Mechanisms of T-DM1/Radiation-Induced Toxicity in Brain Metastases
Abstract
Brain metastasis (BM) occurs in 30%-40% of breast cancer patients with tumors overexpressing the epidermal growth factor receptor (HER2+ tumors) and represents a devastating clinical reality. Most patients with BM are treated with some form of radiation (i.e., stereotactic radiosurgery); however, we know little about the interactions between anti-cancer therapies and radiation in the brain. Recent clinical studies show that patients with HER2+ BM treated with the most promising HER2+ agent target (T-DM1) in combination with radiotherapy (RTx) often develop severe adverse effects (radionecrosis and brain swelling), which forces the suspension of treatment and in some cases causes death. My preliminary data suggest that T-DM1 in enhances radiation-induced toxicity in specialized cells in the brain (named astrocytes), which in turn causes swelling and disrupting specialized vessels in the brain. Here, I propose to define the mechanisms underlying this clinical toxicity, so we can devise ways to prevent it or treat it. My hypothesis is that RTx together with T-DM1 induces brain swelling by modulating astrocytic swelling through of upregulation of AQP4 (a channel water expressed in astrocytes) and disruption of the blood-brain barrier (BBB) by increase of endothelial growth factor (VEGF) secretion by cancer cells and astrocytes. If this hypothesis is correct, a Food and Drug Administration (FDA)-approved-inhibitors known to reach the brain and target AQP4 could be used in combination with FDA-approved drugs to protect the BBB and prevent or treat T-DM1/RTx-induced brain swelling. The usage of FDA-approved drugs, able to cross the BBB, proposed in this investigation will make short the path to test in patients. In addition, these studies will provide with a better understanding of how RTx affects important cells in the brain in the course of cancer treatment. Thus, my proposal will address two overarching challenges in breast cancer: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic and (2) diminish the mortality associated with metastasis. Additional, since RTx is used as part of the main treatment to most patients with BM (even those that are not HER2+), results of this research have the potential to benefit the larger population of breast cancer patients suffering of BM. Radiologist, oncologist, neuroscientific, and cancer research in general will be benefit with the information derived from this proposal and most importantly, the risk of side effects associated with radiotherapy of current and future patients may be lessened. Additionally, this proposal will allow me to strengthen my skills in breast cancer research, specifically relevant to the management of animal models for breast cancer research, in vivo and in vitro model of BBB, and the clinical aspect related with therapeutic approach of BM breast cancer patients. This project will allow me to stablish a network of collaborators and to consolidate my expertise as a breast cancer researcher so that will be competitive for next funding within the next 3 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910033XX0
Entities
People
- María J Contreras-Zárate
Organizations
- United States Army
- University of Colorado Denver