Leveraging genetic mapping for personalized targeting of breast cancer microenvironment

利用基因图谱实现乳腺癌微环境的个性化靶向

基本信息

批准号：
10689152
负责人：
AMIT JOSHI
金额：
$ 34.97万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689152
关键词：
Ablation Abraxane Affect Age of Onset Albumins Award Backcrossings Binding Biological Assay Biological Models Blood Vessels Breast Cancer Cell Breast Cancer Model Breast Cancer Risk Factor Breast Cancer cell line Breast Cancer therapy Breeding Cell Line Chromosome 3 Chromosome Mapping Chromosomes Clinical Data Dependence Disease Disease-Free Survival Distant Dose Drug Carriers Drug Delivery Systems Endothelium Environment Estrogen receptor positive Experimental Genetics Extravasation Fatty acid glycerol esters Female Fluorescence Formulation Genes Genetic Germ-Line Mutation Growth Hematogenous Heritability Human Image Imaging Device Immunity Immunocompetent Immunocompromised Host Inbred Strain Incidence Inherited Link Liposomal Doxorubicin Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Maps Measurable Mediating Modeling Molecular Molecular Target Monoclonal Antibodies Morphology Neoplasm Metastasis Neoplasms in Vascular Tissue Non-Malignant Norway Optics Paclitaxel Parents Perfusion Pharmaceutical Preparations Phenotype Proliferating Rat Strains Rat Transgene Rattus Recovery Reporting Research Resistance Role Sequence Analysis Severe Combined Immunodeficiency Signal Transduction Testing Time Tissues Toxic effect Treatment Efficacy Tumor Angiogenesis Tumor Promotion Tumorigenicity Variant Vascular remodeling Xenograft Model Xenograft procedure angiogenesis antibody conjugate breast cancer progression cancer cell cancer therapy causal variant comparative congenic consomic contrast imaging density genetic manipulation genetic variant image guided improved in vivo evaluation innovation insight intravital microscopy malignant breast neoplasm mammary nanoGold nanocarrier nanomedicine nanoparticle nanotherapy neoplastic cell non-invasive imaging notch protein novel overexpression patient derived xenograft model pharmacologic photothermal therapy prognostic prognostic indicator receptor response risk variant salt sensitive therapeutic nanoparticles tool transcriptome sequencing treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumor xenograft tumorigenesis uptake vasculogenesis whole body imaging

项目摘要

Breast cancer is the most prevalent female malignancy and is highly heritable, yet the majority of breast cancer risk remains undefined. Heritable factors underlie most aspects of breast cancer risk [e.g., incidence, age-of onset, metastatic progression, and disease-free survival]. In addition to variants that impact tumor cells directly (i.e., tumorigenicity), heritability is implicated in multiple components of the tumor microenvironment [e.g., tissue remodeling, angiogenesis, and immunity], which also impact tumorigenesis and progression. However, the genetic variant(s) underlying differences in the tumor microenvironment have rarely been the focus of genetic mapping studies and as such, remain poorly defined. In the parent R01 project, we defined these germline factors and discovered the role of notch-DLL4 expression of 3rd Chromosome on salt sensitive rat as governing tumor proliferation, metastasis, as well as nanoparticle uptake and therapy response in human tumor xenografts. These findings were made by leveraging a new model of breast cancer (termed the Consomic Xenograft Model - CXM) that focused on genetic mapping of strain-specific variant(s) that impact tumor progression through the tumor microenvironment. A consomic rat is one in which an entire chromosome is introgressed into the isogenic background of another inbred strain by selective breeding. Thus, observed phenotypes can be linked to single chromosomes and then further elucidated by comparative sequence analysis and/or selective backcrossing to yield smaller congenics. In CXM, the consomic and parental strains are converted to SCID (severe combined immunodeficiency), so that orthotopically xenografted human breast cancer cells can be tested in vivo. Because the human breast cancer cells are not varied between strains, any differences in breast cancer progression and metastasis, drug delivery, and therapy response or resistance are due solely to genetic differences in the tumor microenvironment, not the malignant cancer cells. We will leverage our discovery of the role of notch-DLL4 expression differences on nanocarrier uptake, distribution and therapy response, and the consomic and congenic rat strains to assess: (1) Define the morphologic features and molecular mechanisms in tumor endothelium which govern drug carrier permeation, retention and clearance and their dependence on inherited genes (2) Identify the impact of co-targeting notch-DLL4 in tumor endothelium with three nanoparticle mediated drug delivery systems on nanoparticle transport, tumor distribution, and therapy response in a panel of representative breast cancer model systems, and (3) Demonstrate the role of inherited tumor micro-environment targeting for treating distant metastatic disease in immunocompromised and immunocompetent consomic rat strains. These studies will provide mechanistic insight to the role of the tumor microenvironment in drug delivery and response to nanoparticle therapies.

