J. C. Hogan, Combinatorial chemistry in drug discovery, Nat. Biotechnol, vol.15, pp.328-330, 1997.

F. Sanger, Sequences, Sequences, and Sequences, Annu. Rev. Biochem, vol.57, pp.1-29, 1988.

C. Meldrum, M. A. Doyle, and R. W. Tothill, Next-Generation Sequencing for Cancer Diagnostics: a Practical Perspective, Clin. Biochem. Rev, vol.32, pp.177-195, 2011.

A. Joachimiak and . High-throughput, Crystallography for Structural Genomics. Curr. Opin

, Struct. Biol, vol.19, pp.573-584, 2009.

J. Van-brunt, Protein Architecture: Designing from the Ground Up, Nat. Biotechnol, vol.4, pp.277-283, 1986.

L. M. Mayr and P. Fuerst, The Future of High-Throughput Screening, J. Biomol. Screen, vol.13, pp.443-448, 2008.

W. S. Comanor, Research and Technical Change in the Pharmaceutical Industry

, Econ. Stat, vol.47, p.182, 1965.

E. J. Jensen, Research Expenditures and the Discovery of New Drugs, J. Ind. Econ, vol.36, p.83, 1987.

P. Joglekar and M. L. Paterson, A closer look at the returns and risks of pharmaceutical R&D, J. Health Econ, vol.5, pp.153-177, 1986.

H. G. Grabowski, J. M. Vernon, and L. G. Thomas, Estimating the Effects of Regulation on Innovation: An International Comparative Analysis of the Pharmaceutical Industry, J. Law Econ, vol.21, pp.133-163, 1978.

V. Prasad, K. De-jesús, and S. Mailankody, The high price of anticancer drugs: origins, implications, barriers, solutions, Nat. Rev. Clin. Oncol, vol.14, pp.381-390, 2017.

J. W. Scannell, A. Blanckley, H. Boldon, and B. Warrington, Diagnosing the decline in pharmaceutical R&D efficiency, Nat. Rev. Drug Discov, vol.11, pp.191-200, 2012.

D. F. Horrobin, Realism in drug discovery-could Cassandra be right?, Nat. Biotechnol, vol.19, pp.1099-1100, 2001.

D. F. Horrobin, Innovation in the pharmaceutical industry, vol.93, p.5, 2000.

D. F. Horrobin, Modern biomedical research: an internally self-consistent universe with little contact with medical reality?, Nat. Rev. Drug Discov, vol.2, pp.151-154, 2003.

S. M. Paul, How to improve R&D productivity: the pharmaceutical industry's grand challenge, Nat. Rev. Drug Discov, vol.9, pp.203-214, 2010.

B. Munos, Lessons from 60 years of pharmaceutical innovation, Nat. Rev. Drug Discov, vol.8, pp.959-968, 2009.

A. Hopkins, J. Mason, and J. Overington, Can we rationally design promiscuous drugs?, Curr. Opin. Struct. Biol, vol.16, pp.127-136, 2006.

T. Fojo and D. R. Parkinson, Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much?

, Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.16, pp.5972-5980, 2010.

M. Huang, A. Shen, J. Ding, and M. Geng, Molecularly targeted cancer therapy: some lessons from the past decade, Trends Pharmacol. Sci, vol.35, pp.41-50, 2014.

M. Gerlinger, Intratumor heterogeneity and branched evolution revealed by multiregion sequencing, N. