Sonodynamic therapy for metastatic melanoma to the brain

Abstract

Brain metastases represent the most common malignant brain tumor in adults. In the U.S., there are approximately 150,000–200,000 new patients with brain metastasis diagnosed each year. Melanoma is one of the most common cancer types to metastasize to the brain, and the B16F10 murine melanoma cell line is a frequently used model to study metastatic melanoma. Treatment options for brain metastasis from melanoma commonly include surgical resection, radiation therapy, stereotactic radiosurgery (SRS), targeted therapy, and immunotherapy. Melanoma is considered a chemoand radiationresistant cancer histology. The median overall survival of patients with brain metastasis remains approximately 6 months from the time of diagnosis of their intracranial disease but can vary widely depending factors such as tumor burden and mutational status. Local control at one year with brain metastasis treated with stereotactic radiosurgery and immune checkpoint inhibitors is approximately 89% but regional brain control at one year is approximately 38%. Furthermore, with the increasing survival in those patients who underwent radiation therapy including radiosurgery treatment, the risk of radiation necrosis has become an obstacle in achieving longer survival and better neurological function. New treatment options are desperately needed to treat patients with brain metastasis from melanoma and other types of metastatic cancer. The application of focused ultrasound (FUS) with a substance that sensitizes cells to the damaging effects of sound is called sonodynamic therapy (SDT) [1]. SDT utilizes high frequency, focused ultrasound and a sonosensitizing substance, both which are themselves generally innocuous to normal cells, but the combination can lead to cellular damage and/or death typically via apoptosis. This approach has shown promise for treating cancers that spread to sensitive areas of the body and, in particular, the brain [2]. Sonodynamic therapy can lead to reactive oxygen species (ROS) generation and cavitation thereby inducing cellular death within cancer [1, 2]. The generation of ROS through sonodynamic therapy has been previously studied with free radical scavengers such as histidine and superoxide dismutase; while the full extent of the role of ROS in mediating SDT induced cytotoxic effects is not fully known, much data to date suggest a role of ROS in SDT mediated cell death [2]. With the advent of several new systems, highly focused ultrasound can now be delivered to brain targets through the intact skull. Such approaches have allowed clinicians to treat essential tremor and tremor predominant Parkinson’s Disease through thermal ablation of select regions of the brain. Other focused ultrasound approaches are being explored including disruption of the blood brain barrier to allow chemotherapy or novel drug into the brain, histotripsy which is a technique to mechanically disrupt a tumor, and mild hyperthermia to induce tumor cell radiosensitization. Sonodynamic therapy has the potential of offering effective tumor control of brain metastases while avoiding adverse radiation effects including an approximately 5% risk of radionecrosis after SRS for brain metastasis. Sonodynamic therapy has been shown to elicit cytotoxic lymphocytes to tumor sites which could help to augment the responsiveness of the tumor to concurrent immunotherapy. Brain metastases from melanoma and other types of cancers have been shown to exhibit 5-aminolevulinic acid (5-ALA) uptake and in vivo fluorescence to guide resections. As 5-ALA is already approved by the Food and Drug Administration and has been shown to be taken up by metastatic disease in the brain, it may serve as a reasonable sonosensitizer for an SDT based approach for treating melanoma and other brain metastases. Other sonosensitizers such as fluorescein are also being explored for the treatment of brain tumors. * Jason Sheehan [email protected]