Tannock IF: Microenvironmental causes of resistance to a drugs
Mechanistic studies of drug resistance in tumours have concentrated on genetic changes in cancer cells. We are studying equally important but neglected mechanisms that depend on the tumour microenvironment. Anti-cancer drugs access solid tumours via the blood, and must penetrate multiple cell layers to reach all cancer cells. We use quantitative immunohistochemistry to assess the distribution of anticancer drugs, and of markers of their activity, in tumours. We have shown limited perivascular distribution of the clinically-used fluorescent anticancer drugs doxorubicin, mitoxantrone, and topotecan in solid tumours, but uniform distribution in normal tissues other than brain. More recently we have used markers of DNA damage and apoptosis to show that several other clinically-used drugs have limited distribution from tumour blood vessels, so that distal cells are resistant to chemotherapy both because of their low proliferative rate and poor drug access.
We are investigating strategies to overcome clinical resistance that include (i) Use of the hypoxia-activated pro-drug TH-302, which penetrates tissue to reach hypoxic regions. We have shown complementary distributions of activity of TH-302 to the anticancer drugs doxorubicin and docetaxel in human tumour xenografts, with increased anti-tumour activity. (ii) Use of the anti-ulcer agent pantoprazole to inhibit the process of autophagy, which is a survival mechanism by which stressed cells recycle cellular breakdown products. We have shown that treatment with docetaxel leads to up-regulation of autophagy, and this is a mechanism of resistance to chemotherapy. Pantoprazole improves anti-tumour effects of chemotherapy by inhibiting autophagy and we have completed a phase I clinical trial of pantoprazole and doxorubicin for treatment of solid tumours. We have initiated a phase II trial of docetaxel and pantoprazole for treatment of men with castration resistant prostate cancer.
Repopulation of surviving tumour cells occurs during and after chemotherapy (as it does after radiotherapy) and we have used double markers of hypoxia (EF5 and pimonidazole) to demonstrate that reoxygenation and repopulation occur from hypoxic tumour regions after treatment with chemotherapy. Paradoxically chemotherapy can lead to survival of hypoxic cells that were destined to die in untreated tumours.