New ways to image and target tumour hypoxia and its molecular responses

Abstract

Tumour hypoxia and its molecular responses have been shown to be associated with poor prognosis. Detection of hypoxia, preferably in a non-invasive manner, could therefore predict treatment outcome and serve as a tool to individualize treatment. This review gives an overview of recent literature on hypoxia imaging markers currently used in clinical trials. Furthermore, recent progress made in targeting hypoxia (hypoxia-activated prodrugs) or hypoxia response (carbonic anhydrase IX inhibitors) is summarized. Last, window-of-opportunity trials implementing non-invasive imaging are proposed as an important tool to prove anti-tumour efficacy of experimental drugs early during drug development.

Prognostic value of dynamic hypoxia PET in head and neck cancer: Results from a planned interim analysis of a randomized phase II hypoxia-image guided dose escalation trial

“…To date, the biological implications of tumour hypoxia and its therapeutic consequences are not fully understood and controversially discussed [4,29]. Tumour hypoxia may be a biomarker identifying a subgroup of patients with tumours of a more malignant phenotype exhibiting higher risk of local and distant failure [38,39].…”

“…Hypoxia positron emission tomography (PET) with [ 18 F]Fluoromisonidazole (FMISO), [ 18 F]Fluoroazomycin arabinoside (FAZA) or [ 18 F]HX4 [ [4][5][6][7][8][16][17][18][19][20][21][22][23][24][25] is a clinically well-established imaging method to detect and quantify tumour hypoxia as well as to provide prognostic information in LASCCHN. The predictive potential of hypoxia PET and other functional modalities to individualize RCT for example by stratified hypoxia modification or radiation dose escalation (DE) is currently under investigation [5,6,16,19,[25][26][27][28][29].Using dynamic [ 18 F]FMISO (dynFMISO) PET/computed tomography (CT), we have developed a voxel-based method for quantitative tumour hypoxia measurement based on tissue perfusion and tracer retention [17,30,31]. DynFMISO provided prognostic information in an initial study including 16 LASCCHN patients, i.e.…”

Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial

“…DCE-CT and HX4-PET scans were made at two time-points before start of radiotherapy: once to measure baseline tumour perfusion and hypoxia and a second time at least 48 h later, at a minimum of 1 h after application of a nitroglycerin patch ( Fig. S1) [6]. The minimum inter-scan interval of 48 h was chosen to allow sufficient time for kidney recuperation and wash-out of iodine contrast and HX4 (HX4 biological T1/2 = 4.3 h, T1/2 18 F = 110 min) to allow accurate retesting [29].…”

“…We initiated a trial to test the effect of nitroglycerin on the OS of NSCLC patients treated with radiotherapy. Because the proposed beneficial effects of nitroglycerin on tumour perfusion and hypoxia were never formally established in humans, patients were asked to undergo a hypoxia PET scan and dynamic contrast enhanced CT (DCE-CT) scan, both before and after treatment with nitroglycerin [6]. We analysed the prognostic value of hypoxia HX4-PET and DCE-CT imaging at baseline.…”

Fluorine-18 Patents (2009–2015). Part 1: Novel Radiotracers

“…Rather than applications for new PET radiotracers for imaging hypoxia, it appears that the existing agents continue to advance through clinical trials. Progress in this regard is beyond the scope of this patent review, but has been summarized in recent review articles [169][170][171].…”