Abstract
In most countries, healthcare service budgets are not likely to support the current explosion in the cost of new oncology drugs. Repurposing the large arsenal of approved, non-anticancer drugs is an attractive strategy to offer more-effective options to patients with cancer, and has the substantial advantages of cheaper, faster and safer preclinical and clinical validation protocols. The potential benefits are so relevant that funding of academically and/or independently driven preclinical and clinical research programmes should be considered at both national and international levels. To date, successes in oncology drug repurposing have been limited, despite strong evidence supporting the use of many different drugs. A lack of financial incentives for drug developers and limited drug development experience within the non-profit sector are key reasons for this lack of success. We discuss these issues and offer solutions to finally seize this opportunity in the interest of patients and societies, globally.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Collins, F. S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).
Johnson, K. A., Blansett, L., Mawrie, R. & Di Biase, S. Innovation in cancer care and implications for health systems—Global oncology trend report. IMS institute for healthcare informatics [online], (2014).
Moses, H. et al. The anatomy of medical research: US and international comparisons. JAMA 313, 174–189 (2015).
Drug development costs jump to $2.6 billion. Cancer Discov. 5, OF2 (2015).
Moffat, J. G., Rudolph, J. & Bailey, D. Phenotypic screening in cancer drug discovery—past, present and future. Nat. Rev. Drug Discov. 13, 588–602 (2014).
OECD Information Technology Outlook 2008. http://dx.doi.org/10.1787/it_outlook-2008-en (OECD Publishing, 2008).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Dienstmann, R., Jang, I. S., Bot, B., Friend, S. & Guinney, J. Database of genomic biomarkers for cancer drugs and clinical targetability in solid tumors. Cancer Discov. 5, 118–123 (2015).
Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl. Med. 4, 127ps10 (2012).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Wolchok, J. D. & Chan, T. A. Cancer: Antitumour immunity gets a boost. Nature 515, 496–498 (2014).
Keith, C. T., Borisy, A. A. & Stockwell, B. R. Multicomponent therapeutics for networked systems. Nat. Rev. Drug Discov. 4, 71–78 (2005).
Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).
Barratt, M. G. & Frail, D. E. (eds) Drug repositioning: bringing new life to shelved assets and existing drugs. (John Wiley & Sons, 2012).
Ashburn, T. T. & Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683 (2004).
Pantziarka, P. et al. The Repurposing Drugs in Oncology (ReDO) Project. Ecancermedicalscience 8, 442 (2014).
Boguski, M. S., Mandl, K. D. & Sukhatme, V. P. Drug discovery. Repurposing with a difference. Science 324, 1394–1395 (2009).
Cavalla, D. Predictive methods in drug repurposing: gold mine or just a bigger haystack? Drug Discov. Today 18, 523–532 (2013).
Sukhai, M. A. et al. New sources of drugs for hematologic malignancies. Blood 117, 6747–6755 (2011).
Jin, G. & Wong, S. T. Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov. Today 19, 637–644 (2014).
Keiser, M. J. et al. Predicting new molecular targets for known drugs. Nature 462, 175–181 (2009).
Barrett, M. J. & Frail, D. E. in Drug repositioning: bringing new life to shelved assets and existing drugs Ch. 6 (eds Andronis, C. et al.) 137–157 (John Wiley & Sons, 2012).
Lamb, J. The Connectivity Map: a new tool for biomedical research. Nat. Rev. Cancer 7, 54–60 (2007).
Jahchan, N. S. et al. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov. 3, 1364–1377 (2013).
Zerbini, L. F. et al. Computational repositioning and preclinical validation of pentamidine for renal cell cancer. Mol. Cancer Ther. 13, 1929–1941 (2014).
Campillos, M., Kuhn, M., Gavin, A.-C., Jensen, L. J. & Bork, P. Drug target identification using side-effect similarity. Science 321, 263–266 (2008).
Amelio, I. et al. DRUGSURV: a resource for repositioning of approved and experimental drugs in oncology based on patient survival information. Cell Death Dis. 5, e1051 (2014).
Talele, T. T., Khedkar, S. A. & Rigby, A. C. Successful applications of computer aided drug discovery: moving drugs from concept to the clinic. Curr. Top. Med. Chem. 10, 127–141 (2010).
