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Core B

核心B

基本信息

批准号：
9804095
负责人：
Douglas Yee
金额：
$ 25.09万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-09 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9804095
关键词：
Adjuvant Advanced Development Alleles Animal Model Animals Antiviral Agents Aromatase Inhibition Benign Biological Models Breast Breast Cancer Model Breeding CDK4 gene Cell Cycle Inhibition Cells Chemicals Clinical Clinical Data Communities Copy Number Polymorphism Cytosine deaminase DNA Development Disease Drug resistance Ensure Enterobacteria phage P1 Cre recombinase Enzymes Estrogen Receptors Estrogen receptor positive Estrogens Evolution FDA approved Family Family member Genes Genetic Genetically Engineered Mouse Genomics Goals Heterogeneity Human Image Immune Introns Malignant Neoplasms Mammals Mammary Neoplasms Mammary gland Modeling Mus Mutagenesis Mutate Mutation NIH 3T3 Cells Neoplasm Metastasis Nuclear Outcome Pharmaceutical Preparations Phenotype Preclinical Testing Primates Process Proteins Publishing RNA analysis Recurrence Reporting Research Personnel Resistance Rodent Role Scientist Services Source Study models Survival Rate System Tamoxifen Testing Therapeutic Time Tissues Transgenic Organisms Work Xenograft Model actionable mutation anticancer research breast cancer survival clinical translation deprivation design effective therapy exome sequencing experimental study hormone therapy improved in vivo in vivo Model inhibitor/antagonist innovation insight mRNA Expression malignant breast neoplasm malignant phenotype mouse model mutant overexpression prevent programs resistance mechanism success therapy development transcriptome sequencing tumor

项目摘要

CORE B – MURINE MODELS ABSTRACT Accumulated mutations are often responsible for malignant phenotypes and the development of therapy resistance in estrogen receptor (ER)-positive breast cancer. We have shown that the APOBEC family of DNA cytosine deaminases is an important source of mutation in breast cancer and particularly in ER-positive disease. One family member, APOBEC3B (A3B), is overexpressed and associated with aggressive phenotypes, manifesting as early disease recurrence and decreased clinical benefit from tamoxifen. We have corroborated these clinical data in a xenograft model in which A3B depletion increases and overexpression decreases benefit from tamoxifen over time. Because mice lack an equivalent to the human A3B enzyme, and because animal models will be vital for the long-term goal of providing more effective treatments for breast tumors driven by the APOBEC mutational process, Core B will develop animal models for use by the Program team, its collaborators, and the greater cancer research community. This goal will be achieved through 2 specific aims. Aim 1 will build on our published and preliminary results and advance the development of ER- positive xenograft models for studies on resistance to estrogen deprivation (modeling aromatase inhibition), cell cycle inhibition (CDK4/6 inhibition), and selective estrogen receptor degraders. Aim 2 will advance the development of genetically engineered mouse models with a Cre-inducible A3B minigene by determining the impact of mammary-specific expression of this enzyme in existing genetic backgrounds predisposed to mammary tumors. The most robust A3B-driven models from Aims 1 and 2 will be used to test candidate A3B inhibitors derived from pan-Program efforts led by Projects 2 & 3 and Cores C & D. We expect Core B models to have a high impact by providing our Program team, its collaborators, and the greater cancer research community with robust animal models to interrogate the APOBEC mutation process in vivo, which will be essential for clinical translation and ultimately improving breast cancer survival rates.

核心 B – 小鼠模型抽象的累积的突变通常导致恶性表型和治疗的发展雌激素受体（ER）阳性乳腺癌的耐药性。我们已经证明 APOBEC DNA 家族胞嘧啶脱氨酶是乳腺癌尤其是 ER 阳性乳腺癌突变的重要来源疾病。一名家族成员 APOBEC3B (A3B) 过度表达并与攻击性相关表型，表现为早期疾病复发和他莫昔芬的临床获益降低。我们有在异种移植模型中证实了这些临床数据，其中 A3B 消耗增加和过度表达随着时间的推移，他莫昔芬的益处会减少。因为小鼠缺乏与人类 A3B 酶相当的酶，并且因为动物模型对于提供更有效的乳腺治疗的长期目标至关重要由 APOBEC 突变过程驱动的肿瘤，Core B 将开发供该计划使用的动物模型团队、其合作者以及更大的癌症研究界。这一目标将通过2 具体目标。目标 1 将建立在我们已发表的初步结果的基础上，推动 ER-的发展用于研究雌激素剥夺抵抗力的阳性异种移植模型（模拟芳香酶抑制），细胞周期抑制（CDK4/6 抑制）和选择性雌激素受体降解剂。目标 2 将推进通过确定具有 Cre 诱导型 A3B 小基因的基因工程小鼠模型的开发该酶在现有遗传背景下的乳腺特异性表达的影响乳腺肿瘤。目标 1 和 2 中最强大的 A3B 驱动模型将用于测试候选 A3B 抑制剂源自项目 2 和 3 以及核心 C 和 D 领导的泛计划工作。我们预计核心 B 模型通过提供我们的项目团队、合作者和更广泛的癌症研究来产生巨大影响社区拥有强大的动物模型来探究体内 APOBEC 突变过程，这将是对于临床转化和最终提高乳腺癌生存率至关重要。