Translational use of focused ultrasound to increase blood-tumor barrier permeability as a mechanism to increase drug accumulation into brain metastases of breast cancer

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Project Summary: Once a cancer has disseminated approximately 20% of the time it will go to brain. The most common brain metastases originate from lung, breast and or skin. Brain metastases often are often not diagnosed until neurological symptoms are pronounced, which usually indicates a significant disease burden. Traditional therapy including surgical resection and radiation therapy have a low degree of efficacy as evidenced by a low two-year survival of 8.1%. The blood-tumor barrier (BTB) while disrupted compared to the blood-brain barrier, remains a physicochemical barrier limiting effective drug accumulation in 90% of lesions. Our long-term goal is to temporarily disrupt the BTB and enhance drug accumulation within metastatic brain lesions. We hypothesize that disruption of the BTB will allow drugs to accumulate at cytotoxic concentrations within the lesions, increasing chemotherapeutic efficacy and prolonging overall survival. Transcranial low intensity focused ultrasound (LiFUS) has been previously used in neurological disorders to non-invasively increase drug accumulation within the brain using increased paracellular transport between endothelial cells. In this study, we propose the investigation of LiFUS exposure on BTB permeability of standard chemotherapies in order to increase tumor cytotoxicity and survival in mice. To do this, we first need to control LiFUS mediated BTB disruption. The first specific aim will elucidate key LiFUS parameters including cavitation dose, power and duration on BTB permeability as well as brain/lesion accumulation of chemotherapeutics. Survival and tumor progression will also be measured using this model, with weekly treatments being completed. The second specific aim will elucidate potential long-term vascular changes induced by the ultrasound waves. Specifically, we will evaluate five proteins that are integral to the BTB, over five time points (24h – 7d), with two doses cavitation doses in naive and treated animals. Two efflux transporters (P-gp, BCRP) will be evaluated for expression and the ability to efflux substrates. Three tight junction proteins will be evaluated for expression and localization. Together, these two phases will potentially provide a novel therapeutic strategy for treating metastatic CNS lesions and understanding the effect of LiFUS on the underlying vascular mechanisms.