Liu, Z. et al. In silico drug repositioning-what we need to know. Drug Discov. Today 18, 110–115 (2013).
Villoutreix, B. O., Lagorce, D., Labbé, C. M., Sperandio, O. & Miteva, M. A. One hundred thousand mouse clicks down the road: selected online resources supporting drug discovery collected over a decade. Drug Discov. Today 18, 1081–1089 (2013).
Röhrig, U. F. et al. Rational design of indoleamine 2, 3-dioxygenase inhibitors. J. Med. Chem. 53, 1172–1189 (2010).
Cheng, F. et al. Prediction of drug-target interactions and drug repositioning via network-based inference. PLoS Comput. Biol. 8, e1002503 (2012).
Brown, D. Unfinished business: target-based drug discovery. Drug Discov. Today 12, 1007–1012 (2007).
Zhang, L. et al. Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: Opportunities for repurposing. J. Clin. Endocrinol. Metab. 97, 319–328 (2012).
Rickles, R. J. et al. Adenosine A2A and β-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening. Mol. Cancer Ther. 11, 1432–1442 (2012).
Borisy, A. A. et al. Systematic discovery of multicomponent therapeutics. Proc. Natl Acad. Sci. USA 100, 7977–7982 (2003).
Roix, J. J. et al. Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity. PLoS ONE 9, e101708 (2014).
Withrow, S. J., Vail, D. M. & Page, R. Withrow and MacEwen's Small Animal Clinical Oncology. (Elsevier Health Sciences, 2013).
Hermo, G. A. et al. Perioperative desmopressin prolongs survival in surgically treated bitches with mammary gland tumours: a pilot study. Vet. J. 178, 103–108 (2008).
Elmslie, R. E., Glawe, P. & Dow, S. W. Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas. J. Vet. Intern. Med. 22, 1373–1379 (2008).
Ghofrani, H. A., Osterloh, I. H. & Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat. Rev. Drug Discov. 5, 689–702 (2006).
Rehman, W., Arfons, L. M. & Lazarus, H. M. The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Ther. Adv. Hematol. 2, 291–308 (2011).
Carella, A. M., Beltrami, G., Pica, G., Carella, A. & Catania, G. Clarithromycin potentiates tyrosine kinase inhibitor treatment in patients with resistant chronic myeloid leukemia. Leuk. Lymphoma 53, 1409–1411 (2012).
Léauté-Labrèze, C. et al. Propranolol for severe hemangiomas of infancy. N. Engl. J. Med. 358, 2649–2651 (2008).
Blatt, J. & Corey, S. J. Drug repurposing in pediatrics and pediatric hematology oncology. Drug Discov. Today 18, 4–10 (2013).
Flynn, P. J. et al. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood 62, 1211–1217 (1983).
Nygren, P. & Larsson, R. Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncol. 53, 427–428 (2013).
Banavali, S., Pasquier, E. & André, N. Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma. Ecancermedicalscience 9, 9–12 (2015).
Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305 (2005).
Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379, 1591–1601 (2012).
Demonaco, H. J., Ali, A. & Hippel, E V. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy 26, 323–332 (2006).
Roberts, K. G. et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N. Engl. J. Med. 371, 1005–1015 (2014).
Mullighan, C. G. et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N. Engl. J. Med. 360, 470–480 (2009).
Schultz, K. R. et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J. Clin. Oncol. 27, 5175–5181 (2009).
Kyle, R. A. & Rajkumar, S. V. Multiple myeloma. N. Engl. J. Med. 351, 1860–1873 (2004).
Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999).
Dimopoulos, M. A., Anagnostopoulos, A. & Weber, D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J. Clin. Oncol. 21, 4444–4454 (2003).
Dimopoulos, M. A. et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann. Oncol. 12, 991–995 (2001).
Anagnostopoulos, A., Weber, D., Rankin, K., Delasalle, K. & Alexanian, R. Thalidomide and dexamethasone for resistant multiple myeloma. Br. J. Haematol. 121, 768–771 (2003).
García-Sanz, R. et al. The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma. Hematol. J. 3, 43–48 (2002).
Mitsiades, N. et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: Therapeutic implications. Blood 99, 4525–4530 (2002).
Richardson, P. G. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100, 3063–3067 (2002).
