管有许多研究 显示ILC独特的临床、组织病理学和分子特征，临床试验和指南大多 忽视ILC的独特方面，并将IDC和ILC视为单一疾病。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， 临床需要ILC目前研究不足，至少部分原因是缺乏认证模型， 目前尚不清楚哪种ILC模型最适合测试有临床意义的问题。 我们将与癌症依赖地图项目（DepMap - CCLE）和PDXNet成员合作， 全面认证ILC模型。我们已经建立了一个团队，在ILC方面具有互补的专业知识 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 并将使用创新的验证策略来交叉比较体外和体内翻译的ILC 模型我们的目标是创建一组强大的精心策划的模型，这些模型经过认证，可以提供 评估原发性和转移性ILC靶向治疗的可靠信息。 在目标1中，我们将从分子上表征ILC模型，并将其与人类ILC进行比较。这将包括19个国际劳工委员会 或“ILC样”细胞系，20个原代ILC类器官，8个患者来源的异种移植物，2个同种移植啮齿动物模型和3个 基因工程小鼠模型（GEMM）。我们将评估组织病理学并进行全面的 基因组、表观基因组和转录组分析。在目标2中，我们将重点关注体外生长表型， 体内转移，以确定哪些模型概括了在人ILC中观察到的独特生长模式。以来 我们最近测序了人类疾病中ILC转移的独特位点（卵巢，GI），我们将比较 我们的转移模型对人ILC转移的分子概况。最后，目标3将侧重于 疗效我们将与布罗德研究所合作，对ILC细胞进行CRISPR和药物筛选 线和类器官，并在DepMap门户网站上提供所有数据。在体内，我们将评估内分泌治疗 并将结果与我们小组领导的正在进行的ILC临床试验进行比较。我们还将 在同种移植啮齿动物ILC模型中表征免疫细胞浸润和对检查点抑制剂的反应， 以评估其对靶向免疫系统的治疗研究的适用性。