Dataset Information

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [¹⁸F]HX4 PET imaging study in colorectal cancer xenografts.

ABSTRACT:

Background

In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [¹⁸F]flortanidazole ([¹⁸F]HX4) small-animal positron emission tomography (μPET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [¹⁸F]HX4 as a predictive and/or prognostic biomarker within this setup.

Methods

Colo205-bearing mice (n = 40) underwent a baseline [¹⁸F]HX4 hypoxia μPET/computed tomography (CT) scan. The next day, mice received 100 mg/kg metformin or saline intravenously (n = 20/group) and [¹⁸F]HX4 was administered intravenously 30 min later, whereupon a second μPET/CT scan was performed to assess changes in tumor hypoxia. Two days later, mice were further divided into four therapy groups (n = 10/group): control (1), metformin (2), radiotherapy (3), and metformin + radiotherapy, i.e., combination (4). Then, they received a second dose of metformin (groups 2 and 4) or saline (groups 1 and 3), followed by a single radiotherapy dose of 15 Gy (groups 3 and 4) or sham irradiation (groups 1 and 2) 30 min later. Tumor growth was followed three times a week by caliper measurements to assess the therapeutic outcome.

Results

[¹⁸F]HX4 uptake decreased in metformin-treated tumors with a mean intratumoral reduction in [¹⁸F]HX4 tumor-to-background ratio (TBR) from 2.53 ± 0.30 to 2.28 ± 0.26 (p = 0.04), as opposed to saline treatment (2.56 ± 0.39 to 3.08 ± 0.39; p = 0.2). The median tumor doubling time (TDT) was 6, 8, 41, and 43 days in the control, metformin, radiotherapy and combination group, respectively (log-rank p < 0.0001), but no metformin-specific therapy effects could be detected. Baseline [¹⁸F]HX4 TBR was a negative prognostic biomarker for TDT (hazard ratio, 2.39; p = 0.02).

Conclusions

Metformin decreased [¹⁸F]HX4 uptake of Colo205-tumors, but had no additive effect on radiotherapy efficacy. Nevertheless, [¹⁸F]HX4 holds promise as a prognostic imaging biomarker.

SUBMITTER: De Bruycker S

PROVIDER: S-EPMC6677842 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [<sup>18</sup>F]HX4 PET imaging study in colorectal cancer xenografts.

De Bruycker Sven S Vangestel Christel C Staelens Steven S Wyffels Leonie L Detrez Jan J Verschuuren Marlies M De Vos Winnok H WH Pauwels Patrick P Van den Wyngaert Tim T Stroobants Sigrid S

EJNMMI research 20190802 1

<h4>Background</h4>In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [<sup>18</sup>F]flortanidazole ([<sup>18</sup>F]HX4) small-animal positron emission tomography (μPET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [<sup>18</sup>F]HX4 as a predictive and/or prognostic biomarker within this setup.<h4>Methods</h4>Colo205-bearing mice (n = 40) underwent a baseline ...[more]

PMID: 31375940

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Project description:BackgroundEsophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo.MethodsIn vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 μL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 μl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. 18F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation).ResultsA T/B ≥ 3.59 on pre-treatment 18F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B ≥ 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth.ConclusionsTumor tissue hypoxia as measured with 18F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.

Project description:IntroductionThe presence of hypoxia in head-and-neck squamous cell carcinoma is a negative prognostic factor. PET imaging with [18F] HX4 can be used to visualize hypoxia, but it is currently unknown how this correlates with prognosis. We investigated the prognostic value of [18F] HX4 PET imaging in patients treated with definitive radio(chemo)therapy (RTx).Materials and methodsWe analyzed 34 patients included in two prospective clinical trials (NCT01347281, NCT01504815). Static [18F] HX4 PET-CT images were collected, both pre-treatment (median 4 days before start RTx, range 1-16), as well as during RTx (median 13 days after start RTx, range 3-17 days). Static uptake at both time points (n = 33 pretreatment, n = 28 during RTx) and measured changes in hypoxic fraction (HF) and hypoxic volume (HV) (n = 27 with 2 time points) were analyzed. Univariate cox analyses were done for local progression free survival (PFS) and overall survival (OS) at both timepoints. Change in uptake was analyzed by comparing outcome with Kaplan-Meier curves and log-rank test between patients with increased and decreased/stable hypoxia, similarly between patients with and without residual hypoxia (rHV = ratio week 2/baseline HV with cutoff 0.2). Voxelwise Spearman correlation coefficients were calculated between normalized [18F] HX4 PET uptake at baseline and week 2.ResultsAnalyses of static images showed no prognostic value for [18F] HX4 uptake. Analysis of dynamic changes showed that both OS and local PFS were significantly shorter (log-rank P < 0.05) in patients with an increase in HV during RTx and OS was significantly shorter in patients with rHV, with no correlation to HPV-status. The voxel-based correlation to evaluate spatial distribution yielded a median Spearman correlation coefficient of 0.45 (range 0.11-0.65).ConclusionThe change of [18F] HX4 uptake measured on [18F] HX4 PET early during treatment can be considered for implementation in predictive models. With these models patients with a worse prognosis can be selected for treatment intensification.

Dataset Information

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [¹⁸F]HX4 PET imaging study in colorectal cancer xenografts.

Background

Methods

Results

Conclusions

Publications

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [<sup>18</sup>F]HX4 PET imaging study in colorectal cancer xenografts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [18F]HX4 PET imaging study in colorectal cancer xenografts.

Background

Methods

Results

Conclusions

Publications

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [<sup>18</sup>F]HX4 PET imaging study in colorectal cancer xenografts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Effects of metformin on tumor hypoxia and radiotherapy efficacy: a [¹⁸F]HX4 PET imaging study in colorectal cancer xenografts.