Targeting the Epithelial Type II Interleukin-4 Receptor in Metastatic Breast Cancer
Abstract
There is no arguing the urgent need for effective approaches to thwart metastatic breast cancer. Therefore, the overarching challenge on which we are focused is to eliminate the mortality associated with metastatic breast cancer. Metastasis is complex and consists of many steps, but ultimately requires that tumor cells survive and grow in organs very dissimilar to the breast. The goal of this proposal is to investigate whether targeting of a particular protein that is increased in breast cancer cells will prevent metastatic cells from adapting and growing in stressful environments. This protein, called "type II IL4 receptor," appears to give cancer cells the ability to fine-tune or adapt their metabolism so that they can survive and grow even when available nutrients are limited. Since every cell in the body, both normal and cancer, uses the same basic metabolic mechanisms, it is difficult to directly target cancer cell metabolism. However, because of their rapid growth and other energy-using activities, cancer cells are especially dependent on particular metabolic pathways. We believe, and already have some evidence, that type II IL4 receptor is partly responsible for increasing metabolic activity in cancer cells. Therapeutic inhibition of type II IL4 receptor would then provide a means to target metastatic tumor cells and potentially disable their metabolic adaptations. Unfortunately, there is another very similar protein -- type I IL4 receptor -- present on B and T white blood cells that is important for proper functioning of the immune system. Until now, it has been impossible to specifically target type II IL4 receptor without also impacting type I IL4 receptor. However, we now have reagents called "IL4 superkines" that were developed to discriminate between these two related proteins. We will use humanized mouse models to test if these new reagents truly can target breast cancer cells while sparing immune cells. This would be important to prevent unwanted side effects. PET (positron emission tomography) imaging, which is widely used clinically, is based on detecting uptake of nutrients such as glucose by cancer cells. It can potentially be used as a method to monitor the effect of blocking type II IL4 receptor on cancer cells. We will therefore examine the utility of PET imaging as a readout of treatment success in mouse models. The final part of our proposal is to identify exactly what metabolic pathways are under the control of type II IL4 receptor and to test whether interfering with these pathways together with blocking type II IL4 receptor would be highly lethal to metastatic cancer cells. At the conclusion of this project, we expect to have identified a new therapeutic agent for metastatic breast cancer and an associated imaging approach that can be used for monitoring treatment efficacy in patients. We envision that the new superkine agents being tested here could proceed rapidly to clinical trials based on successful completion of these studies since there is already a company developing them for other diseases. For initial clinical trials, the target patient population would be women diagnosed with invasive breast cancer, particularly of the aggressively metastatic basal subtype. Ultimately, however, IL4 superkines could be used to block progression to metastatic disease whenever this is a possibility.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610559
Entities
People
- Barbara Mary Fingleton
Organizations
- United States Army
- Vanderbilt University