Leveraging genetic mapping for personalized targeting of breast cancer microenvironment

点击翻译按钮获取中文摘要

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.