Diabetes Drives Breast Cancer Metastasis Through RAGE Signaling
Abstract
Breast cancer (BC) is the most commonly diagnosed cancer, and the second leading cause of death in women as a result of tumor cell metastasis. There is an urgent need to further understand why some cancers become metastatic and to develop safe and effective treatments for use in BC. A growing body of evidence has convincingly shown that women with diabetes are not only more likely to develop BC, but also have a higher risk of death as a result of increased cancer metastasis. While many women have both diabetes and BC and they share major risk factors, the biological link between these two deadly disease states is less clear. Our research has shown that a protein called "RAGE" increases the severity of both the complications of diabetes and BC malignancy in animal models of these diseases states. RAGE is a receptor present on the surface of normal cells, but gets switched on by many of the inflammatory proteins produced in both cancer and diabetes. We have shown that by reducing the expression of RAGE in highly metastatic BC, we can prevent BC metastasis in mouse models. Furthermore, we show that a new drug that specifically blocks RAGE makes BC cells less metastatic in mice. We will test how diabetes drives BC metastasis through genetic deletion of RAGE in either BC cells or inflammatory cells using animal models. We will also test in mice whether our new RAGE drug inhibitor affects BC progression and metastasis. Completion of the aims of this study not only holds great promise for understanding why diabetes increases cancer metastasis, but also the development of a novel treatment for BC metastasis. Which overarching challenges does this research address? Our research proposal addresses multiple overarching challenges central to the BCRP s vision to end breast cancer. These include: (1) Identify what makes the breast susceptible to cancer development; (2) determine why some, but not all, women get BC; (3) identify what drives BC growth; determine how to stop it; (4) identify why some BCs become life-threatening metastasis; (5) revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective; and (6) eliminate the mortality associated with metastatic BC. What types of patients will it help and how will it help them? The research questions addressed in our proposal are highly significant for the BC patient and survivor community. The diagnosis of BC regardless of severity is devastating for the patient; an experience that I am personally familiar with as my mother (Dr. Hudson s) is a BC survivor. Having better ways of safely and effectively treating patients with BC to prevent or reduce unnecessary chemotherapy treatment would be a great clinical tool. Furthermore, women with diabetes have a far greater risk of not only developing BC, but also having metastasis. Understanding whether RAGE makes BC worse in women with diabetes is critical in order to effectively prevent metastasis. The results of Aim 3 would lead to the development of clinical trials for a RAGE inhibitor drug that could reduce and prevent BC spread in the body. The results from Aims 1and 2 would inform on new ways to design drugs against RAGE-ligand signaling and the use of combination therapies for pathways impacted by RAGE-ligand signaling for use in the treatment of BC especially in diabetic women. What are the potential clinical applications, benefits, and risks? Obviously the major objective for the BC patient and survivor community is the development of new, safe, and effective therapeutics that can prevent metastasis. The results of Aim 3 hold great promise in this realm, as the success in our preclinical studies in mouse models of BC would lead to the rapid development of clinical trials in people for the RAGE inhibitor. Further, mechanistic studies of Aims 1 and 2 would inform on targets downstream of RAGE for combination therapy approaches with the R
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710376
Entities
People
- Barry Hudson
Organizations
- United States Army
- University of Miami