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  • 1
    Keywords: EXPRESSION ; IN-VIVO ; PATHWAY ; LUNG-CANCER ; ACTIVATION ; RADIATION-THERAPY ; chemotherapy ; SQUAMOUS-CELL CARCINOMA ; CISPLATIN ; tumor microenvironment ; HIF-1 ; GLUCOSE-METABOLISM ; UNFAVORABLE PROGNOSIS ; HUMAN TUMOR XENOGRAFT ; HIF-1-ALPHA ; Local tumor control ; Fractionated radiation ; HIF pathway inhibition ; INDUCIBLE FACTOR-1-ALPHA
    Abstract: BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy. METHODS: When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD50) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations. RESULTS: BAY-87-2243 markedly decreased nuclear HIF-1alpha expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD50 from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD50. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control. CONCLUSIONS: Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.
    Type of Publication: Journal article published
    PubMed ID: 25234922
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  • 2
    Keywords: DNA ; REPAIR ; SQUAMOUS-CELL CARCINOMA ; radiation sensitivity ; DOUBLE-STRAND BREAKS ; radiosensitivity ; CANCER-TREATMENT ; FRACTIONATED-IRRADIATION ; PHOSPHORYLATED HISTONE H2AX ; CLONOGENIC CELLS
    Abstract: PURPOSE: Evaluation of micromilieu-dependent quantified gammaH2AX foci as a potential predictive biomarker in well-oxygenated tumour areas in 9 HNSCC xenograft models in vivo. MATERIALS & METHODS: GammaH2AX foci were quantified in perfused tumour areas 30min (initial gammaH2AX foci) and 24h (residual gammaH2AX foci) after exposure to a single dose of 4Gy. The initial and residual normalised gammaH2AX foci were correlated with TCD50 after single dose irradiation under clamped blood flow (SDclamp) or a fractionated irradiation setting under ambient blood flow (fx). RESULTS: A significant negative correlation between initial and residual normalised gammaH2AX foci and TCD50 SDclamp and TCD50 fx for 9 HNSCC tumour xenograft models in vivo was found. Residual normalised gammaH2AX foci showed higher intertumoural variability and their correlation with TCD50 was more robust. CONCLUSIONS: For the first time a significant negative correlation between gammaH2AX foci and local tumour control after irradiation has been demonstrated. Our results underline the potential of residual gammaH2AX foci as a predictive biomarker for local tumour control after radiotherapy.
    Type of Publication: Journal article published
    PubMed ID: 23891089
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  • 3
    Keywords: IONIZING-RADIATION ; IN-VIVO ; TYROSINE KINASE ; NUDE-MICE ; SQUAMOUS-CELL CARCINOMA ; POLO-LIKE KINASE-1 ; GROWTH DELAY ; RADIOBIOLOGICAL HYPOXIA ; HSCC XENOGRAFTS ; BI 6727
    Abstract: PURPOSE: Polo-like kinase 1 (PLK1) plays an important role in mitotic progression, is frequently overexpressed and associated with a poor prognosis of cancer patients, thus providing a promising target in anticancer treatment. Aim of the current project was to evaluate the effect of the novel PLK1 inhibitor BI 6727 in combination with irradiation. MATERIAL AND METHODS: In vitro proliferation and radiation cell survival assays as well as in vivo local tumour control assays after single treatment and combined radiation and drug application were carried out using the squamous cell carcinoma models A431 and FaDu. In addition, cell cycle phases were monitored in vitro and in vivo. RESULTS: BI 6727 showed a dose-dependent antiproliferative effect and an increase in the mitotic fraction. BI 6727 alone reduced clonogenic cell survival, while radiosensitivity in vitro (SF2) and in vivo (single-dose TCD50 under clamped hypoxia) was not affected. In contrast, local tumour control was significantly improved after application of BI 6727 simultaneously to fractionated irradiation (A431: TCD50=60.5Gy [95% C.I. 57; 63] after IR alone and 〈30Gy after combined treatment; FaDu: 49.5Gy [43; 56Gy] versus 32.9Gy [26; 40]). CONCLUSIONS: Despite the lack of direct cellular radiosensitisation, PLK1 inhibition with BI 6727 during fractionated irradiation significantly improves local tumour control when compared to irradiation alone. This result is likely explained by a considerable effect on cell cycle and an independent cytotoxic potential of BI 6727.
