Author:
Chaiyawat Parunya,Phanphaisarn Areerak,Sirikaew Nutnicha,Klangjorhor Jeerawan,Thepbundit Viraporn,Teeyakasem Pimpisa,Phinyo Phichayut,Pruksakorn Dumnoensun,Settakorn Jongkolnee
Abstract
AbstractOsteosarcoma is one of the most aggressive bone tumors in children and adolescents. Development of effective therapeutic options is still lacking due to the complexity of the genomic background. In previous work, we applied a proteomics-guided drug repurposing to explore potential treatments for osteosarcoma. Our follow-up study revealed an FDA-approved immunosuppressant drug, mycophenolate mofetil (MMF) targeting inosine-5′-phosphate dehydrogenase (IMPDH) enzymes, has an anti-tumor effect that appeared promising for further investigation and clinical trials. Profiling of IMPDH2 and hypoxanthine–guanine phosphoribosyltransferase (HPRT), key purine-metabolizing enzymes, could deepen understanding of the importance of purine metabolism in osteosarcoma and provide evidence for expanded use of MMF in the clinic. In the present study, we investigated levels of IMPDH2, and HPRT in biopsy of 127 cases and post-chemotherapy tissues in 20 cases of high-grade osteosarcoma patients using immunohistochemical (IHC) analysis. Cox regression analyses were performed to determine prognostic significance of all enzymes. The results indicated that low levels of HPRT were significantly associated with a high Enneking stage (P = 0.023) and metastatic status (P = 0.024). Univariate and multivariate analyses revealed that patients with low HPRT expression have shorter overall survival times [HR 1.70 (1.01–2.84), P = 0.044]. Furthermore, high IMPDH2/HPRT ratios were similarly associated with shorter overall survival times [HR 1.67 (1.02–2.72), P = 0.039]. Levels of the enzymes were also examined in post-chemotherapy tissues. The results showed that high IMPDH2 expression was associated with shorter metastasis-free survival [HR 7.42 (1.22–45.06), P = 0.030]. These results suggest a prognostic value of expression patterns of purine-metabolizing enzymes for the pre- and post-chemotherapy period of osteosarcoma treatment.
Funder
National Science and Technology Development Agency
Publisher
Springer Science and Business Media LLC
Reference42 articles.
1. Pruksakorn, D. et al. Age standardized incidence rates and survival of osteosarcoma in Northern Thailand. Asian Pac. J. Cancer Prev. 17, 3455–3458 (2016).
2. Wittig, J. C. et al. Osteosarcoma: a multidisciplinary approach to diagnosis and treatment. Am. Fam. Phys. 65, 1123–1132 (2002).
3. Meyers, P. A. et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J. Clin. Oncol. 23, 2004–2011. https://doi.org/10.1200/JCO.2005.06.031 (2005).
4. Bishop, M. W., Janeway, K. A. & Gorlick, R. Future directions in the treatment of osteosarcoma. Curr. Opin. Pediatr. 28, 26–33. https://doi.org/10.1097/MOP.0000000000000298 (2016).
5. Pruksakorn, D. et al. Survival rate and prognostic factors of conventional osteosarcoma in Northern Thailand: A series from Chiang Mai University Hospital. Cancer Epidemiol. 39, 956–963. https://doi.org/10.1016/j.canep.2015.10.016 (2015).
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献