STROMAMECH · Targeting stromal cells to modify tumor mechanical microenvironment and optimize drug delivery

Targeting stromal cells to modify tumor mechanical microenvironment and optimize drug delivery

Current chemotherapeutic agents are potent enough to kill cancer cells. Nonetheless, failure of standard chemotherapies for many cancer types (e.g., pancreatic and breast cancers) is primarily attributed to these agents never reaching cancer cells in amounts sufficient for complete cure. In solid tumours, blood vessels are often compressed, drastically reducing perfusion, thus resulting in insufficient drug delivery. Vessel compression is a consequence of mechanical stresses accumulated within the tumour during progression. Alleviation of these stresses has the potential to reopen compressed vessels and improve tumour perfusion. Here, we proposed to test the hypothesis that judicious depletion of stromal cells, namely the cancer-associated fibroblasts (CAFs), has the potential to alleviate stress levels in highly desmoplastic and hypoperfused tumours and, thus, enhance chemotherapy. To explore this hypothesis, a combination of cutting-edge computational and experimental techniques were employed. Specifically, in vivo studies were performed in mice using vismodegib (GDC-0449; Erivedge®), a clinically approved sonic hedgehog signalling pathway inhibitor, to reduce the population of CAFs in pancreatic and breast tumor models. CAFs reduction improved tumor perfusion and the efficacy of common cytotoxic drugs, namely gemcitabine, Abraxane® and Doxil®. A mathematical model was also developed to provide insights to the model predictions about how CAFs contribute to the accumulation of forces in tumors. Failure of standard cancer therapies has dramatic effects on the health and quality of life of cancer patients and their families, both physically and emotionally. Thus, an improved therapeutic strategy is desperately needed. The main hypothesis of the proposed study was that if the delivery of drugs to the tumor is optimized, then the treatment efficacy will be enhanced even at a lower dose of the cytotoxic drug. Therefore, from a societal point of view the benefit from the development of a new therapeutic anti-cancer strategy is that it can potentially improve the efficacy of cytotoxic drugs by optimizing their intratumoral distribution leading to the desired outcome of prolonged disease-free survival. The overall objectives of the STROMAMECH project were: - Execution of in vivo experiments on tumours grown in mice in order to prove the main hypothesis of the project that judicious depletion of stromal cells, namely the cancer-associated fibroblasts (CAFs), has the potential to alleviate stress levels in highly desmoplastic and hypoperfused tumours and, thus, enhance chemotherapy. - Development of a structure-based, biomechanical model for tumour growth focusing on the contribution of CAFs to provide insights to experimental data.

Data: CORDIS, © European Union