乳腺癌是女性最常见的恶性肿瘤，具有高度遗传性，但大多数乳腺癌风险仍未明确。遗传因素是乳腺癌风险大多数方面的基础[例如发病率、年龄发病、转移进展和无病生存]。除了直接影响肿瘤细胞的变异之外（即致瘤性），遗传性与肿瘤微环境的多个组成部分有关[例如，组织重塑、血管生成和免疫]，这也影响肿瘤的发生和进展。然而，肿瘤微环境差异背后的遗传变异很少成为研究的焦点遗传图谱研究及其本身的定义仍然不明确。在父 R01 项目中，我们定义了这些种系因子，并发现第三染色体Notch-DLL4表达对盐敏感大鼠的作用控制人体肿瘤增殖、转移以及纳米颗粒摄取和治疗反应肿瘤异种移植物。这些发现是通过利用乳腺癌的新模型得出的（称为Consomic异种移植模型 - CXM），专注于菌株特异性变体的遗传图谱通过肿瘤微环境影响肿瘤进展。健康大鼠是一种具有完整的通过选择性育种，染色体渗入到另一个近交株的同基因背景中。因此，观察到的表型可以与单个染色体联系起来，然后通过比较进一步阐明序列分析和/或选择性回交以产生更小的同源体。在 CXM 中，经济和亲本菌株被转化为 SCID（严重联合免疫缺陷），因此原位异种移植的人类乳腺癌细胞可以在体内进行测试。因为人类乳腺癌细胞不是菌株之间存在差异，乳腺癌进展和转移、药物输送和治疗反应或耐药性仅归因于肿瘤微环境的遗传差异，而不是恶性癌细胞。我们将利用我们对 notch-DLL4 表达差异的作用的发现纳米载体的摄取、分布和治疗反应，以及同体和同类大鼠品系来评估： (1)明确肿瘤内皮细胞的形态特征和药物调控分子机制载体渗透、保留和清除及其对遗传基因的依赖性 (2) 确定与三种纳米颗粒介导的药物递送系统共同靶向肿瘤内皮中的Notch-DLL4 一组代表性乳腺癌中的纳米颗粒转运、肿瘤分布和治疗反应模型系统，以及（3）展示遗传性肿瘤微环境靶向在治疗远处转移中的作用免疫功能低下和免疫功能正常的康体大鼠品系中的转移性疾病。这些研究将提供关于肿瘤微环境在药物递送和响应中的作用的机制见解纳米粒子疗法。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic variations in human papillomavirus and cervical cancer outcomes.

人乳头瘤病毒和宫颈癌结果的遗传变异。

DOI：
发表时间：
2019
期刊：
影响因子：
6.4
作者：
Rader, Janet S;Tsaih, Shirng;Fullin, Daniel;Murray, Miriam W;Iden, Marissa;Zimmermann, Michael T;Flister, Michael J
通讯作者：
Flister, Michael J

SmgGDS is a transient nucleolar protein that protects cells from nucleolar stress and promotes the cell cycle by regulating DREAM complex gene expression.

SmgGDS 是一种瞬时核仁蛋白，可保护细胞免受核仁应激，并通过调节 DREAM 复合物基因表达来促进细胞周期。

DOI：
发表时间：
2017-12-14
期刊：
影响因子：
8
作者：
Gonyo, P;Bergom, C;Brandt, A C;Tsaih, S;Sun, Y;Bigley, T M;Lorimer, E L;Terhune, S S;Rui, H;Flister, M J;Long, R M;Williams, C L
通讯作者：
Williams, C L

Dynamic NIR Fluorescence Imaging and Machine Learning Framework for Stratifying High vs. Low Notch-Dll4 Expressing Host Microenvironment in Triple-Negative Breast Cancer.

动态近红外荧光成像和机器学习框架，用于对三阴性乳腺癌中表达高与低 Notch-Dll4 的宿主微环境进行分层。

DOI：
发表时间：
2023-02-25
期刊：
影响因子：
5.2
作者：
Shafiee, Shayan;Jagtap, Jaidip;Zayats, Mykhaylo;Epperlein, Jonathan;Banerjee, Anjishnu;Geurts, Aron;Flister, Michael;Zhuk, Sergiy;Joshi, Amit
通讯作者：
Joshi, Amit

Erratum: Methods for detecting host genetic modifiers of tumor vascular function using dynamic near-infrared fluorescence imaging: errata.

勘误表：使用动态近红外荧光成像检测肿瘤血管功能的宿主遗传修饰剂的方法：勘误表。

DOI：
发表时间：
2018
期刊：
影响因子：
3.4
作者：
Jagtap, Jaidip;Sharma, Gayatri;Parchur, Abdul K;Gogineni, Venkateswara;Bergom, Carmen;White, Sarah;Flister, Michael J;Joshi, Amit
通讯作者：
Joshi, Amit

Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy.

剪接转换 SmgGDS 同种型的致癌比率作为减少恶性肿瘤的策略。

DOI：
发表时间：
2020
期刊：
影响因子：
11.1
作者：
Brandt, Anthony C;McNally, Lisa;Lorimer, Ellen L;Unger, Bethany;Koehn, Olivia J;Suazo, Kiall F;Rein, Lisa;Szabo, Aniko;Tsaih, Shirng;Distefano, Mark D;Flister, Michael J;Rigo, Frank;McNally, Mark T;Williams, Carol L
通讯作者：
Williams, Carol L