Zeldis, J. B., Knight, R., Hussein, M., Chopra, R. & Muller, G. A review of the history, properties, and use of the immunomodulatory compound lenalidomide. Ann. N. Y. Acad. Sci. 1222, 76–82 (2011).
Lopez-Girona, A. et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26, 2326–2335 (2012).
Chamberlain, P. P. et al. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. 21, 803–809 (2014).
Cuzick, J. et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann. Oncol. 26, 47–57 (2015).
Rothwell, P. M. et al. Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet 377, 31–41 (2011).
Jacobs, E. J., Newton, C. C., Gapstur, S. M. & Thun, M. J. Daily aspirin use and cancer mortality in a large US Cohort. J. Natl Cancer Inst. 104, 1208–1217 (2012).
Liao, X. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N. Engl. J. Med. 367, 1596–1606 (2012).
Domingo, E. et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J. Clin. Oncol. 31, 4297–4305 (2013).
Nishihara, R. et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA 309, 2563–2571 (2013).
Chan, A. T., Ogino, S. & Fuchs, C. S. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302, 649–658 (2009).
Fink, S. P. et al. Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD). Sci. Transl. Med. 6, 233re2 (2014).
Nan, H. et al. Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants. JAMA 313, 1133–1142 (2015).
Yin, M., Zhou, J., Gorak, E. J. & Quddus, F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 18, 1248–1255 (2013).
Gandini, S. et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev. Res. (Phila.) 7, 867–885 (2014).
Gronich, N. & Rennert, G. Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat. Rev. Clin. Oncol. 10, 625–642 (2013).
Blandino, G. et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat. Commun. 3, 865 (2012).
Janzer, A. et al. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc. Natl Acad. Sci. USA 111, 10574–10579 (2014).
Orecchioni, S. et al. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int. J. Cancer 544, 534–544 (2014).
Kordes, S. et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16, 1–9 (2015).
Yin, M., Zhou, J., Gorak, E. J. & Quddus, F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 18, 1248–1255 (2013).
Sakoda, L. C. et al. Metformin use and lung cancer risk in patients with diabetes. Cancer Prev. Res. (Phila.) 8, 174–179 (2015).
Orecchioni, S. et al. Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer. Cancer Res. 73, 5880–5891 (2013).
Birsoy, K. et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508, 108–112 (2014).
Pernicova, I. & Korbonits, M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol. 10, 143–156 (2014).
Hirsch, H. A., Iliopoulos, D. & Struhl, K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl Acad. Sci. USA 110, 972–977 (2013).
Eikawa, S. et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc. Natl Acad. Sci. USA 112, 1809–1814 (2015).
Hart, C. et al. Anakoinosis: communicative reprogramming of tumor systems—for rescuing from chemorefractory neoplasia. Cancer Microenviron. 8, 75–92 (2015).
Prost, S. et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature http://dx.doi.org/10.1038/nature15248 (2015).
Dagher, R. et al. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin. Cancer Res. 8, 3034–3038 (2002).
Schenk, T., Stengel, S. & Zelent, A. Unlocking the potential of retinoic acid in anticancer therapy. Br. J. Cancer 111, 2039–2045 (2014).
Sandler, R. S. et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N. Engl. J. Med. 348, 883–890 (2003).
Ishikawa, H. et al. The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut 63, 1755–1759 (2014).
Cole, B. F. et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J. Natl Cancer Inst. 101, 256–66 (2009).
DiPersio, J. F. et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma. J. Clin. Oncol. 27, 4767–4773 (2009).
DiPersio, J. F. et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 113, 5720–5726 (2009).
DiPersio, J. F., Uy, G. L., Yasothan, U. & Kirkpatrick, P. Plerixafor. Nat. Rev. Drug Discov. 8, 105–106 (2009).
De Clercq, E. The bicyclam AMD3100 story. Nat. Rev. Drug Discov. 2, 581–587 (2003).
Arrowsmith, J. & Harrison, R. in Drug repositioning bringing new life to shelved assets and existing drugs ch. 1 (eds Barratt M. J. & Frail, D. E.) 7–32 (2012).
Lou, Y. et al. The effectiveness of propranolol in treating infantile haemangiomas: a meta-analysis including 35 studies. Br. J. Clin. Pharmacol. 78, 44–57 (2014).
