Core B

核心B

• 批准号: 10474991
• 负责人: Douglas Yee
• 金额: $ 31.63万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/10474991
• 关键词: Adjuvant; Advanced Development; Alleles; Animal Model; Animals; Aromatase Inhibition; Benign; Biological Models; Breast Cancer Model; Breeding; CDK4 gene; Cell Cycle Inhibition; 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; Genomic DNA; Goals; Heterogeneity; Human; Immunocompetent; Introns; Malignant Neoplasms; Mammary Neoplasms; Modeling; Mus; Mutagenesis; Mutate; Mutation; Neoplasm Metastasis; Nuclear; Outcome; Pharmaceutical Preparations; Phenotype; Preclinical Testing; Primates; Process; Proteins; Publishing; RNA analysis; Recurrence; Reporting; Research Personnel; Resistance; Role; Scientist; Services; Source; Study models; Survival Rate; System; Tamoxifen; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Work; Xenograft Model; Xenograft procedure; anticancer research; breast cancer survival; chemical carcinogen; clinical translation; deprivation; design; driver mutation; effective therapy; exome sequencing; experimental study; hormone therapy; improved; in vivo; in vivo Model; inhibitor; innovation; insight; mRNA Expression; malignant breast neoplasm; malignant phenotype; mammary; mouse model; mutant; overexpression; prevent; programs; resistance mechanism; success; therapy development; transcriptome sequencing; tumor

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 摘要 累积的突变通常是恶性表型和治疗发展的原因 雌激素受体（ER）阳性乳腺癌的耐药性。我们已经证明，DNA的APOBEC家族 胞嘧啶脱氨酶是乳腺癌，特别是ER阳性乳腺癌中突变的重要来源。 疾病一个家族成员APOBEC 3B（A3 B）过表达，与侵袭性 表型，表现为早期疾病复发和他莫昔芬的临床益处降低。我们有 在异种移植模型中证实了这些临床数据，其中A3 B消耗增加并且过表达 随着时间的推移，他莫昔芬的益处减少。因为小鼠缺乏与人类A3 B酶相当的酶， 因为动物模型对于提供更有效的乳腺癌治疗的长期目标至关重要， 由APOBEC突变过程驱动的肿瘤，核心B将开发供该计划使用的动物模型 团队，其合作者和更大的癌症研究社区。这一目标将通过2 明确的目标。目标1将建立在我们发表的和初步的结果，并推进ER的发展- 用于研究对雌激素剥夺的抗性的阳性异种移植物模型（模拟芳香酶抑制）， 细胞周期抑制（CDK 4/6抑制）和选择性雌激素受体降解剂。目标2将推动 通过测定Cre诱导的A3 B小基因的表达， 这种酶在现有遗传背景中的乳腺特异性表达的影响， 乳腺肿瘤目标1和2中最稳健的A3 B驱动模型将用于测试候选A3 B 抑制剂来自项目2和3以及核心C & D领导的泛计划工作。我们希望Core B型号 通过提供我们的项目团队，其合作者和更大的癌症研究来产生很大的影响 社区与强大的动物模型，以询问APOBEC突变过程在体内，这将是 对于临床转化和最终提高乳腺癌存活率至关重要。