MRI-based high-precision irradiation in an orthotopic pancreatic tumor mouse model

Dobiasch, Sophie; Kampfer, S.; Habermehl, Daniel; Duma, Marciana Nona; Felix, Klaus; Strauss, Albert; Schilling, Daniela; Wilkens, Jan J.; Combs, Stephanie E.

doi:10.1007/s00066-018-1326-y

Cited by 13 publications

(9 citation statements)

References 17 publications

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“…However, we could not assess overall survival in KPC mice as the treatment schedule with irradiations, ultrasound examinations (including repeated sedations), and drug administration is not feasible for longer than two weeks. Magnetic-resonance imaging-guided imaging approaches may be suitable to further optimize targeted radiotherapy in mice [47].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer

Goetze¹,

Buchholz²,

et al. 2019

Cells

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Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer

Goetze¹,

Buchholz²,

et al. 2019

Cells

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“…We therefore evaluated our MR-guided RT approach using a single high dose to obtain proof-of-concept. While MR-guided RT has been reported in rat models of prostate, pancreas, and brain tumors [34][35][36], to the best of our knowledge, the potential of this approach has not been previously demonstrated in HNSCC. Our results also highlight the superior targeting ability of VMAT with minimal dose to OAR.…”

Section: Discussionmentioning

confidence: 89%

Development and Validation of a Clinically Relevant Workflow for MR-Guided Volumetric Arc Therapy in a Rabbit Model of Head and Neck Cancer

Bolookat

Malhotra

Rich

et al. 2020

Cancers

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There is increased interest in the use of magnetic resonance imaging (MRI) for guiding radiation therapy (RT) in the clinical setting. In this regard, preclinical studies can play an important role in understanding the added value of MRI in RT planning. In the present study, we developed and validated a clinically relevant integrated workflow for MRI-guided volumetric arc therapy (VMAT) in a VX2 rabbit neck tumor model of HNSCC. In addition to demonstrating safety and feasibility, we examined the therapeutic impact of MR-guided VMAT using a single high dose to obtain proof-of-concept and compared the response to conventional 2D-RT. Contrast-enhanced MRI (CE-MRI) provided excellent soft tissue contrast for accurate tumor segmentation for VMAT. Notably, MRI-guided RT enabled improved tumor targeting ability and minimal dose to organs at risk (OAR) compared to 2D-RT, which resulted in notable morbidity within a few weeks of RT. Our results highlight the value of integrating MRI into the workflow for VMAT for improved delineation of tumor anatomy and optimal treatment planning. The model combined with the multimodal imaging approach can serve as a valuable platform for the conduct of preclinical RT trials.

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“…Our experiments provide evidence for the in vitro radiosensitizing effect of VS-4718 in multicellular 2D and 3D models of PDAC. With the advancement of irradiation techniques in preclinical models, our data will open the door in the future to allow the evaluation of the radiosensitizing effect of FAK inhibition in vivo [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

et al. 2020

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Introduction Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase protein frequently overexpressed in cancer and has been linked to an increase in the stem cell population of tumors, resistance to therapy, and metastatic spread. Pharmacological FAK inhibition in pancreatic cancer has received increased attention over the last few years, either alone or in combination with other therapeutics including chemotherapy and immunotherapy. However, its prognostic value and its role in radioresistance of pancreatic ducal adenocarcinoma (PDAC) is unknown. Methods and materials Using the TCGA and GTEx databases, we investigated the genetic alterations and mRNA expression levels of PTK2 (the encoding-gene for FAK) in normal pancreatic tissue and pancreatic cancer and its impact on patient survival. Furthermore, we evaluated the expression of FAK and its tyrosine domain Ty-397 in three pancreatic cancer cell lines. We went further and evaluated the role of a commercial FAK tyrosine kinase inhibitor VS-4718 on the viability and radiosensitization of the pancreatic cell lines as well as its effect on the extracellular matrix (ECM) production from the pancreatic stellate cells. Furthermore, we tested the effect of combining radiation with VS-4718 in a three-dimensional (3D) multicellular pancreatic tumor spheroid model. Results A database analysis revealed a relevant increase in genetic alterations and mRNA expression of the PTK2 in PDAC, which were associated with lower progression-free survival. In vitro, there was only variation in the basal phosphorylation level of FAK in cell lines. VS-4718 radiosensitized pancreatic cell lines only in the presence of ECM-producing pancreatic stellate cells and markedly reduced the ECM production in the stromal cells. Finally, using a 3D multicellular tumor model, the combination of VS-4718 and radiotherapy significantly reduced the growth of tumor aggregates. Conclusion Pharmacological inhibition of FAK in pancreatic cancer could be a novel therapeutic strategy as our results show a radiosensitization effect of VS-4718 in vitro in a multicellular 2D-and in a 3D-model of pancreatic cancer.

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MRI-based high-precision irradiation in an orthotopic pancreatic tumor mouse model

Cited by 13 publications

References 17 publications

Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer

Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer

Development and Validation of a Clinically Relevant Workflow for MR-Guided Volumetric Arc Therapy in a Rabbit Model of Head and Neck Cancer

FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

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