1.png)
Repurposing drugs in endometrial cancer using genomic variants database
Abstract
Endometrial cancer (EC) is the fourth most frequent gynecological cancers, and its incidence and mortality rates have increased over the last decade. Cytotoxic therapy with carboplatin and paclitaxel is the recommended first-line treatment for EC patients. However, the options for following therapy are limited. The latest advances in molecular studies have uncovered the nature of genetic alterations in EC, compelling methods for further research into the treatment of EC since they may disclose to tailored pharmacological therapy. The aim of this study to identify novel drug candidates in treating EC using genomics variants and biological pathway. The genomic variants of EC were downloaded from cBioportal database. We established connection between the biological EC risk genes from cBioportal database and the DrugBank database. Finally, we used Connectivity Map (CMap) analysis to identify possible drugs whose mechanisms coincided with therapeutic targets and rank them based on the scoring system. We identified novel potential candidate drugs for EC, they are Bosutinib and Nilutamide which exhibit robust scores in the CMap analysis compare to paclitaxel. We also discovered BCR-ABL1 and AR as potential biomarker-driven therapy in EC. This study demonstrates the possibility of using genetic network analysis combined with bioinformatics to repurpose drugs for the treatment of EC. Further study will investigate the mechanisms of using BCR-ABL1 and AR targeting in the treatment of EC.
Keywords
Full Text:
PDFReferences
Ackroyd, S. A., Huang, E. S., Kurnit, K. C., & Lee, N. K. (2021). Pembrolizumab and lenvatinib versus carboplatin and paclitaxel as first-line therapy for advanced or recurrent endometrial cancer: A Markov analysis. Gynecol Oncol, 162(2), 249-255. https://doi.org/10.1016/j.ygyno.2021.05.038
Adikusuma, W., Chou, W. H., Lin, M. R., Ting, J., Irham, L. M., Perwitasari, D. A., Chang, W. P., & Chang, W. C. (2022). Identification of Druggable Genes for Asthma by Integrated Genomic Network Analysis. Biomedicines, 10(1). https://doi.org/10.3390/biomedicines10010113
Afief, A. R., Irham, L. M., Adikusuma, W., Perwitasari, D. A., Brahmadhi, A., & Cheung, R. (2022). Integration of genomic variants and bioinformatic-based approach to drive drug repurposing for multiple sclerosis. Biochem Biophys Rep, 32, 101337. https://doi.org/10.1016/j.bbrep.2022.101337
Ajabnoor, G., Alsubhi, F., Shinawi, T., Habhab, W., Albaqami, W. F., Alqahtani, H. S., Nasief, H., Bondagji, N., Elango, R., Shaik, N. A., & Banaganapalli, B. (2022). Computational approaches for discovering significant microRNAs, microRNA-mRNA regulatory pathways, and therapeutic protein targets in endometrial cancer. Front Genet, 13, 1105173. https://doi.org/10.3389/fgene.2022.1105173
American Cancer Society (2019, 27th March 2019). What is endometrial cancer? Retrieved 18th July 2022 from
Banno, K., Iida, M., Yanokura, M., Irie, H., Masuda, K., Kobayashi, Y., Tominaga, E., & Aoki, D. (2015). Drug repositioning for gynecologic tumors: a new therapeutic strategy for cancer. ScientificWorldJournal, 2015, 341362. https://doi.org/10.1155/2015/341362
