Dataset Information

Combining antiangiogenic therapy and radiation in nasopharyngeal carcinoma.

ABSTRACT: Radiation therapy is the primary treatment in nasopharyngeal carcinoma (NPC), and the effect of radiation therapy is strongly related to the oxygen content of cancer cells. That means, it is imperative to balance the interactions between radiotherapy and anti-angiogenesis therapy when giving combination therapy to improve clinical outcomes. The complicated mechanisms between antiangiogenic agents and radiation involve many interactions between the cancer cells, vasculature, and cancer stroma. The proliferation and metastasis of cancer depends on angiogenesis, while rapid growth of cancers will cause hypoxia, which contributes to radioresistance. Antiangiogenic agents can modulate the cancer blood flow and oxygenation through target cancer vasculature, leading to increased radiosensitivity. This study discusses the mechanisms of the synergistic effect of the antiangiogenic therapy with radiation therapy in metastatic NPC, and reviews the data supporting this strategy as a promising treatment for metastatic NPC.

SUBMITTER: Chen Z

PROVIDER: S-EPMC4454898 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Combining antiangiogenic therapy and radiation in nasopharyngeal carcinoma.

Chen Zhuo Z Xu Xin-Hua XH

Saudi medical journal 20150601 6

Radiation therapy is the primary treatment in nasopharyngeal carcinoma (NPC), and the effect of radiation therapy is strongly related to the oxygen content of cancer cells. That means, it is imperative to balance the interactions between radiotherapy and anti-angiogenesis therapy when giving combination therapy to improve clinical outcomes. The complicated mechanisms between antiangiogenic agents and radiation involve many interactions between the cancer cells, vasculature, and cancer stroma. Th ...[more]

PMID: 25987106

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Project description:Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern China, southeastern Asia and northern Africa. Radiation resistance remains a serious obstacle to successful treatment in NPC. This study aimed to explore the metabolic feature of radiation-resistant NPC cells and identify new molecular-targeted agents to improve the therapeutic effects of radiotherapy in NPC. Methods: Radiation-responsive and radiation-resistant NPC cells were used as the model system in vitro and in vivo. Metabolomics approach was used to illustrate the global metabolic changes. 13C isotopomer tracing experiment and Seahorse XF analysis were undertaken to determine the activity of fatty acid oxidation (FAO). qRT-PCR was performed to evaluate the expression of essential FAO genes including CPT1A. NPC tumor tissue microarray was used to investigate the prognostic role of CPT1A. Either RNA interference or pharmacological blockade by Etomoxir were used to inhibit CPT1A. Radiation resistance was evaluated by colony formation assay. Mitochondrial membrane potential, apoptosis and neutral lipid content were measured by flow cytometry analysis using JC-1, Annexin V and LipidTOX Red probe respectively. Molecular markers of mitochondrial apoptosis were detected by western blot. Xenografts were treated with Etomoxir, radiation, or a combination of Etomoxir and radiation. Mitochondrial apoptosis and lipid droplets content of tumor tissues were detected by cleaved caspase 9 and Oil Red O staining respectively. Liquid chromatography coupled with tandem mass spectrometry approach was used to identify CPT1A-binding proteins. The interaction of CPT1A and Rab14 were detected by immunoprecipitation, immunofluorescence and in situ proximity ligation analysis. Fragment docking and direct coupling combined computational protein-protein interaction prediction method were used to predict the binding interface. Fatty acid trafficking was measured by pulse-chase assay using BODIPY C16 and MitoTracker Red probe. Results: FAO was active in radiation-resistant NPC cells, and the rate-limiting enzyme of FAO, carnitine palmitoyl transferase 1 A (CPT1A), was consistently up-regulated in these cells. The protein level of CPT1A was significantly associated with poor overall survival of NPC patients following radiotherapy. Inhibition of CPT1A re-sensitized NPC cells to radiation therapy by activating mitochondrial apoptosis both in vitro and in vivo. In addition, we identified Rab14 as a novel CPT1A binding protein. The CPT1A-Rab14 interaction facilitated fatty acid trafficking from lipid droplets to mitochondria, which decreased radiation-induced lipid accumulation and maximized ATP production. Knockdown of Rab14 attenuated CPT1A-mediated fatty acid trafficking and radiation resistance. Conclusion: An active FAO is a vital signature of NPC radiation resistance. Targeting CPT1A could be a beneficial regimen to improve the therapeutic effects of radiotherapy in NPC patients. Importantly, the CPT1A-Rab14 interaction plays roles in CPT1A-mediated radiation resistance by facilitating fatty acid trafficking. This interaction could be an attractive interface for the discovery of novel CPT1A inhibitors.

