Elimination of the Neurocognitive Defects Following Whole Brain Irradiation for Breast Cancer Metastases
Abstract
The management of patients with brain metastases from breast cancer is a major clinical challenge. Such metastases occur in roughly 20% of unselected patients with advanced breast cancer, but this increases to some 40% of patients with HER2-positive advanced breast cancer. Brain metastases are associated with poor prognosis, neurological deterioration, diminished quality of life, and short survival. Treatment can be surgery, whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), chemotherapy, and combinations. However, WBRT remains the mainstay treatment for patients with multiple metastases, who are not eligible for surgery or SRS and this treatment improves overall survival by approximately 4-6 months compared to no treatment and provides relief of neurologic symptoms. However, the tumors invariably recur, showing that there is a major need for improvement in the effectiveness of the treatment. There are also detrimental neurological consequences of the WBRT that could be eliminated with lower radiation doses, but this would reduce the antitumor efficacy. Thus, there is a need to eliminate these neurological consequences without losing antitumor efficacy. We believe that we can remedy this situation. We have recently developed a new approach for the treatment of tumors based on inhibiting the influx of bone marrow derived cells (macrophages) that we have found restore the radiation damaged blood vessels in the tumors. We do this by using drugs that block a signaling pathway provided by the SDF-1/CXCR4 axis. This is initiated in the irradiated tumor, which following irradiation expresses high levels of stromal cell-derived factor-1 (SDF-1). This in turn mobilizes the blood-forming cells from the bone marrow and captures them in the tumor. When we block the interaction of SDF-1 with its receptor CXCR4 on the bone marrow cells, this process is blocked and the tumor fails to restore its blood vessels after irradiation. Our project addresses two overarching challenges, namely, (1) eliminate the mortality associated with metastatic breast cancer (at a minimum we expect to double survival time compared to irradiation only) and (2) replace toxic treatments with safer alternatives (we anticipate being able to reduce the brain radiation dose as this causes neurocognitive effects). The strategy we propose will be able to be used on all patients with brain metastases, not just the ones with multiple metastases, but also those with single lesions treated with focused irradiation. If we demonstrate the efficacy of the treatment in mice showing that we can double the survival time of animals with brain metastases of breast cancer without increasing brain toxicity and reduce brain toxicity while still increasing antitumor efficacy, this will go a long way to putting this strategy into immediate clinical testing as the agents we are using are clinically approved. It will also increase the likelihood of clinical testing if we show that we can use MRI to image macrophage uptake in the metastases and thus monitor the efficacy of the treatment. Our study will not eliminate breast cancer, but it will be able to help cure more patients with the disease without detrimental neurological side effects as brain metastases are a major contributor to death from breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510031
Entities
People
- John Brown
Organizations
- Stanford University
- United States Army