Bousfiha, A., Jeddane, L., Picard, C., Al-Herz, W., Ailal, F., Chatila, T., Cunningham-Rundles, C., Etzioni, A., Franco, J. L., Holland, S. M., Klein, C., Morio, T., Ochs, H. D., Oksenhendler, E., Puck, J., Torgerson, T. R., Casanova, J. L., Sullivan, K. E., & Tangye, S. G. (2020). Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol, 40(1), 66-81. https://doi.org/10.1007/s10875-020-00758-x
Cancer Genome Atlas Research Network. (2013). Integrated genomic characterization of endometrial carcinoma. Nature, 497(7447), 67-73. https://doi.org/10.1038/nature12113
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., Antipin, Y., Reva, B., Goldberg, A. P., Sander, C., & Schultz, N. (2012). The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov, 2(5), 401-404. https://doi.org/10.1158/2159-8290.Cd-12-0095
Connor, E. V., & Rose, P. G. (2018). Management Strategies for Recurrent Endometrial Cancer. Expert Rev Anticancer Ther, 18(9), 873-885. https://doi.org/10.1080/14737140.2018.1491311
Hashmi, A. A., Hussain, Z. F., Qadri, A., Irfan, M., Ramzan, S., Faridi, N., Khan, A., & Edhi, M. M. (2018). Androgen receptor expression in endometrial carcinoma and its correlation with clinicopathologic features. BMC Res Notes, 11(1), 289. https://doi.org/10.1186/s13104-018-3403-9
Hunsu, V. O., Facey, C. O. B., Fields, J. Z., & Boman, B. M. (2021). Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies. Int J Mol Sci, 22(14). https://doi.org/10.3390/ijms22147731
Irham, L. M., Adikusuma, W., & Perwitasari, D. A. (2022). Genomic variants-driven drug repurposing for tuberculosis by utilizing the established bioinformatic-based approach. Biochem Biophys Rep, 32, 101334. https://doi.org/10.1016/j.bbrep.2022.101334
Irham, L. M., Adikusuma, W., Perwitasari, D. A., Dania, H., Maliza, R., Faridah, I. N., Santri, I. N., Phiri, Y. V. A., & Cheung, R. (2022). The use of genomic variants to drive drug repurposing for chronic hepatitis B. Biochem Biophys Rep, 31, 101307. https://doi.org/10.1016/j.bbrep.2022.101307
Irie, H., Banno, K., Yanokura, M., Iida, M., Adachi, M., Nakamura, K., Umene, K., Nogami, Y., Masuda, K., Kobayashi, Y., Tominaga, E., & Aoki, D. (2016). Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning. Oncol Lett, 11(2), 1287-1293. https://doi.org/10.3892/ol.2016.4075
Lamb, J., Crawford, E. D., Peck, D., Modell, J. W., Blat, I. C., Wrobel, M. J., Lerner, J., Brunet, J. P., Subramanian, A., Ross, K. N., Reich, M., Hieronymus, H., Wei, G., Armstrong, S. A., Haggarty, S. J., Clemons, P. A., Wei, R., Carr, S. A., Lander, E. S., & Golub, T. R. (2006). The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 313(5795), 1929-1935. https://doi.org/10.1126/science.1132939
Liao, Y., Wang, J., Jaehnig, E. J., Shi, Z., & Zhang, B. (2019). WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res, 47(W1), W199-w205. https://doi.org/10.1093/nar/gkz401
Lortet-Tieulent, J., Ferlay, J., Bray, F., & Jemal, A. (2018). International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. J Natl Cancer Inst, 110(4), 354-361. https://doi.org/10.1093/jnci/djx214
Lu, K. H., & Broaddus, R. R. (2020). Endometrial Cancer. N Engl J Med, 383(21), 2053-2064. https://doi.org/10.1056/NEJMra1514010
