Strategies for radiosensitisation targetting the tumour microenvironment


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Ruth Muschel1
1University of Oxford, Oxford, UK

Abstract

Radiation therapy is used for the treatment of many tumours and often it is an important factor in successful outcomes. However treatment is far from uniformly successful and tumours not uncommonly recur at the irradiated site. The failure of radiation treatment is generally attributed to two categories; resistance to radiation by the cancer cells themselves and the tumor microenvironment especially hypoxia. Hypoxia is a common feature of cancers leading to radiation resistance. We have shown that inhibitors of the oncogenic signaling pathway RAS- Phosphoinositide 3-kinase (PI3K) sensitize tumours to radiation both by enhancing intrinsic radiosensitivity and by reduction of hypoxia. Treatment of mice with tumours with drugs inhibiting the RAS- PI3K pathway leads to dramatic improvement in vascular function with blood flow and perfusion increasing 2-3 fold. This treatment induced rapid tumour vascular remodeling resulting in vessels with decreased tortuosity and increased pericyte coverage similar to changes sometimes referred to to as vascular normalization. Unlike the transient vascular normalization induced by anti-angiogenic agents, this effect is durable. One result of improved vascular function is better delivery of chemotherapy leading to improved tumour control. Another is greater efficacy of radiation therapy. Taken together then inhibition of the RAS-PI3K signaling pathway has the potential to enhance cancer therapy both by improved delivery of pharmaceutical agents and through reduction in the tumor hypoxia enhancing killing by radiation. These results also suggest that it may be possible to monitor therapy with RAS-PI3K inhibition by tracking vascular function and hypoxia.