Loss of NF1 drives hormone dependent mammary carcinogenesis in a rat model with intact immune system

在具有完整免疫系统的大鼠模型中，NF1的缺失会导致激素依赖性乳腺癌发生

基本信息

批准号：
10642882
负责人：
ROBERT A KESTERSON
金额：
$ 53.62万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642882
关键词：
Acceleration Address Advanced Development Affect Age Alleles Base Pairing Binding Breast Cancer Patient Cell Line Cell Proliferation Cells Clinical Data Data Set Databases Development Disease Drug Targeting Estrogen Antagonists Estrogen Receptors Estrogens Evaluation Female Future Genes Genetic Transcription Genotype Goals Growth Harvest Heterozygote Histology Histopathology Hormone Receptor Hormones Human Human Biology Immune Immune Targeting Immune system Immunotherapy In Vitro Knock-in Knock-out Lead MAP Kinase Gene MEKs Macrophage Maintenance Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Mutation NF1 gene NF1 mutation Oncogenic Outcome Ovariectomy Partner in relationship Pathogenicity Patients Phenotype Play Population Pre-Clinical Model Pregnancy RAS driven tumor Rattus Receptor Signaling Resistance Role Sampling Signal Transduction Spinal Syndrome Tamoxifen Testing The Cancer Genome Atlas Therapeutic Time Tissues Tumor Cell Line Validation Variant Vertebral column Xenograft Model antagonist biobank cancer biomarkers cancer risk cancer type cell type differential expression genetic corepressor hormonal signals hormone therapy in vivo inhibitor lung lesion malignant breast neoplasm mouse model mutant neoplastic novel novel marker novel therapeutics patient derived xenograft model pre-clinical prognostic prognostic indicator public database response response biomarker synergism targeted treatment therapeutic evaluation therapeutic target therapy resistant transcriptome sequencing treatment response tumor tumor growth tumor initiation tumor microenvironment

项目摘要

Loss of NF1 plays a major role as an oncogenic driver in many cancer types and can be found in up to 33% of all breast cancers (BC). Loss of NF1 is also a prognostic indicator for increased cancer risk at an earlier age, poorer outcomes, and therapeutic resistance. In addition, certain NF1 genotypes may increase cancer risks, while others do not. NF1 is largely perceived as a classic Ras-opathy syndrome due to inactivating mutations in neurofibromin affecting Ras-MAPK signaling. However, recently it has been shown that NF1 binds estrogen receptor (ER) and acts as a transcriptional corepressor. This helps explain some of these BC findings specifically in ER+ BC patients. In this model, specific changes to NF1 that abrogate ER signaling lead to Ras driven tumor resistance to endocrine therapy in up to 20% of ER+ patients as cells are able to grow in low levels of E2 (and tamoxifen). We have generated novel rat models deficient for Nf1 that have a very robust ER+ BC phenotype, therefore more closely recapitulating clinical tumors compared to other preclinical models. Our models include a pathogenic patient missense allele c.3827G>A, p.R1276Q (knockin or KI), associated in humans with spinal NF1 and malignancy, as well as a 14 base pair deletion c.3661_3674del, p.P1220fs*1223 (knockout or KO) model. Phenotypic differences between our models indicate that the variant matters, and restriction of tumor development to pregnancy in the KI females indicates hormone induction plays a major role in tumor development. Rats also develop lung lesions positive for metastatic BC markers. Our overall goal is to characterize the phenotype of these rat models in terms of histopathology, Ras signaling, hormone signaling, immune components, and targeted drug response and compare/contrast them with what is known regarding patients with somatic or germline inactivation of NF1 and breast cancer. Ultimately, this will provide better prognostic predictions for patients and better therapeutics for treatment. Aim 1 will evaluate tumor onset, growth, histology, and molecular characterization of Ras and estrogen signaling over time and compare/contrast with human BC tumor samples. Aim 2 will characterize the Nf1 deficient tumor microenvironment (TME), identify immuno-targets, and evaluate immuno-targeting with and without Ras-targeting therapeutics. Aim 3 will evaluate the role of hormones in tumor initiation, maintenance and targeting therapeutics. We will better define which hormone(s) drive both initiation and maintenance of mammary tumors deficient for Nf1 and utilize this information to target them both with and without co-targeting Ras to show synergy. As HR+ BC accounts for ~80% of patient cases, and that appropriate mammalian models with intact immune systems are lacking, we believe that our proposed studies are highly significant and will substantially advance the development of new therapies to this disease.

NF1 缺失在许多癌症类型中作为致癌驱动因素发挥着重要作用，高达 33% 的癌症中都存在 NF1 缺失。所有乳腺癌 (BC)。 NF1 缺失也是早期癌症风险增加的一个预后指标，较差的结果和治疗耐药性。此外，某些 NF1 基因型可能会增加癌症风险，而其他人则不然。 NF1 在很大程度上被认为是一种典型的 Ras 病综合征，原因是 NF1 失活突变神经纤维蛋白影响 Ras-MAPK 信号传导。然而，最近有研究表明 NF1 与雌激素结合受体（ER）并充当转录辅阻遏物。这有助于具体解释 BC 的一些发现 ER+ BC 患者。在此模型中，NF1 的特定变化消除了 ER 信号传导，导致 Ras 驱动的肿瘤高达 20% 的 ER+ 患者对内分泌治疗产生耐药性，因为细胞能够在低水平的 E2 中生长（并且他莫昔芬）。我们已经生成了 Nf1 缺陷的新型大鼠模型，其具有非常强大的 ER+ BC 表型，因此，与其他临床前模型相比，它更准确地再现了临床肿瘤。我们的型号包括致病性患者错义等位基因 c.3827G>A，p.R1276Q（敲入或 KI），与脊髓 NF1 人类相关和恶性肿瘤，以及 14 个碱基对缺失 c.3661_3674del、p.P1220fs*1223（敲除或 KO）模型。我们的模型之间的表型差异表明变异很重要，并且肿瘤的限制 KI 雌性从发育到妊娠表明激素诱导在肿瘤发生中起重要作用发展。大鼠还会出现转移性 BC 标记物阳性的肺部病变。我们的总体目标是从组织病理学、Ras 信号传导、激素信号传导等方面表征这些大鼠模型的表型，免疫成分和靶向药物反应，并将它们与已知的相关内容进行比较/对比 NF1 体细胞或种系失活和乳腺癌患者。最终，这将提供更好的患者的预后预测和更好的治疗方法。目标 1 将评估肿瘤的发生、生长、 Ras 和雌激素信号随时间的组织学和分子特征，并与人类 BC 肿瘤样本。目标 2 将描述 Nf1 缺陷肿瘤微环境 (TME) 的特征，确定免疫靶标，并评估使用和不使用 Ras 靶向治疗的免疫靶向。目标3将评估激素在肿瘤发生、维持和靶向治疗中的作用。我们将更好地定义哪种激素可驱动缺乏 Nf1 的乳腺肿瘤的发生和维持，并利用该激素信息来靶向它们，无论是否共同靶向Ras，以显示协同作用。由于 HR+ BC 占约 80% 的患者病例，并且缺乏具有完整免疫系统的适当哺乳动物模型，我们相信我们提出的研究具有非常重要的意义，将极大地推动新的开发针对这种疾病的治疗方法。