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An In-SILICO Modeling for Molecular Drug Designing that Patient Derived Anti-Cancerous Cells

Junaid Ali, Muhammad Umer Khan, Sher Ali, Muhammad Yasir, Muhammad Ghani

Abstract


Glioblastoma Multiform (GBM) is an aggressive disease associated with poor survival. It is essential to account for the complexity of GBM biology to improve diagnostic as well as therapeutic strategies. This complexity is best represented by the increasing amounts of profiling (“OMICS”) data available due to advances in biotechnology. Brain metastases remain a daunting adversary that negatively impact patient survival. Metastatic brain tumors affect up to 45% of all cancer patients with systemic cancer and account for ~20% of all cancer-related deaths. The brain micro-environment modulates metastatic tumor growth; however, defining the precise genetic events that promote metastasis in the brain niche represents an important, unresolved problem. Understanding these events will reveal disease-based targets and offer effective strategies to treat brain metastases. Effective therapeutic strategies based upon the biology of brain metastases represent an urgent, unmet need with immediate potential for clinical impact. In-SILICO docking method have been used to solve Glioblastoma (GBM) problem. Mostly CDK’s (Cyclin-Dependent Kinase) protein causes the severe Brain Tumor in human being. In this article strong inhibitor are used to block the action of CDK’s. This protein is encoded by the human genome to cause the initial tumor cells in brain & in the later this cause the death. But now it is possible to treat easily by using the effective inhibitor against brain tumor. This methodology is used to check out the protein-ligand binding affinity that shows the results against brain tumor and their ability to control the disease effectively. Among the drug-mutation associations reported in the Garnett study, this In-SILICO model accurately predicted ~85% of the associations. While testing the model in a prospective manner using simulations of patient-derived GBM cell lines. This study will also help to find out causes and the treatments on clinical bases.


Keywords


Glioblastoma Multiform, CDK, Daunting Adversary, Indirubin Molecule, In-SILICO Docking, Brain Metastases.

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Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller III CA, Kato T, Saeki K and Matsuda T. (2001). J. Biol. Chem., 276, 31475–31478.

Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML, Pettersson S, Hanberg A and Poellinger L. (2002). Proc. Natl. Acad. Sci. USA, 99, 9990–9995.

Bradshaw TD, Trapani V, Vasselin DA and Westwell AD. (2002). Curr. Pharm. Design, 8, 2475–2490.

Deisboeck TS, Wang Z, Macklin P, Cristini V: Multiscale cancer modeling. Annu Rev Biomed Eng 2011.

Rowlands JG and Gustafsson JA. (1997). Crit. Rev. Toxicol., 27, 109–134.

Deisboeck TS, Zhang L, Yoon J, Costa J: In silico cancer modeling: is it ready for prime time? NatClinPractOncol 2009.

Denison MS and Nagy SR. (2003). Annu. Rev. Pharmacol. Toxicol, 43, 309–334.

Denison MS, Phelen D and Elferink CJ. (1998). Xenobiotics, Receptors and Gene Expression. Denison MS and Helferich W (eds). Taylor & Francis: Philadelphia, PA, pp. 3–33.

Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 2003; 116:1175–86.

Elferink CJ. (2003). Cell cycle regulators as therapeutic targets. Meijer L, Jezequel A and Roberge M (eds). Progr. Cell Cycle Res., 5, 261–267.

Etienne-Manneville S, Hall A. Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature 2003; 421:753–6.

Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21:2683–710.

Giannini C, Sarkaria JN, Saito A, Uhm JH, Galanis E, Carlson BL, et al. Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol 2005; 7:164–76.

Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 2003; 21:1624–36.

Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, et al. Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 2008; 68:9125–30.

Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumors. Nat Rev Neurosci 2007; 8:620–2.

Koliopanos A, Kleeff J, Xiao Y, Safe S, Zimmermann A, Buchler MW and Friess H. (2002). Oncogene, 21, 6059–6070.

Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 2005; 23:2411–22.

Lucio-Eterovic AK, Piao Y, de Groot JF. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res 2009; 15:4589–99.

Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G, Seligson D, Kremen TJ, Palotie A, Liau LM, Cloughesy TF, Nelson SF: Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 2003.

Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J, Fujii-Kuriyama Y and Ishikawa T. (2000). Proc. Natl. Acad. Sci. USA, 97, 779–782.

TCGA: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008.

Tracqui P, Cruywagen GC, Woodward DE, Bartoo GT, Murray JD, Alvord EC Jr: A mathematical model of glioma growth: the effect of chemotherapy on spatio-temporal growth. Cell Prolif 1995.

Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., ... & Alexe, G. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell, 17(1), 98-110.

Woodward DE, Cook J, Tracqui P, Cruywagen GC, Murray JD, Alvord EC Jr: A mathematical model of glioma growth: the effect of extent of surgical resection. Cell Prolif 1996.


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