Leveraging genetic mapping for personalized targeting of breast cancer microenvironment

乳腺癌是最常见的女性恶性肿瘤，具有高度遗传性，但大多数乳腺癌 风险仍未确定。遗传因素是乳腺癌风险的大多数方面的基础[例如，年龄发生率 发病、转移进展和无病生存期]。除了直接影响肿瘤细胞的变异之外， (i.e.,致瘤性），遗传性涉及肿瘤微环境的多个组分[例如， 组织重塑、血管生成和免疫]，其也影响肿瘤发生和进展。然而，在这方面， 肿瘤微环境差异背后的遗传变异很少成为肿瘤微环境研究的焦点。 基因图谱研究，因此，仍然没有明确的定义。在父R 01项目中，我们定义了 结果表明，Notch-DLL 4基因在盐敏感大鼠中的表达， 控制肿瘤增殖、转移以及纳米颗粒摄取和人类治疗反应 肿瘤异种移植物这些发现是通过利用一种新的乳腺癌模型得出的 （称为同源异种移植模型- CXM），其专注于菌株特异性变体的遗传作图 通过肿瘤微环境影响肿瘤进展。一只普通的老鼠是一个完整的 通过选择育种将染色体渗入另一个近交系的等基因背景中。因此，在本发明中， 观察到的表型可以与单染色体相关联，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物。在CXM中，经济和 亲本菌株转化为SCID（严重联合免疫缺陷）， 异种移植的人乳腺癌细胞可以在体内测试。因为人类乳腺癌细胞 不同菌株之间的差异，乳腺癌进展和转移，药物递送， 治疗反应或耐药仅仅是由于肿瘤微环境的遗传差异，而不是 恶性癌细胞。我们将利用我们发现的notch-DLL 4表达差异在 纳米载体摄取、分布和治疗反应，以及同源和同类大鼠品系，以评估： (1)明确肿瘤内皮细胞的形态学特征和调控药物的分子机制 载体的渗透、滞留和清除及其对遗传基因的依赖性（2） 用三种纳米颗粒介导的药物递送系统共靶向肿瘤内皮细胞中的notch-DLL 4， 一组代表性乳腺癌患者的纳米颗粒转运、肿瘤分布和治疗反应 模型系统，和（3）证明遗传性肿瘤微环境靶向治疗远端肿瘤的作用。 免疫功能低下和免疫活性正常的大鼠品系中的转移性疾病。这些研究将 提供了对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

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.