    Type of Publication: Journal article published
    PubMed ID: 23891096
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  • 4
    Abstract: PURPOSE: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. METHODS AND MATERIALS: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD50) was calculated. RESULTS: BAY-84-7296 decreased nuclear HIF-1alpha expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P〈.0001) and in UT-SCC-14 (0.3% vs 19%, P〈.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD50, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD50. CONCLUSIONS: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation.
    Type of Publication: Journal article published
    PubMed ID: 24331663
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  • 5
    Keywords: radiotherapy ; RADIATION-THERAPY ; CHROMATIN ; REPAIR ; CELLULAR RADIOSENSITIVITY ; DOUBLE-STRAND BREAKS ; INTRINSIC RADIOSENSITIVITY ; RECTAL-CANCER ; HISTONE H2AX ; DNA-DAMAGE CHECKPOINT
    Abstract: PURPOSE: To apply our previously published residual ex vivo gammaH2AX foci method to patient-derived tumour specimens covering a spectrum of tumour-types with known differences in radiation response. In addition, the data were used to simulate different experimental scenarios to simplify the method. MATERIALS AND METHODS: Evaluation of residual gammaH2AX foci in well-oxygenated tumour areas of ex vivo irradiated patient-derived tumour specimens with graded single doses was performed. Immediately after surgical resection, the samples were cultivated for 24h in culture medium prior to irradiation and fixed 24h post-irradiation for gammaH2AX foci evaluation. Specimens from a total of 25 patients (including 7 previously published) with 10 different tumour types were included. RESULTS: Linear dose response of residual gammaH2AX foci was observed in all specimens with highly variable slopes among different tumour types ranging from 0.69 (95% CI: 1.14-0.24) to 3.26 (95% CI: 4.13-2.62) for chondrosarcomas (radioresistant) and classical seminomas (radiosensitive) respectively. Simulations suggest that omitting dose levels might simplify the assay without compromising robustness. CONCLUSION: Here we confirm clinical feasibility of the assay. The slopes of the residual foci number are well in line with the expected differences in radio-responsiveness of different tumour types implying that intrinsic radiation sensitivity contributes to tumour radiation response. Thus, this assay has a promising potential for individualized radiation therapy and prospective validation is warranted.
    Type of Publication: Journal article published
    PubMed ID: 26297183
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  • 6
    Abstract: PURPOSE: To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors. METHODS: Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis-Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M0 was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M0 was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity. RESULTS: After optimization, high pixel-based correlations up to R(2) = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p 〈 0.05), with R(2) ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M0 differed significantly (p 〈 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s. CONCLUSIONS: It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M0, whose optimum value differed significantly between tumor models.
    Type of Publication: Journal article published
    PubMed ID: 27370131
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  • 7
    Keywords: CELLS ; radiotherapy ; REPAIR ; DNA-DAMAGE ; CELLULAR RADIOSENSITIVITY ; DOUBLE-STRAND BREAKS ; CANCER-TREATMENT ; FRACTIONATED-IRRADIATION ; PHOSPHORYLATED HISTONE H2AX ; GENOME MAINTENANCE
    Abstract: PURPOSE: To establish a clinically applicable protocol for quantification of residual gammaH2AX foci in ex vivo irradiated tumour samples and to apply this method in a proof-of-concept feasibility study to patient-derived tumour specimens. MATERIAL AND METHODS: Evaluation of gammaH2AX foci formation and disappearance in excised FaDu tumour specimens after (a) different incubation times in culture medium, 4Gy irradiation and fixation after 24h (cell recovery), (b) 10h medium incubation, 4Gy irradiation and fixation after various time points (double strand break repair kinetics), and (c) 10h medium incubation, irradiation with graded single radiation doses and fixation after 24h (dose-response). The optimised protocol was applied to patient-derived samples of seminoma, prostate cancer and glioblastoma multiforme. RESULTS: Post excision or biopsy, tumour tissues showed stable radiation-induced gammaH2AX foci values in oxic cells after 〉6h of recovery in medium. Kinetics of foci disappearance indicated a plateau of residual foci after 〉12h following ex vivo irradiation. Fitting the dose-response of residual gammaH2AX foci yielded slopes comparable with in situ irradiation of FaDu tumours. Significant differences in the slopes of ex vivo irradiated patient-derived tumour samples were found. CONCLUSION: A novel clinically applicable method to quantify residual gammaH2AX foci in ex vivo irradiated tumour samples was established. The first clinical results suggest that this method allows to distinguish between radiosensitive and radioresistant tumour types. These findings support further translational evaluation of this assay to individualise radiation therapy.
