Pericyte-mediated vessel maturation in cancer therapies – Ang_maturation_cancer

Judicious application of anti-angiogenesis agents can correct vessel abnormalities to improve response to conventional cancer therapies. However, the concept of vascular normalization is relatively young and strategies targeting Vascular Endothelial Growth Factor (VEGF), the prime anti-angiogenic drug target, appear to only transiently normalize the vasculature. It will be thus advantageous to define which other strategies lead to vascular normalization, which compounds increase its duration to improve cancer therapy and what are the optimized anti-angiogenic regimens that improve conventional therapies. Recently, we have revealed a novel mechanism of action of thalidomide and have provided to our knowledge, the first evidence that a therapy targeting pericytes to stimulate vessel maturation can have beneficial effects on bleeding by normalizing the vessel anomalies. Thalidomide’s derivatives represent a promising new class of compounds for treatment of cancer and are actively under clinical investigation. Our aim and ambition are to identify derivatives of thalidomide with more specificity and potent activity toward pericytes and more generally to validate that strategies targeting pericytes to stimulate vessel maturation are of therapeutic advantage in cancer therapies by increasing the normalization time window to improve conventional. Translating our “vessel stabilization concept” into in vivo models will require establishment of imaging technology for high-resolution detection of vessel morphology and maturation changes. The use of 2-photon excitation microscopy with MicroProbe objective lens and fiber-optic gradient index (GRIN) lenses will allow spatial high resolution and tissue penetration overcoming physical access issues. These techniques will facilitate longitudinal studies and experimental determination of the normalization time window. Comparison with functional vessel parameters (blood flow, leakage, oxygen delivery) and the relevant response of the tumor to conventional therapies will be investigated. Our pilot experiments encourage us to believe that we may be able to validate our “vessel stabilization concept” in cancer therapies, and to develop a new class of molecules that stimulate sustained vessel normalization. More generally, we will set up a neat technological imaging platform and develop markers for drug combination testing that will be eligible for technology transfer to a biotechnology company.