Drug repurposing in Oncology: Opportunities and challenges
Corresponding Author(s) : AnubhavDubey
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 9 No. 1 (2021): 2021 Volume - 9 Issue-1
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).
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. Torre, L. A. Global cancer statistics, 2012. CA Cancer J. Clin.65, 2015, 87–108.
. Kirsch, J. et al. Biosensor technology: recent advances in threat agent detection and medicine. Chem. Soc. Rev. 42, 2013, 8733–8768.
. Shaked, Y. The pro-tumorigenic host response to cancer therapies.Nat. Rev. Cancer 19, 2019, 667–685.
. Eder, J., Sedrani, R. &Wiesmann, C. The discovery of first-in-class drugs: origins and evolution. Nat. Rev. Drug Discov. 13, 2014, 577–587.
. Munos, B. Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug Discov. 8, 2009, 959–968.
. Mullard, A. Partnering between pharma peers on the rise. Nat. Rev. Drug Discov. 10, 2011, 561–562.
. Moffat, J. G., Rudolph, J. & Bailey, D. Phenotypic screening in cancer drug discovery— past, present and future. Nat. Rev. Drug Discov. 13, 2014, 588–602.
. Su, M. Availability, cost, and prescription patterns of antihypertensive medications in primary health care in China: a nationwide cross-sectional survey. Lancet 390, 2017, 2559–2568.
. Nosengo, N. Can you teach old drugs new tricks? Nature 534, 2016, 314–316.
. Kurzrock, R., Kantarjian, H. M., Kesselheim, A. S. &Sigal, E. V. New drug approvals in oncology. Nat. Rev. Clin. Oncol.17, 2020, 140–146.
. Paul, S. M. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9, 2010, 203–214.
. Petsko, G. A. When failure should be the option.BMC Biol. 8, 2010, 61.
. Bedard, P. L., Hyman, D. M., Davids, M. S. &Siu, L. L. Small molecules, big impact: 20 years of targeted therapy in oncology. Lancet 395, 2020, 1078–1088.
. Shibue, T. & Weinberg, R. A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol.14, 2017, 611–629.
. Pushpakom, S. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 18, 2019, 41–58.
. Pantziarka, P. Scientific advice—is drug repurposing missing a trick? Nat. Rev. Clin. Oncol.14, 2017, 455–456.
. Corsello, S. M. et al. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med. 23, 2017, 405–408.
. Clohessy, J. G. &Pandolfi, P. P. Mouse hospital and co-clinical trial project-from bench to bedside. Nat. Rev. Clin. Oncol.12, 2015, 491–498.
. Bertolini, F., Sukhatme, V. P. & Bouche, G. Drug repurposing in oncology-patient and health systems opportunities. Nat. Rev. Clin. Oncol.12, 2015, 732–742.
. Huang, A., Garraway, L. A., Ashworth, A. & Weber, B. Synthetic lethality as an engine for cancer drug target discovery. Nat. Rev. Drug Discov. 19, 2020, 23–38.
. Roumenina, L. T. Context-dependent roles of complement in cancer. Nat. Rev. Cancer 19, 698–715 (2019).
. Rancati, G., Moffat, J., Typas, A. &Pavelka, N. Emerging and evolving concepts in gene essentiality. Nat. Rev. Genet. 19, 2018, 34–49.
. Tambuyzer, E. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat. Rev. Drug Discov. 19, 2020, 93–111.
. Dallavalle, S. Improvement of conventional anticancer drugs as new tools against multidrug resistant tumors. Drug Resist Updates 50, 2020, 100682.
. Wang, S., Dong, G. & Sheng, C. Structural simplification of natural products. Chem. Rev. 119, 2019, 4180–4220.
. Patel, M. N. Objective assessment of cancer genes for drug discovery. Nat. Rev. Drug Discov. 12, 2013, 35–50.
. Swinney, D. C. Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin. Pharm. Ther. 93, 2013, 299–301.
. Moffat, J. G. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat. Rev. Drug Discov. 16, 2017, 531–543.
. Flory, J. &Lipska, K. Metformin in 2019. JAMA 321, 2019, 1926–1927.
. Morris, A. In search of the mechanisms of metformin in cancer.Nat. Rev. Endocrinol. 14, 2018, 628.
. Martin, M. & Marais, R. Metformin: a diabetes drug for cancer, or a cancer drug for diabetics? J. Clin. Oncol.30, 2012, 2698–2700.
. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol.15, 2018, 81–94.
. Turner, N. C. & Reis-Filho, J. S. Genetic heterogeneity and cancer drug resistance.LancetOncol. 13, 2012, e178–e185.
. Lee, J. K. Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy. Nat. Genet. 50, 2018, 1399–1411.
. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 2011, 646–674.
