Antivascular cancer treatments: imaging biomarkers in pharmaceutical drug development.

Abstract

Over the last several years there have been a large number of drugs brought into the clinic for the treatment of cancer targeting antiangiogenic or antivascular mechanisms. The matrix metalloproteinase inhibitors (MMPIs) are an example of one group of antiangiogenic agents which were first tested in man beginning 1997 [1]. Pre-clinical studies had demonstrated inhibition of endothelial cell growth, inhibition of angiogenesis with matrigel plug assays, and inhibition of metastasis. There was no expectation from such studies though that these agents would cause tumour regression in the manner that cytotoxic drugs do. Thus, the pattern of development of oncology agents where in Phase I doses are escalated until dose limiting toxicity is seen and the next lowest dose is chosen as the maximum tolerated dose (MTD) was perceived to be inappropriate [2]. It was proposed that for drugs with a wider therapeutic window than traditional cytotoxics, and a mechanism of action that may lead to cytostasis, rather than tumour regression, that an ‘‘optimal biological dose’’ (OBD) lower than the MTD might be more appropriate to take forward into Phase II. However in order to discriminate the OBD some means of measuring the desired biological activity or ‘‘biomarker’’ is needed. At the time when the MMPIs entered the clinic very few such biomarkers were available. However some exploratory markers were examined by more recent entrants to the antiangiogenic field such as endostatin [3, 4], the vascular endothelial growth factor (VEGF) pathway targeted drugs [5‐8] and vascular targeting agents [11, 12]. In addition to biomarkers in tumour tissue and blood samples, a range of imaging technologies are available or under development that have the potential for use as biomarkers of antiangiogenic and antivascular drug effects. These can be categorized by the distance ‘‘downstream’’ from the drug interaction with its molecular target: