Role of IL13RA2 as a Functional Biomarker in Breast Cancer Brain Metastasis
Abstract
Brain metastases are a significant problem in breast cancer patients, since as many as 16% will suffer of this type of metastasis, and about 80% of them will die within in year of diagnosis. Among the different types of breast tumors, patients who have tumors lacking hormone receptors (also known as triple-negative) and those expressing high levels of HER2 (HER2+) are likely to develop brain metastasis. In the search for molecules that are associated with the ability of breast cancer cells to growth in the brain, investigators have found that a receptor for IL-13 known as IL13RA2 is expressed in cell lines adapted to the brain microenvironment. However, there are no further studies to investigate how IL13RA2 works or what is its contribution to brain metastases. Importantly, IL13RA2 is expressed in very aggressive primary brain tumors (i.e., glioblastoma) but not in the normal brain, and there are current clinical trials using this receptor to treat such tumors. Therefore, we hypothesize that IL13RA2 plays a role in the ability of breast cancer cells to grow in the brain and constitutes a novel therapeutic target for the treatment of brain metastases. If this premise is correct, anti-IL13RA2 therapies that are already in clinical trials could be used to target brain metastatic cells and decrease metastatic tumor burden in breast cancer patients. To test this hypothesis, we will perform experiments to determine if IL13RA2 can alter the ability of brain metastatic cells to migrate, invade, and proliferate and to elucidate what are the signals activated by IL13RA2 responsible for these effects (Aim 1). We will also measure the ability of cells that express high and low levels of IL13RA2 to colonize the brain using mouse models and novel patient-derived tumors (Aim 2). Finally, we will measure IL13RA2 in brain metastases from de-identified consenting patients to determine if IL13RA2 expression is frequent in brain metastatic tumors so that can be considered a target for clinical trials (Aim 3). In the long term, this proposal will give us information as how IL13RA2 functions in the context of the brain and could serve to elucidate new targets for future therapeutics. Importantly, these studies are likely to have short-term benefits for patients affected by brain metastasis, because it will allow us to determine if IL13RA2 expression is frequent enough to be useful as a therapeutic target for brain metastatic tumors for which there are not current targeted therapies. Therefore, it can have immediate effects in the treatment of patients with brain metastasis for which there are no current therapies available. In summary, this proposal addresses at least two overarching challenges in breast cancer research: (1) it will examine a novel mechanism responsible for growth of brain metastases and (2) it can revolutionize treatment of brain metastasis by using anti-IL13RA2-targeted therapies that are already in clinical trials; therefore, it has the potential to eliminate the mortality associated with brain metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510352
Entities
People
- Diana M Cittelly
Organizations
- United States Army
- University of Colorado Denver