Normalising tumour vessels and microenvironment to treat cancer: from the bench to bedside and back

Rakesh Jain
Massachusetts General Hospital and Harvard Medical School, Boston, USA

Solid tumours require blood vessels for growth, and many new cancer therapies are targeted against the tumour vasculature. The widely held view is that these antiangiogenic therapies destroy the tumour vasculature, thereby depriving the tumour of oxygen and nutrients. Indeed that is the ultimate goal of antiangiogenic therapies. However, emerging preclinical and clinical evidence support an alternative hypothesis – that judicious application of agents that block angiogenesis directly (for example, Avastin, Recentin) and indirectly (for example, Herceptin) can also transiently ’normalise‘ the abnormal structure and function of tumour vasculature. In addition to being more efficient for oxygen and drug delivery, the normalised vessels are fortified with pericytes, which can hinder intravasation of cancer cells – a necessary step in hematogenous metastasis.

Drugs that induce vascular normalisation can also normalise the tumour microenvironment – reduce hypoxia and interstitial fluid pressure – and thus increase the efficacy of many conventional therapies if both are carefully scheduled. Reduced interstitial fluid pressure can decrease tumour-associated oedema as well as the probability of lymphatic dissemination. Independent of these effects, alleviation of hypoxia can decrease the selection pressure for a more malignant phenotype. Finally, the increase in proliferation of cancer cells during the ’vascular normalisation window‘ can potentially sensitise tumours to cytotoxic agents.

Our recent Phase II clinical trials in patients with rectal carcinomas and glioblastomas (GBM) support our pre-clinical findings on vascular normalisation. Moreover, in GBM patients, the normalisation window – identified using advanced MRI techniques – can last one to four months, and the resulting changes in tumour vasculature correlate with circulating molecular and cellular biomarkers in these patients. The encouraging results on patients survival from the GBM Phase II trial has led to an international multi-center randomised Phase III clinical trial in GBM patients and has spawned a number of trials for non-CNS tumours.