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.

在许多癌症类型中，NF1的损失在多达33％的癌症类型中起着致癌驱动力的主要作用所有乳腺癌（BC）。 NF1的丧失也是较早年龄癌症风险增加的预后指标，较差的结果和治疗性抗性。此外，某些NF1基因型可能会增加癌症风险，而其他人则没有。由于在神经纤维蛋白影响RAS-MAPK信号传导。但是，最近已经显示NF1结合雌激素受体（ER），充当转录核心。这有助于解释其中一些BC的发现在ER+ BC患者中。在此模型中，对NF1的具体变化，废除ER信号导致RAS驱动肿瘤由于细胞能够在低水平的E2（和他莫昔芬）。我们已经生成了缺乏具有非常健壮的ER+ BC表型的NF1缺乏的新型大鼠模型，因此，与其他临床前模型相比，更紧密地概括了临床肿瘤。我们的模型包括致病患者错过等位基因C.3827G> A，P.R1276Q（敲击或Ki），与脊髓NF1的人类有关和恶性肿瘤，以及14个基对删除C.3661_3674DEL，P.P1220FS*1223（淘汰或KO）型号。我们的模型之间的表型差异表明变异很重要，肿瘤的限制 Ki女性的妊娠发育表明激素诱导在肿瘤中起主要作用发展。大鼠还会发展为转移性BC标记阳性的肺病变。我们的总体目标是以组织病理学，RAS信号，激素信号传导的方式表征这些大鼠模型的表型免疫成分和针对药物反应，并将其与已知的相比 NF1和乳腺癌的体细胞或种系失活的患者。最终，这将提供更好的对患者的预后预测和更好的治疗治疗方法。 AIM 1将评估肿瘤发作，生长，随着时间的推移，RAS和雌激素信号传导的组织学和分子表征，并将/对比与人BC肿瘤样品。 AIM 2将表征NF1缺乏肿瘤微环境（TME），识别免疫目标，并在没有RAS靶向治疗的情况下评估免疫目标。目标3意志评估激素在肿瘤启动，维持和靶向治疗中的作用。我们将更好地定义哪种激素（S）驱动了缺乏NF1的乳腺肿瘤的启动和维持信息以在有或没有共同目标的RAS的情况下针对它们以显示协同作用。作为人力资源+ BC的帐户〜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，我们认为我们拟议的研究非常重要，并将大大推动新的发展治疗这种疾病。