Lu, X., Jing, L., Liu, S., Wang, H., & Chen, B. (2022). miR-149-3p Is a Potential Prognosis Biomarker and Correlated with Immune Infiltrates in Uterine Corpus Endometrial Carcinoma. Int J Endocrinol, 2022, 5006123. https://doi.org/10.1155/2022/5006123
Massimino, M., Stella, S., Tirrò, E., Pennisi, M. S., Vitale, S. R., Puma, A., Romano, C., S, D. I. G., Tomarchio, C., F, D. I. R., & Manzella, L. (2020). ABL1-Directed Inhibitors for CML: Efficacy, Resistance and Future Perspectives. Anticancer Res, 40(5), 2457-2465. https://doi.org/10.21873/anticanres.14215
Morice, P., Leary, A., Creutzberg, C., Abu-Rustum, N., & Darai, E. (2016). Endometrial cancer. Lancet, 387(10023), 1094-1108. https://doi.org/10.1016/S0140-6736(15)00130-0
Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., Doig, A., Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D., & Pirmohamed, M. (2019). Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov, 18(1), 41-58. https://doi.org/10.1038/nrd.2018.168
Randall, M. E., Filiaci, V., McMeekin, D. S., von Gruenigen, V., Huang, H., Yashar, C. M., Mannel, R. S., Kim, J. W., Salani, R., DiSilvestro, P. A., Burke, J. J., Rutherford, T., Spirtos, N. M., Terada, K., Anderson, P. R., Brewster, W. R., Small, W., Aghajanian, C. A., & Miller, D. S. (2019). Phase III Trial: Adjuvant Pelvic Radiation Therapy Versus Vaginal Brachytherapy Plus Paclitaxel/Carboplatin in High-Intermediate and High-Risk Early Stage Endometrial Cancer. J Clin Oncol, 37(21), 1810-1818. https://doi.org/10.1200/jco.18.01575
Reichert, Z. R., & Hussain, M. (2016). Androgen Receptor and Beyond, Targeting Androgen Signaling in Castration-Resistant Prostate Cancer. Cancer J, 22(5), 326-329. https://doi.org/10.1097/ppo.0000000000000214
Santri, I. N., Irham, L. M., Djalilah, G. N., Perwitasari, D. A., Wardani, Y., Phiri, Y. V. A., & Adikusuma, W. (2022). Identification of Hub Genes and Potential Biomarkers for Childhood Asthma by Utilizing an Established Bioinformatic Analysis Approach. Biomedicines, 10(9). https://doi.org/10.3390/biomedicines10092311
Sharma, T. S. K., & Hwa, K. Y. (2021). Rational design and preparation of copper vanadate anchored on sulfur doped reduced graphene oxide nanocomposite for electrochemical sensing of antiandrogen drug nilutamide using flexible electrodes. J Hazard Mater, 410, 124659. https://doi.org/10.1016/j.jhazmat.2020.124659
Siegel, R. L., Miller, K. D., & Jemal, A. (2015). Cancer statistics, 2015. CA Cancer J Clin, 65(1), 5-29. https://doi.org/10.3322/caac.21254
Siegel, R. L., Miller, K. D., Wagle, N. S., & Jemal, A. (2023). Cancer statistics, 2023. CA Cancer J Clin, 73(1), 17-48. https://doi.org/10.3322/caac.21763
Subramanian, A., Narayan, R., Corsello, S. M., Peck, D. D., Natoli, T. E., Lu, X., Gould, J., Davis, J. F., Tubelli, A. A., Asiedu, J. K., Lahr, D. L., Hirschman, J. E., Liu, Z., Donahue, M., Julian, B., Khan, M., Wadden, D., Smith, I. C., Lam, D., Liberzon, A., Toder, C., Bagul, M., Orzechowski, M., Enache, O. M., Piccioni, F., Johnson, S. A., Lyons, N. J., Berger, A. H., Shamji, A. F., Brooks, A. N., Vrcic, A., Flynn, C., Rosains, J., Takeda, D. Y., Hu, R., Davison, D., Lamb, J., Ardlie, K., Hogstrom, L., Greenside, P., Gray, N. S., Clemons, P. A., Silver, S., Wu, X., Zhao, W. N., Read-Button, W., Wu, X., Haggarty, S. J., Ronco, L. V., Boehm, J. S., Schreiber, S. L., Doench, J. G., Bittker, J. A., Root, D. E., Wong, B., & Golub, T. R. (2017). A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell, 171(6), 1437-1452.e1417. https://doi.org/10.1016/j.cell.2017.10.049
