Drug resistance and the tumour microenvironment: strategies to improve the clinical benefit from chemotherapy
Speaker: Ian Tannock
Princess Margaret Cancer Centre and University of Toronto (Canada)
Host: Atanasio Pandiella
Salón de Actos del CIC
Most studies of resistance to anticancer drugs have evaluated molecular mechanisms in single cancer cells. Equally important, but rather neglected, is drug resistance due to the solid tumour microenvironment. Blood vessels and blood flow in tumours are irregular leading to large gradients in nutrient concentration, and we have shown that there are similar gradients in drug concentration within tumours following treatment with chemotherapy. Cells distant from functional blood vessels tend to be resistant, both because they are exposed to lower concentration of drugs, and because they are slowly proliferating.
We have investigated two strategies to overcome drug resistance that is due to the microenvironment of solid tumours. One approach is to use hypoxia-activated pro-drugs, such as TH-302, that are activated in hypoxic regions of tumours, and can then act selectively against hypoxic and neighbouring cells that are distant from tumour blood vessels. TH-302 has given promising results in clinical trials for pancreatic cancer and is now in phase 3 trials. The second strategy depends on the observation that poorly nourished or stressed tumour cells use the process of autophagy to recycle cellular components to facilitate their survival. Autophagy depends on fusion of autophagosomes with acidic lysosomes, and can be inhibited by higher doses of proton pump inhibitors, such as pantoprazole. We have shown that autophagy is upregulated following treatment with several anticancer drugs, and that inhibition of autophagy by pantoprazole increase the effects of docetaxel and doxorubicin against several human tumour xenografts. We have completed a phase I trial of high-dose i.v. pantoprazole with doxorubicin, and a phase II trial of pantoprazole and docetaxel for men with metastatic castration-resistant prostate cancer is in progress.