This project will develop a new approach to treat an aggressive and deadly form of metastatic breast cancer known as meningeal metastases, or metastases to the lining covering the brain. We propose to investigate an effective, long lasting, and targeted therapy with oncolytic replication conditional herpes simplex virus 1 (HSV-1) that will potentially have a large impact on the treatment of meningeal metastases by reducing toxicity, promoting effective treatment outcome, and most significantly -prolonging life expectancy. Meningeal metastasis is a deadly complication of breast cancer affecting approximately 5% of patients. At present, there is no effective therapy for meningeal metastases, and the median survival of the treated patients is about 3 months. Published data suggest that the incidence of this disease increases, probably due to the longer survival of patients with systemic cancer. The need for new therapeutic interventions is urgent. The replication conditional herpes simplex type-1 (HSV-1) has been genetically engineered to replicate preferentially in cancer cells utilizing their enhanced mitotic activity. As such replicaion in cancer cells will kill these cells while leaving the normal tissue unharmed. This novel treatment will be investigated in a mouse model of meningeal metastases that has been fully characterized with molecular imaging with MRI over successive time points. The potential therapeutic effect of HSV-1 oncolysis on meningeal metastases will be investigated with molecular imaging and in vitro tissue analyses sequentially over time. Virus replication in the meningeal metastases will be determined by molecular imaging with positron emission tomography (PET) using FHBG as the substrate for the thymidine kinase enzyme specific for the virus. The therapeutic effect of oncolytic HSV-1 on meningeal metastases will be determined by molecular imaging with Gd enhanced MRI. If a therapeutic effect is achieved, the impact on therapy and patient survival will be huge and will be of direct clinical significance.
Meningeal metastasis is a devastating and often fatal complication of breast cancer that affects 5-8% of patients. It results when circulating cancer cells seed in the meninges. Their subsequent growth causes severe neurological complications involving the cranial nerves, cerebrum and spinal cord, limiting life expectancy to less than 4 months. Current treatment is largely palliative. Aggressive multimodal therapies including intrathecal chemotherapy are often ineffective. Given this clear unmet clinical need, I am proposing to assess surgically delivered targeted replication conditional oncolytic herpes simplex 1 (HSV-1) therapy as a novel platform to treat meningeal metastases from breast cancer. These modified viruses replicate in and kill tumor cells while sparing normal adjacent tissue.