https://orcid.org/0000-0001-6805-5989
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Abstract
Purpose
Chordoma is a locally aggressive tumor that most commonly affects the base of the skull/clivus, cervical, and sacral spine. Conventional radiotherapy (RT), cannot be safely increased further to improve disease control due to the risk of toxicity to the surrounding critical structures. Tumor-targeted hyperthermia (HT) combined with Proton Beam Radiation Therapy (PBRT) is known to act as a potent radiosensitizer in cancer control. In this study, we investigated whether PBRT efficacy for chordoma can be enhanced in combination with HT as a radiosensitizer.
Material and methods
Human chordoma cell lines, U-CH2 and Mug-chor1 were treated in vitro with HT followed by PBRT with variable doses. The colony-forming assay was performed, and dose-response was characterized by linear-quadratic model fits. HSP-70 and Brachyury (TBXT) biomarkers for chordoma aggression levels were quantified by western blot analysis. Gene microarray analysis was performed by U133 Arrays. Pathway Analysis was also performed using IPA bioinformatic software.
Results
Our findings in both U-CH2 and Mug–Chor1 cell lines demonstrate that hyperthermia followed by PBRT has an enhanced cell killing effect when compared with PBRT-alone (p < .01). Western blot analysis showed HT decreased the expression of Brachyury protein (p < .05), which is considered a biomarker for chordoma tumor aggression. HT with PBRT also exhibited an RT-dose-dependent decrease of Brachyury expression (p < .05). We also observed enhanced HSP-70 expression due to HT, RT, and HT + RT combined in both cell lines. Interestingly, genomic data showed 344 genes expressed by the treatment of HT + RT compared to HT (68 genes) or RT (112 genes) as individual treatment. We also identified activation of death receptor and apoptotic pathway in HT + RT treated cells.
Conclusion
We found that Hyperthermia (HT) combined with Proton Beam Radiation (PBRT) could significantly increase chordoma cell death by activating the death receptor pathway and apoptosis which has the promise to treat metastatic chordoma.
Acknowledgments
Authors thanks to Department of Radiation Oncology Chair, William Regine for providing financial support and help in discussion for possible clinical significance and trial.
Ethical approval
This study was duly approved by the University of Maryland School of Medicine Ethics Committee.
Authors’ contributions
This study was designed by HDS, JM, JE and ZV, the research work was performed by PS, JE, BB, MC, TD and NM. The manuscript was written by HDS, JM, AS, DBR and SM.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All generated data in this study has been presented in this manuscript.
Additional information
Funding
Notes on contributors
Prerna Singh
Prerna Singh, Department of Radiation Oncology, University of Maryland School of Medicine. She has recently completed her MS degree in Molecular Medicine program at the University of Maryland School of Medicine.
John Eley
Dr John Eley is an Assistant Professor in the Department of Radiation Oncology, Vanderbilt University School of Medicine. He obtained his PhD from the University of Texas Graduate School of Biomedical Sciences at Houston in Medical Physics. Further, completed his fellowship from the University of Texas MD Anderson Cancer Center in Proton Therapy.
Ali Saeed
Dr Ali Saeed obtained his MD, PhD, from the University of Miami School of Medicine. He is a resident physician in the University of Maryland Medical System and Department of Radiation Oncology, University of Maryland School of Medicine.
Binny Bhandary
Binny Bhandary completed her MS in biology from Kansas State University and currently works as Research Specialist in Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD.
Nayab Mahmood
Nayab Mahmood is an undergraduate student at the Department of Biology and College of Information Science, University of Maryland at College Park.
Minjie Chen
Dr Minjie Chen is a Post-Doctoral fellow in the Division of Translational Radiation Sciences, University of Maryland School of Medicine, Radiation Oncology. She completed her PhD from Medical College of Georgia, Augusta University.
Tijana Dukic
Tijana Dukic completed her DDS from Serbia and currently she is working as Research Specialist in the Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine.
Sina Mossahebi
Dr Sina Mossahebi received his M.S. and Ph.D. degrees in Physics and Biophysics, respectively, from Washington University in St. Louis. After finishing his graduate school, he completed a one-year Medical Physics Certificate Program in Medical Physics at the University of Chicago. In 2015, he was accepted to Medical Physics residency program at the University of Maryland School of Medicine. Upon completion of his residency, Dr. Mossahebi joined as an Assistant Professor and Clinical Medical Physicist at the University of Maryland School of Medicine to help with the Medical Physics efforts at the Maryland Proton Treatment Center.
Dario B. Rodrigues
Dr Dario B. Rodrigues completed his Ph.D. in Biomedical Engineering from New University of Lisbon, Portugal in 2013 and completed his Postdoctoral Research from Duke University. He is an Assistant Professor in Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine. His specialty is to treat cancer using focused heat generated by radio waves, a thermal therapy technique also known as hyperthermia, which is a potent enhancer of chemo- and radiotherapy. As a physicist, Dr. Rodrigues performs adjuvant hyperthermia treatments of pelvic, abdominal, and superficial tumors.
Javed Mahmood
Dr Javed Mahmood is a Senior Clinical Scientist at Bristol Myers Squibb. He received his Ph.D. degree in Biochemistry from Hokkaido University. He published various articles in international journals. Dr. Mahmood`s research interests are focused on laboratory and translational research studies in tumor and normal tissue radiobiology, metastasis and aspects of the tumor microenvironment, notably tumor hypoxia.
Zeljko Vujaskovic
Dr Zeljko Vujaskovic, M.D., Ph.D., is a Physician/Scientist and Professor who heads the Division of Translational Radiation Sciences in the Department of Radiation Oncology at the University of Maryland School of Medicine (UMSOM) in Baltimore. He received his M.D. from University of Zagreb School of Medicine, Croatia and PhD from Colorado State University, Fort Collins. From 1999 to 2012, Dr. Vujaskovic served as a clinical radiation oncologist and director of the Normal Tissue Injury Laboratory at Duke University, where he was an Associate Professor of Radiation Oncology, Pathology, and Medical Physics. At Duke he also directed the Clinical Hyperthermia Program and served as associate director of the General Clinical Research Center. His laboratory focused on elucidating mechanisms underlying radiation injury and radiation therapy-induced toxicities in normal tissue. With his laboratory members, he published a series of seminal articles on tissue hypoxia and radiation exposure. For more than 30 years, his career has been defined by transdisciplinary research that bridges the gap between basic science and clinical research to ultimately improve outcomes and long-term quality of life among cancer patients.
Hem D. Shukla
Dr Hem D. Shukla is an Assistant Professor at the Division of Translational Radiation Sciences in the Department of Radiation Oncology at the University of Maryland School of Medicine. He obtained his Ph.D. in Biochemistry at R. D. University Jabalpur in India and completed his post-doctoral training from University of Massachusetts Amherst. Later, he finished his training in cancer biology from National Institutes of Health and Institute of Cell Engineering at Johns Hopkins University School of Medicine. Dr. Shukla is currently working as an active team member in the Division of Translational Radiation Sciences (DTRS, UMB) under the leadership of Dr. Zeljko Vujaskovic MD, PhD. The main focus of his research is radiation-induced modulation of immuno-suppressive tumor microenvironment in pancreatic and non-small cell lung cancers. His lab is also interested in cancer immunotherapy and using targeted therapeutics to inhibit specific pathways mutated in cancers.