Project description:Background and purpose: Adaptive radiotherapy (ART) can compensate for the dosimetric impacts induced by anatomic and geometric variations in patients with nasopharyngeal carcinoma (NPC); Yet, the need for ART can only be assessed during the radiation treatment and the implementation of ART is resource intensive. Therefore, we aimed to determine tumoral biomarkers using pre-treatment MR images for predicting ART eligibility in NPC patients prior to the start of treatment. Methods: Seventy patients with biopsy-proven NPC (Stage II-IVB) in 2015 were enrolled into this retrospective study. Pre-treatment contrast-enhanced T1-w (CET1-w), T2-w MR images were processed and filtered using Laplacian of Gaussian (LoG) filter before radiomic features extraction. A total of 479 radiomics features, including the first-order (n = 90), shape (n = 14), and texture features (n = 375), were initially extracted from Gross-Tumor-Volume of primary tumor (GTVnp) using CET1-w, T2-w MR images. Patients were randomly divided into a training set (n = 51) and testing set (n = 19). The least absolute shrinkage and selection operator (LASSO) logistic regression model was applied for radiomic model construction in training set to select the most predictive features to predict patients who were replanned and assessed in the testing set. A double cross-validation approach of 100 resampled iterations with 3-fold nested cross-validation was employed in LASSO during model construction. The predictive performance of each model was evaluated using the area under the receiver operator characteristic (ROC) curve (AUC). Results: In the present cohort, 13 of 70 patients (18.6%) underwent ART. Average AUCs in training and testing sets were 0.962 (95%CI: 0.961-0.963) and 0.852 (95%CI: 0.847-0.857) with 8 selected features for CET1-w model; 0.895 (95%CI: 0.893-0.896) and 0.750 (95%CI: 0.745-0.755) with 6 selected features for T2-w model; and 0.984 (95%CI: 0.983-0.984) and 0.930 (95%CI: 0.928-0.933) with 6 selected features for joint T1-T2 model, respectively. In general, the joint T1-T2 model outperformed either CET1-w or T2-w model alone. Conclusions: Our study successfully showed promising capability of MRI-based radiomics features for pre-treatment identification of ART eligibility in NPC patients.

Project description:BACKGROUND:Conventional phantom-based planar dosimetry (2D-PBD) quality assurance (QA) using gamma pass rate (GP (%)) is inadequate to reflect clinically relevant dose error in intensity-modulated radiation therapy (IMRT), owing to a lack of information regarding patient anatomy and volumetric dose distribution. This study aimed to evaluate the dose distribution accuracy of IMRT delivery for nasopharyngeal carcinoma (NPC), which passed the 2D-PBD verification, using a measurement-guided 3D dose reconstruction (3D-MGR) method. METHODS:Radiation treatment plans of 30 NPC cases and their pre-treatment 2D-PBD data were analyzed. 3D dose distribution was reconstructed on patient computed tomography (CT) images using the 3DVH software and compared to the treatment plans. Global and organ-specific dose GP (%), and dose-volume histogram (DVH) deviation of each structure was evaluated. Interdependency between GP (%) and the deviation of the volumetric dose was studied through correlation analysis. RESULTS:The 3D-MGR achieved global GP (%) similar to conventional 2D-PBD in the same criteria. However, structure-specific GP (%) significantly decreased under stricter criteria, including the planning target volume (PTV). The average deviation of all inspected dose volumes (DV) and volumetric dose (VD) parameters ranged from -?2.93% to 1.17%, with the largest negative deviation in V100% of the PTVnx of -?15.66% and positive deviation in D1cc of the spinal cord of 6.66%. There was no significant correlation between global GP (%) of 2D-PBD or 3D-MGR and the deviation of the most volumetric dosimetry parameters (DV or VD), when the Pearson's coefficient value of 0.8 was used for correlation evaluation. CONCLUSION:Even upon passing the pre-treatment phantom based dosimetric QA, there could still be risk of dose error like under-dose in PTVnx and overdose in critical structures. Measurement-guided 3D volumetric dosimetry QA is recommended as the more clinically efficient verification for the complicated NPC IMRT.

Dataset Information

Combining antiangiogenic therapy and radiation in nasopharyngeal carcinoma.

Publications

Combining antiangiogenic therapy and radiation in nasopharyngeal carcinoma.

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