    Type of Publication: Journal article published
    PubMed ID: 25866027
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  • 8
    Abstract: OBJECTIVE: To investigate local tumour control after dose-escalation based on [18F]2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) obtained before and early during fractionated irradiation. MATERIALS AND METHODS: 85 mice bearing FaDu xenografts underwent FDG-PET twice: first immediately prior to the first 2-Gy fraction of irradiation (PET1_0) and second after 18 degrees Gy (PET2_18). After these 9 fractions, animals were randomly allocated to: (1) continuation of 2-Gy fractions (cumulative dose of 60 degrees Gy; n=31), (2) dose-escalation with 3-Gy fractions (cumulative EQD2-dose 86.25 degrees Gy [alpha/beta-value: 10]; n=25), or (3) with 4-Gy fractions (cumulative EQD2-dose 116 degrees Gy; n=29). The effects of SUVmax0 degrees Gy, SUVmax18 degrees Gy, and dose on local tumour control were analysed in two ways. First, the Cox proportional hazards model was used with two covariates: continuous SUVmax values and dose. Second, the Kaplan-Meier method was used, with tumours classified according to SUVmax greater than or less than (1) median maximum standardized uptake value (SUVmax) at PET1_0 and PET2_18, or (2) the cut-off value 2.5. RESULTS: The multivariate Cox analysis revealed a significant negative association between higher SUVmax determined before start of treatment and local control (HR=1.59, [95% CI 1.04, 2.42], p=0.031), whereas higher dose had a significant positive effect (HR=0.95, [0.93, 0.98], p〈0.001). In contrast, FDG uptake at 18Gy did not correlate with local control (HR=1.14, [0.53, 2.45], p=0.73). Neither FDG uptake prior to irradiation nor at 18Gy correlated with local control irrespective of the delivered dose (log-rank test) when using the median SUVmax values for stratification (SUVmax0Gy: 60Gy: p=0.25, 86.25Gy: p=0.47, 116Gy: p=0.88 and SUVmax18Gy: 60Gy: p=0.42, 86.25Gy: p=0.34, 116Gy: p=0.99). By contrast, stratifying the animals by the cut-off 2.5 at PET1_0 reveals a significant difference in local control for the 60Gy group (p=0.034), but not for the other dose groups. At PET2_18, no significant effect for any dose group was detected. CONCLUSIONS: The multivariate Cox analysis revealed a significantly higher hazard of recurrence for mice with higher SUVmax determined before start of treatment. These results support the hypothesis that patients with high pre-therapeutic FDG uptake should be considered at increased risk of local failure and therefore as possible candidates for dose escalation strategies.
    Type of Publication: Journal article published
    PubMed ID: 27544820
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  • 9
    Abstract: INTRODUCTION: The aim of the study is to assess inter-patient and intra-patient heterogeneity in tumour cell radiosensitivity using the ex vivo gammaH2AX assay in prostate cancer specimens. METHODS: Excised specimens from untreated prostate cancer patients were cultivated 24h in media, irradiated ex vivo and fixed after 24h. Residual gammaH2AX foci were counted and the slope of the dose response was calculated. Intra-patient heterogeneity was studied from three to seven different biopsies. RESULTS: In pathology-confirmed tumour samples from 21 patients the slope of residual gammaH2AX foci and radiation dose showed a substantial heterogeneity ranging from 0.82 to 3.17 foci/Gy. No correlation was observed between the slope values and the Gleason score (p=0.37), prostate specific antigen (p=0.48) and tumour stage (p=0.89). ANOVA indicated that only in 1 out of 9 patients, biopsies from different tumour locations yielded statistically significant differences. Variance component analysis indicated higher inter-patient than intra-patient variability. Bootstrap simulation study demonstrated that one biopsy is sufficient to estimate the mean value of residual gammaH2AX per dose level and account for intra-patient heterogeneity. CONCLUSIONS: In prostate cancer inter-patient heterogeneity in tumour cell radiation sensitivity is pronounced and higher than intra-patient heterogeneity supporting the further development of the gammaH2AX ex vivo assay as a biomarker for individualized treatment.
    Type of Publication: Journal article published
    PubMed ID: 28919005
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  • 10
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