Shakhar, G. & Ben-Eliyahu, S. In vivo β-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J. Immunol. 160, 3251–3258 (1998).
Horowitz, M., Neeman, E., Sharon, E. & Ben-eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213–226 (2015).
De Giorgi, V. et al. Treatment with β-blockers and reduced disease progression in patients with thick melanoma. Arch. Intern. Med. 171, 779–781 (2011).
Powe, D. G. et al. β-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628–638 (2010).
Pasquier, E. et al. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget. 2, 797–809 (2011).
Glasner, A. et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J. Immunol. 184, 2449–2457 (2010).
Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010).
Lamkin, D. M. et al. Chronic stress enhances progression of acute lymphoblastic leukemia via β-adrenergic signaling. Brain. Behav. Immun. 26, 635–641 (2012).
De la Torre, A. N. et al. Effect of coadministration of propranolol and etodolac (VT-122) plus sorafenib for patients with advanced hepatocellular carcinoma (HCC) [abstract 390]. J. Clin. Oncol. 33, S3 (2015).
Bhattacharyya, G. S. et al. Effect of coadministered beta blocker and COX-2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) paclitaxel [abstract 302]. J. Clin. Oncol. 33, S3 (2015).
Mercurio, S. et al. Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in pilocytic astrocytoma. Acta Neuropathol. Commun. 1, 17 (2013).
Pasquier, E. et al. β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br. J. Cancer 108, 2485–2494 (2013).
Luciani, F. et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J. Natl Cancer Inst. 96, 1702–1713 (2004).
López-Aguilar, E. et al. Security and maximal tolerated doses of fluvastatin in pediatric cancer patients. Arch. Med. Res. 30, 128–131 (1999).
Dirix, L. Discovery and exploitation of novel targets by approved drugs. J. Clin. Oncol. 32, 720–721 (2014).
Murteira, S., Millier, A., Ghezaiel, Z. & Lamure, M. Drug reformulations and repositioning in the pharmaceutical industry and their impact on market access: regulatory implications. J. Mark. Access Health Policy 2, 22813 (2014).
Gatta, G. et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur. J. Cancer 47, 2493–2511 (2011).
Cavalla, D. Off-label Prescribing: Justifying Unapproved Medicine 1st edn 143–174 (John Wiley & Sons Ltd, 2015).
Mailankody, S. & Prasad, V. Comparative effectiveness questions in oncology. N. Engl. J. Med. 370, 1478–1481 (2014).
Sukhatme, V. P., Fang, K., Lo, A. & Sukhatme, V. Financial orphan therapies looking for adoption. Health Affairs Blog [online], (2014).
Collins, F. S. Mining for therapeutic gold. Nat. Rev. Drug Discov. 10, 397 (2011).
Ghosh, J. et al. Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India. Indian J. Cancer 48, 391–396.
André, N., Banavali, S., Snihur, Y. & Pasquier, E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 14, e239–e248 (2013).
Hale, V. G., Woo, K. & Lipton, H. L. From the field — Oxymoron no more: The potential of nonprofit drug companies to deliver on the promise of medicines for the developing world. Health Aff. (Millwood) 24, 1057–1063 (2005).
Klein, B. E. & Dalby, K. J. Nonprofit drug companies. Health Aff. (Millwood) 24, 1684–1685 (2005).
Weir, S. J., DeGennaro, L. J. & Austin, C. P. Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership. Cancer Res. 72, 1055–1058 (2012).
Langley, R. E. et al. Add-Aspirin trial: A phase III, double blind, placebo-controlled, randomized trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common nonmetastatic solid tumors [abstract TPS1617]. J. Clin. Oncol. 32, S5 (2014).
Goodwin, P. J., Ligibel, J. A. & Stambolic, V. Metformin in breast cancer: time for action. J. Clin. Oncol. 27, 3271–3273 (2009).
Parmar, M. K. B., Carpenter, J. & Sydes, M. R. More multiarm randomised trials of superiority are needed. Lancet 384, 283–284 (2014).
Sydes, M. R. et al. Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials 13, 168 (2012).
Leiter, A. et al. Use of crowdsourcing for cancer clinical trial development. J. Natl Cancer Inst. 106, dju258 (2014).