. Kelly-Irving, M., Delpierre, C. &Vineis, P. Beyond bad luck: induced mutations and hallmarks of cancer. Lancet Oncol.18, 2017, 999–1000.
. Li, T., Kung, H. J., Mack, P. C. &Gandara, D. R. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J.Clin. Oncol. 31, 2013, 1039–1049.
. Pauli, C. et al. Personalized in vitro and in vivo cancer models to guide precision medicine. Cancer Discov.7, 2017, 462–477.
. Aguirre, A. J. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov.8, 2018, 1096–1111.
. Rubio-Perez, C. In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunities. Cancer Cell.27, 2015, 382–396.
. Cheng, F. A genome-wide positioning systems network algorithm for in silico drug repurposing. Nat. Commun. 10, 2019, 3476.
. Kim, M. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat. Commun. 10, 2019, 3991.
. 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.
. Klaeger, S. The target landscape of clinical kinase drugs.Science 358, 2017, 4368.
. Roulois, D. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 2015, 961–973.
. Katsnelson, A. Drug development: target practice. Nature 498, 2013, S8–S9.
. Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, 2017, 2380.
. Sarmento-Ribeiro, A. B. The emergence of drug resistance to targeted cancer therapies: clinical evidence. Drug Resist Updat.47, 2019, 100646.
. Boyer, A. Drug repurposing in malignant pleural mesothelioma: a breath of fresh air? Eur. Respir. Rev. 27, 2018, 170098.
. Zhang, Q. I. Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing. Oncol.Lett.11, 2016, 3265–3272.
. Hernandez, J. J.Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics. Front Oncol. 7, 2017, 273.
. Efferth, T. From ancient herb to modern drug: artemisiaannua and artemisininfor cancer therapy. Semin Cancer Biol. 46, 2017, 65–83.
. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer.Cell 100, 57–70 (2000).
. Lin, J. J., Riely, G. J. & Shaw, A. T. Targeting ALK: precision medicine takes on drug resistance. Cancer Discov.7, 2017, 137–155.
. Diamond, E. L. Diverse and targetable kinase alterations drive histiocyticneoplasms. Cancer Discov.6, 2016, 154–165.
. Rodrik-Outmezguine, V. S. mTOR kinase inhibition causes feedbackdependentbiphasic regulation of AKT signaling. Cancer Discov.1, 2011, 248–259..
. 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.
. 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.
. Sharif, A. Sirolimus after kidney transplantation. BMJ 349, 2014, g6808.
. Fattori, R. &Piva, T. Drug-eluting stents in vascular intervention. Lancet 361, 2003, 247–249.
. Farb, A. et al. Oral everolimus inhibits in-stent neointimal growth. Circulation 106, 2002, 2379–2384.
. Grabiner, B. C. A diverse array of cancer-associated MTOR mutations arehyperactivating and can predict rapamycin sensitivity. Cancer Discov.4, 2014, 554–563.
. Dancey, J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol.7, 209–219 (2010).
. Meric-Bernstam, F. & Gonzalez-Angulo, A. M. Targeing the mTOR signaling network for cancer therapy. J. Clin. Oncol.27, 2008, 2278–2287.
. 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.
. 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.
. 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.
. 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.
. O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 2006, 1500–1508.
. 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.
. Dowling, R. J. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328, 2010, 1172–1176.
. Maiso, P. Defining the role of TORC1/2 in multiple myeloma. Blood 118, 2011, 6860–6870.
. 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.
. 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.
. 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.
. 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.
. 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.
. 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.
. Newell, P. Ras pathway activation in hepatocellular carcinoma and antitumoraleffect of combined sorafenib and rapamycin in vivo. J. Hepatol. 51, 2009, 725–733.
. 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.
. Kirkendall, W. M. Prazosin and clonidine for moderately severe hypertension.
. JAMA 240, 1978, 2553–2556.
. Skrott, Z. Alcohol-abuse drug disulfiram targets cancer via p97 segregaseadaptor NPL4. Nature 552, 2017, 194–199.
. Clifford, G. M. & Farmer, R. D. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur. Urol. 38, 2000, 2–19.
. Waldo, R. Prazosin relieves Raynaud's vasospasm. JAMA 241, 1979, 1037.
. Lang, C. C., Choy, A. M., Rahman, A. R. & Struthers, A. D. Renal effects of low dose prazosin in patients with congestive heart failure. Eur. Heart J. 14, 1993, 1245–1252.
. Mulvihill-Wilson, J. Hemodynamic and neuroendocrine responses to acute and chronic alpha-adrenergic blockade withprazosin and phenoxybenzamine. Circulation 67, 1983, 383–393.
. Iwai-Kanai, E. alpha- and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation 100, 1999, 305–311.