Grant: Foundation Grant

Angiogenesis; Biomarkers For Targeted Therapy; Brain Tumours; Cellular Communication; Coagulation System; Dormancy; Exosomes; Metastasis; Oncogenes; Vascular Ageing

<html> <body> <p> <strong>The overarching direction</strong> of my research program is in rational diagnostic and therapeutic exploitation of <em>unconventional (exosomal) mechanisms of tumor-vascular interactions</em>. This focus&nbsp;stems from our long standing interests in the role of oncogenes as regulators of the multicellular and vascular milieu in cancer, something that&nbsp;drove our earlier discoveries of the oncogenic regulation of tumor angiogenesis (1995), coagulation (2005), vesiculation (2008) and dormancy (2014).<br> <br> <strong>Exploring new disease paradigms.</strong> In spite of the revolutionary progress in tumor genomics and&nbsp;the advent of&nbsp;rational (targeted) therapies many human cancers remain incurable. Thus, gaps must exist in the present therapeutic paradigms predicated on molecular aberrations <em>within</em> cancer cells. We suggest that oncogenic events profoundly affect processes occurring <em>between</em> cells and in the realm of <em>multicellular interactions</em>, wherein we seek new opportunities. The vasculature is of special interest as the key element of host responses to tumorigenesis, and the ultimate determinant of the systemic nature of human cancer. We focus on novel <em>cancer-specific</em> and <em>unconventional</em> mediators of these interactions, including how oncogenic drivers reprogram patterns of cellular communication through intercellular trafficking of extracellular vesicles (EVs) containing oncogenic cargo (<em>oncosomes</em>).<br> <br> <strong>The major questions</strong> shaping the&nbsp;course our program are threefold: (i) What are the biological effects of the EV exchange in formation of the tumor-vascular interface and progression of primary and metastatic brain tumors (do EV pathways intersect with other mediators)?; (ii) Can EV mediated cellular communication be targeted therapeutically, and how? (iii) Is the natural packaging and multiplexing of molecular information during&nbsp;the EV biogenesis informative and actionable in the clinic, asbiomarker platform? While our efforts concentrate on brain tumors, these questions are widely applicable to other disease contexts, and we invest our expertise and capacities in the respective collaborations.<br> <br> <strong>The expected impact</strong> of these studies on cancer care&nbsp;may be&nbsp;significant. In the long run, targeting EV communication pathways may translate into new classes of <em>anti-interactive</em> therapeutics with either primary or adjunctive role. These explorations have already begun through studies (including ours) on targeting exosomes to suppress experimental metastasis¹, drug resistance², or angiogenesis³. A more immediate, novel and potentially disruptive applications pertain developing EV-based biomarkers harbouring information, as to driver mutations, molecular&nbsp;evolution and therapy-induced changes in cancer cells and their vascular and inflammatory surroundings (&lsquo;liquid biopsy&rsquo;).<br> <br> <strong>Our expertise</strong> stems from decades of sustained interest in cellular interactions⁴, oncogenic regulation of the vascular compartment⁵, vesicular communication in cancer^3;6-9 and&nbsp;niche effects^10;12, as reflected in our publications (CV), over 8,000 citations (WOS), and funded grants (CIHR). We have also built a collaborative network in all areas related to this application including genomics^12-14, stem cells¹⁵, angiogenesis⁹, and new technologies⁸.<br> <br> <strong>Our mentorship activities</strong> comprise 18 trainees directly supervised and several careers facilitated in academia, health sector and industry. Our relocation to the new, state-of-the-art, Glen campus and multidisciplinary research environment (2015) will dramatically enhance our training potential.</p> </body> </html>