Rudin, C. M. et al. Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J. Thorac. Oncol. 8, 619–623 (2013).
Mikasa, K. et al. Significant survival benefit to patients with advanced non-small-cell lung cancer from treatment with clarithromycin. Chemotherapy 43, 288–296 (1997).
Saad, A. S., Shaheen, S. M., Elhamamsy, M. H. & Badary, O. A. An open-label randomized controlled phase II study of clarithromycin (CL) plus CVP in patients (pts) with previously untreated stage III/IV indolent non Hodgkin lymphoma (NHL) [abstract e19510]. J. Clin. Oncol. 32 (2014).
Pantziarka, P., Bouche, G., Meheus, L., Sukhatme, V. & Sukhatme, V. P. Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent. Ecancermedicalscience 9, 513 (2015).
Deva, S. & Jameson, M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. Cochrane Database of Systematic Reviews, Issue 8. Art. No.: CD007814 http://dx.doi.org/10.1002/14651858.CD007814.pub2 (2012).
Pantziarka, P., Bouche, G., Meheus, L., Sukhatme, V. & Sukhatme, V. P. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience 8, 485 (2014).
Yasuda, H. et al. Randomized phase II trial comparing nitroglycerin plus vinorelbine and cisplatin with vinorelbine and cisplatin alone in previously untreated stage IIIB/IV non-small-cell lung cancer. J. Clin. Oncol. 24, 688–694 (2006).
Reinmuth, N. et al. Randomized, double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Lung Cancer 83, 363–368 (2014).
Dingemans, A.-M. C. A randomized phase II study comparing paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170). Ann. Oncol. http://dx.doi.org/10.1093/annonc/mdv370 (2015).
Davidson, A. et al. A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial. Ann. Oncol. http://dx.doi.org/10.1093/annonc/mdv373 (2015).
Kawata, S. et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br. J. Cancer 84, 886–891 (2001).
Belpomme, D. et al. Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma. Ann. Oncol. 11, 1471–1476 (2000).
Dufour, P. et al. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy 6, 9–12 (1993).
Nechushtan, H. et al. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist 20, 366–367 (2015).
Sotelo, J., Briceño, E. & López-González, M. A. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 144, 337–343 (2006).
Briceño, E., Calderon, A. & Sotelo, J. Institutional experience with chloroquine as an adjuvant to the therapy for glioblastoma multiforme. Surg. Neurol. 67, 388–391 (2007).
Altinbas, M. et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J. Thromb. Haemost. 2, 1266–1271 (2004).
Lecumberri, R. et al. Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. Thromb. Res. 132, 666–670 (2013).
Wang, H. et al. Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. Cancer http://dx.doi.org/10.1002/cncr.29456 (2015).
Acknowledgements
F.B. receives financial support from AIRC (Associazione Italiana per la Ricerca sul Cancro), Fondazione Umberto Veronesi, and Ministero della Salute. G.B. would like to thank Nicolas André, Lydie Meheus, Pan Pantziarka and Matthew Sydes for useful discussions of some of the ideas presented in this article.
Author information
Authors and Affiliations
Contributions
F.B. and G.B. researched data for this article, all authors made a substantial contribution to discussions of content, writing the manuscript and editing and/or reviewing the manuscript prior to submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
PowerPoint slides
Rights and permissions
About this article
Cite this article
Bertolini, F., Sukhatme, V. & Bouche, G. Drug repurposing in oncology—patient and health systems opportunities. Nat Rev Clin Oncol 12, 732–742 (2015). https://doi.org/10.1038/nrclinonc.2015.169
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2015.169
This article is cited by
-
Repurposing approved non-oncology drugs for cancer therapy: a comprehensive review of mechanisms, efficacy, and clinical prospects
European Journal of Medical Research (2023)
-
Design, Development, In Silico, and In Vitro Characterization of Camptothecin-Loaded Mixed Micelles: In Vitro Testing of Verapamil and Ranolazine for Repurposing as Coadjuvant Therapy in Cancer
Journal of Pharmaceutical Innovation (2023)
-
The evidence for repurposing anti-epileptic drugs to target cancer
Molecular Biology Reports (2023)
-
Exploring new uses for existing drugs: innovative mechanisms to fund independent clinical research
Trials (2021)
-
Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand
Cancer Gene Therapy (2021)