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 71(3), 209-249. https://doi.org/10.3322/caac.21660
Surveillance, Epidemiology and End Results, (SEER) Program. (2023). Cancer Stat Facts: Uterine Cancer. Retrieved 7 April 2023 from https://seer.cancer.gov/statfacts/html/corp.html
Tangen, I. L., Onyango, T. B., Kopperud, R., Berg, A., Halle, M. K., Øyan, A. M., Werner, H. M., Trovik, J., Kalland, K. H., Salvesen, H. B., & Krakstad, C. (2016). Androgen receptor as potential therapeutic target in metastatic endometrial cancer. Oncotarget, 7(31), 49289-49298. https://doi.org/10.18632/oncotarget.10334
Torricelli, F., Sauta, E., Manicardi, V., Mandato, V. D., Palicelli, A., Ciarrocchi, A., & Manzotti, G. (2023). An Innovative Drug Repurposing Approach to Restrain Endometrial Cancer Metastatization. Cells, 12(5). https://doi.org/10.3390/cells12050794
Watanabe, E., Yokoi, A., Yoshida, K., Sugiyama, M., Kitagawa, M., Nishino, K., Yamamoto, E., Niimi, K., Yamamoto, Y., & Kajiyama, H. (2023). Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma. Cancer Med, 12(4), 4543-4556. https://doi.org/10.1002/cam4.5243
Wishart, D. S., Feunang, Y. D., Guo, A. C., Lo, E. J., Marcu, A., Grant, J. R., Sajed, T., Johnson, D., Li, C., Sayeeda, Z., Assempour, N., Iynkkaran, I., Liu, Y., Maciejewski, A., Gale, N., Wilson, A., Chin, L., Cummings, R., Le, D., Pon, A., Knox, C., & Wilson, M. (2018). DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res, 46(D1), D1074-d1082. https://doi.org/10.1093/nar/gkx1037
Wu, X., Zhong, X., Huo, X., Zhang, J., Yang, X., & Zhang, Y. (2022). The Clinicopathological Significance and Prognostic Value of Androgen Receptor in Endometrial Carcinoma: A Meta-Analysis. Front Oncol, 12, 905809. https://doi.org/10.3389/fonc.2022.905809
Zhang, S., Gong, T. T., Liu, F. H., Jiang, Y. T., Sun, H., Ma, X. X., Zhao, Y. H., & Wu, Q. J. (2019). Global, Regional, and National Burden of Endometrial Cancer, 1990-2017: Results From the Global Burden of Disease Study, 2017. Front Oncol, 9, 1440. https://doi.org/10.3389/fonc.2019.01440
Zhao, Y., Zhu, Y., Wang, H., & Ji, C. (2021). Case Report: Successful Treatment of Cutaneous Squamous Cell Carcinoma in Three Patients With a Combination of Acitretin and Clarithromycin. Front Oncol, 11, 650974. https://doi.org/10.3389/fonc.2021.650974
Zhu, L., & Chen, L. (2019). Progress in research on paclitaxel and tumor immunotherapy. Cell Mol Biol Lett, 24, 40. https://doi.org/10.1186/s11658-019-0164-y
DOI: http://dx.doi.org/10.12928/pharmaciana.v13i3.27201
Refbacks
- There are currently no refbacks.
Copyright (c) 2024 Darmawi Darmawi, Donel S, Wiwin Suhandri, Winarto Winarto, Wirawan Adikusuma, Lalu Muhammad Irham, Wiwit Ade Fidiawati, Renardy Reza Razali, Auren Nathania, Leina Putri Zahra
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Office: Faculty of Pharmacy, Universitas Ahmad Dahlan
Jl. Prof. Dr. Soepomo, S.H., Janturan, Warungboto, Umbulharjo, Yogyakarta, Indonesia
Kode pos 55164
Email: pharmaciana@pharm.uad.ac.id