Drug repurposing in Oncology: Opportunities and challenges
Corresponding Author(s) : AnubhavDubey
anubhavdwivedi803@gmail.com
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 9 No. 1 (2021): 2021 Volume - 9 Issue-1
Abstract
The strategy of using existing drugs originally developed for one disease to treat other indications has found success across medical fields. Such drug repurposing promises faster access of drugs to patients while reducing costs in the long and difficult process of drug development. However, the number of existing drugs and diseases, together with the heterogeneity of patients and diseases, notably including cancers, can make repurposing time consuming and inefficient. In a current research, it is also found that cancer cells have a property of intra-tumor heterogeneity i.e., formation of sub-group of cancer cells that shows more complexity in revelation of their genetic makeup and this property gives birth to a sub-class of cancer cells that are known as cancer stem cells (CSCS).
Keywords
Repurposed drug
Drug development
Cancer stem cells
Heterogeneity
1.
AnubhavDubey, Deepanshi Tiwari, Yatendra Singh, Om Prakash, PankajSingh. Drug repurposing in Oncology: Opportunities and challenges. Int. J. of Allied Med. Sci. and Clin. Res. [Internet]. 2021 Mar. 24 [cited 2026 Jan. 23];9(1):68-87. Available from: https://ijamscr.com/ijamscr/article/view/975
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References
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[23]. Rancati, G., Moffat, J., Typas, A. &Pavelka, N. Emerging and evolving concepts in gene essentiality. Nat. Rev. Genet. 19, 2018, 34–49.
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[33]. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol.15, 2018, 81–94.
[34]. Turner, N. C. & Reis-Filho, J. S. Genetic heterogeneity and cancer drug resistance.LancetOncol. 13, 2012, e178–e185.
[35]. Lee, J. K. Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy. Nat. Genet. 50, 2018, 1399–1411.
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[40]. Aguirre, A. J. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov.8, 2018, 1096–1111.
[41]. Rubio-Perez, C. In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunities. Cancer Cell.27, 2015, 382–396.
[42]. Cheng, F. A genome-wide positioning systems network algorithm for in silico drug repurposing. Nat. Commun. 10, 2019, 3476.
[43]. Kim, M. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat. Commun. 10, 2019, 3991.
[44]. Huang, L. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 2015, 1364–1371.
[45]. Klaeger, S. The target landscape of clinical kinase drugs.Science 358, 2017, 4368.
[46]. Roulois, D. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 2015, 961–973.
[47]. Katsnelson, A. Drug development: target practice. Nature 498, 2013, S8–S9.
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[51]. Zhang, Q. I. Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing. Oncol.Lett.11, 2016, 3265–3272.
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[53]. Efferth, T. From ancient herb to modern drug: artemisiaannua and artemisininfor cancer therapy. Semin Cancer Biol. 46, 2017, 65–83.
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[56]. Diamond, E. L. Diverse and targetable kinase alterations drive histiocyticneoplasms. Cancer Discov.6, 2016, 154–165.
[57]. Rodrik-Outmezguine, V. S. mTOR kinase inhibition causes feedbackdependentbiphasic regulation of AKT signaling. Cancer Discov.1, 2011, 248–259..
[58]. Ahronian, L. G Clinical acquired resistance to RAF Inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov.5, 2015, 358–367.
[59]. Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat. Rev. Drug Discov. 10, 2011, 868–880.
[60]. Sharif, A. Sirolimus after kidney transplantation. BMJ 349, 2014, g6808.
[61]. Fattori, R. &Piva, T. Drug-eluting stents in vascular intervention. Lancet 361, 2003, 247–249.
[62]. Farb, A. et al. Oral everolimus inhibits in-stent neointimal growth. Circulation 106, 2002, 2379–2384.
[63]. Grabiner, B. C. A diverse array of cancer-associated MTOR mutations arehyperactivating and can predict rapamycin sensitivity. Cancer Discov.4, 2014, 554–563.
[64]. Dancey, J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol.7, 209–219 (2010).
[65]. Meric-Bernstam, F. & Gonzalez-Angulo, A. M. Targeing the mTOR signaling network for cancer therapy. J. Clin. Oncol.27, 2008, 2278–2287.
[66]. Altman, J. K. et al. Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin. Cancer Res. 17, 2011, 4378–4388.
[67]. Brown, V. I. et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. NatlAcad.Sci.Usa. 100, 2003, 15113–15118.
[68]. Sillaber, C. et al. Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. Eur. J. Clin. Invest. 38, 2008, 43–52.
[69]. Mancini, M. et al. RAD 001 (everolimus) preventsmTOR and Akt late reactivation in response to imatinib in chronic myeloid leukemia. J. Cell Biochem. 109, 2010, 320–328.
[70]. O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 2006, 1500–1508.
[71]. Choo, A. Y. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl Acad. Sci. USA.105, 2008, 17414–17419.
[72]. Dowling, R. J. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328, 2010, 1172–1176.
[73]. Maiso, P. Defining the role of TORC1/2 in multiple myeloma. Blood 118, 2011, 6860–6870.
[74]. McHugh, D. J. A phase I trial of IGF-1R inhibitor cixutumumab and mTORinhibitor temsirolimus in metastatic castration-resistant prostate cancer.Clin.Genitourin Cancer 18, e2 (2020), 171–178.
[75]. Rugo, H. S. A randomized phase II trial of ridaforolimus,dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients withadvanced breast cancer. Breast Cancer Res Treat. 165, 2017, 601–609.
[76]. Mitsiades, C. S., Hayden, P. J., Anderson, K. C. & Richardson, P. G. From the bench to the bedside: emerging new treatments in multiple myeloma. Best.Pract.Res Clin.Haematol.20, 2007, 797–816.
[77]. Rao, R. D. Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia 7, 2005, 921–929.
[78]. Cirstea, D. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol. Cancer Ther.9, 2010, 963–975.
[79]. Zibelman, M. Phase I study of the mTORinhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. Investig. N. Drugs 33, 2015, 1040–1047.
[80]. Newell, P. Ras pathway activation in hepatocellular carcinoma and antitumoraleffect of combined sorafenib and rapamycin in vivo. J. Hepatol. 51, 2009, 725–733.
[81]. Malizzia, L. J. & Hsu, A. Temsirolimus, an mTOR inhibitor for treatment of patients with advanced renal cell carcinoma. Clin. J. Oncol. Nurs.12, 2008, 639–646.
[82]. Kirkendall, W. M. Prazosin and clonidine for moderately severe hypertension.
[83]. JAMA 240, 1978, 2553–2556.
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