Mechano-modulation of tumor microenvironment with mechanotherapeutics and sonopermeation to optimize nano-immunotherapy

Inefficient drug delivery to tumors can reduce dramatically treatment efficacy and thus, affect negatively the life of cancer patients. This is particularly evident in desmoplastic cancers where interactions among cancer cells, stromal cells and the fibrotic matrix cause tumor stiffening and accumulation of mechanical forces that compress tumor blood vessels. Indeed, in subsets of pancreatic cancers and sarcomas, 95% of intratumoral blood vessels may be compressed and up to 80% totally collapsed leading to reduced blood flow (hypo-perfusion) and drug delivery. Hypo-perfusion also leads to hypoxia that helps cancer cells evade the immune system and increase their invasive and metastatic potential. Use of mechanotherapeutics and ultrasound sonopermeation are two mechano-modulation strategies that separately have been employed to treat vascular abnormalities in tumors. Even though these strategies have reached the clinic, their promise has yet to be realized by cancer patients owning to limitations of the methods. My hypothesis is that these strategies can uniquely complement each other and have not only additive, but highly multiplicative synergistic effects on modulating the desmoplastic tumor microenvironment and improving the efficacy of the promising but still of limited use nano-immunotherapy. However, it is crucial that specific guidelines should be developed. To achieve this ground-breaking goal, I will employ a mixture of cutting-edge computational and experimental techniques. I will perform in vivo mice studies in pancreatic cancers and sarcomas to investigate under what conditions these mechano-modulation strategies can be optimally combined to improve treatment efficacy, prevent metastasis and increase survival. In parallel, I will develop new mathematical models to provide useful guidelines for optimizing the experimental protocol. MMSCancer will introduce novel therapeutic strategies for the treatment of drug resistant tumors leading to better therapies.