While both therapies alone have demonstrated efficacy in mice, the greatest reduction inmetastatic brain tumor size occurred when the two therapies were combined. Therefore, because both therapies are already being evaluated in clinical trials for treatment of primary malignant brain tumors, there is a unique opportunity for the rapid translation of this technology from laboratory to clinic for breast cancer. If similar results are demonstrated in the clinic, this therapy duo could also be applied to other cancers that have metastasized to the brain.
New research out of the UCLA Jonsson Comprehensive Cancer Center (JCCC) led by Carol Kruse, professor of neurosurgery, combined two therapies currently undergoing individual clinical trials to determine if the two used in tandem could demonstrate a greater efficacy and reduction of tumor size than either therapy alone. Dr. Kruse’s combination therapy includes both a cellular and gene therapy component in a mouse model to address the difficulty of treating brain metastases of breast cancer, the most common cancer among women. When caught early, before metastasis has occurred, breast cancer can have a very positive prognosis. However, metastasis, especially to the brain, is a leading cause of health deterioration and death from the disease. “There is a significant lack of federally funded research addressing translational studies on brain metastases of systemic cancers,” Dr. Kruse said, “even though metastatic brain tumors occur ten times more frequently than primary brain tumors in humans. These patients have a dismal prognosis because the brain represents a ‘sanctuary site’ where appropriate access by many chemotherapeutics is ineffective. Our research addresses this unmet need.” The ‘sanctuary site’ that Dr. Kruse referred to is known as the blood-brain barrier (BBB). The BBB is a dynamic interface that actively separates the brain from the circulatory system and protects the CNS (Central Nervous System) from potentially harmful chemicals, or in the case of brain tumors, conventional cancer treatments. It is also typical for metastasis to occur in multiple areas of the brain, which limits the applicability and efficacy of radiation therapy. Addressing these factors was the primary focus of the study published August 1, 2013 in the journal Clinical Cancer Research. The first component of the treatment, gene therapy, was developed by Dr. Noriyuki Kasahara, professor in the Department of Medicine at UCLA. This particular gene therapy utilizes a generally nontoxic drug called 5-flurocytosine (5-FC) to kill the cancer cells. While the drug itself would not ordinarily have this type of affect, the researchers gene-modified the cancer cells through infection with a virus carrying their gene of interest. Once the cancer cells were infected by the gene-carrying virus, 5-FC was administered to the mouse models. The inserted gene instructed the cancer cells to convert the nontoxic 5-FC into a toxic form that resulted in cellular necrosis. The second component of the treatment, cellular therapy, is a type of immunotherapy that utilizes T cells that have been sensitized in the lab to kill breast cancer cells. The researchers injected the T cells into the brain in the areas where the cancer had spread. Their research showed evidence that the T cells were able to move through the tissue and recognize and kill the tumor cells while preserving the surrounding healthy cells.