Principal investigator: Dr. Gregory Czarnota

We recently discovered that ultrasound-stimulated and microbubble (USMB)-mediated

endothelial cellular perturbation can significantly enhance the effectiveness of radiation 40- to 60-fold in vivo. Data indicate that this synergy, which causes damage to tumour blood vessels, depends on acoustical stimulation and the involvement of the acid sphingomyelinase (ASMase) pathway, sphingosine-1-phosphate (S1P), and ceramide, a lipid associated with the induction of apoptotic signalling, as a molecular transducer. We recently demonstrated that USMB-mediated endothelial cellular perturbation depends on membrane-related enzymatic physiological pathways and genetic factors that can be modulated by targeted inhibitors or antibodies that disrupt S1P signalling or target the vasculature. When such inhibitors are used with USMB enhanced treatment, effects are superior to either treatment alone.

Subproject 1:  We will investigate the biology of the ASMase pathway involved in treatments using genetic and chemical approaches that modulate vasculature and ceramide-related signalling. We will compare ASMase knockout mice along with radiation-resistant and parental human tumour lines to investigate the importance of the ASMase pathway. Tumour treatments will be carried out using clinically-relevant doses of radiation (conventional to high-dose ablative), and assessments carried out using immunohistochemistry and quantitative ultrasound- and micro power Doppler imaging. Similar experiments will be run using combinations of USMB and radiation with chemical and antibody inhibition of the ceramide pathway to assess the synergy of our novel combination therapy for overcoming tumour radiation resistance.

Subproject 2:  We will scale up and translate this treatment methodology to conduct first-inhuman studies in cancer patients. In order to translate this methodology to cancer patients, we will complete scale-up treatments with clinically approved MRI guidance in animal tumour models and optimize physical parameters related to ultrasound-stimulated microbubble enhanced radiation treatments. We will also translate this treatment methodology in order to conduct first-in-human studies in cancer patients.

Our ultimate goal is to use this novel methodology to enhance radiation treatments. This innovative technology stands to have a high impact in how radiation treatments are given and has the potential to lower the total dose of radiation administered while making treatments more effective. This project will generate new knowledge about the cellular and molecular effects involved, and will incorporate first-in-human evaluations, leading to near-term clinical impact.