Developing and credentialing murine models of ILC

本申请是对特别利益通知(NOSI)的回应 被确认为NOT-CA-23-045，并根据父母奖R01CA252378和肿瘤学 模特论坛。 浸润性小叶乳腺癌(ILC)是乳腺癌中第二常见的特殊组织亚型。 在美国，乳腺癌每年高达4万例，如果被认为是 在女性最常见的癌症中，独立恶性肿瘤排第六位。E-钙粘蛋白(CDH1)的丢失 是ILC的病原学特征，在95%以上的病例中在蛋白水平上丢失。我们 最近报道的30,000例乳腺癌的临床结果表明，患有乳腺癌的患者 与非特殊类型(NST)相比，ILC复发较晚，预后较差 (1)。尽管大量研究表明独特的临床、组织病理学和分子生物学 ILC的特点、临床试验和指南大多忽略了ILC和治疗的独特方面 NST和ILC作为一种单一的疾病，这个问题已经被乳房认识到并表达出来 癌症倡导者社区。 与NST相比，ILC的研究不足，部分原因是可获得的模型有限，以及 缺乏认证来识别那些忠实地代表人类疾病的人。因此，它 目前尚不清楚哪些ILC模型最适合用于临床意义的测试 问题。我们的团队在ILC模型开发方面处于领先地位， ILC细胞系、患者来源的有机物(PDO)和患者来源的特征 异种移植物(PDX)。我们致力于持续开发、认证和共享 ILC的新模型。作为NCI肿瘤模型论坛和NCI R01CACA252378的一部分，我们 已经建立并鉴定了在2D和大量PDO中生长的ILC细胞系模型。在这 补充我们将开发和认证ER+乳腺癌的新小鼠模型， 具有临床相关ILC基因驱动因素的小鼠及其突变的转基因表达研究 雌激素受体。我们还将开发和认证老鼠衍生的有机化合物以供起诉 其他研究人员。通过这种方式，我们的目标是加快ILC的研究。

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045 and under the parent award R01CA252378 and the Oncology Models Forum. Invasive lobular breast cancer (ILC) is the second most common special histological subtype of breast cancer accounting for up to 40,000 cases yearly 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, being lost at the protein level in over 95% of cases. We recently reported clinical outcomes in >30,000 cases of breast cancer showing that patients with ILC suffer from late recurrences and worse outcome compared to the No Special Type (NST) (1). 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 NST and ILC as a single disease, a problem that has been recognized and voiced by the breast cancer advocate community. ILC is understudied compared to NST, in part due to the limited availability of models and to a paucity of credentialing to identify those that faithfully represent the human disease. As such, it is currently unclear which ILC models are most appropriate to test clinically meaningful questions. Our team is at the forefront of ILC model development with generation and characterization of ILC cell lines, patient-derived organoids (PDO) and patient derived xenografts (PDX). We are committed to continued development, credentialing and sharing of novel models of ILC. As part of the NCI Oncology Models Forum and NCI R01CACA252378 we have developed and characterized ILC cell line models grown in 2D and numerous PDO. In this supplement we will develop and credential novel mouse models of ER+ mammary cancer, studying mice with clinically relevant ILC genetic drivers and transgenic expression of mutant estrogen receptor. We will also develop and credential mouse-derived organoids for sue by other researchers. In this way we aim to accelerate ILC research.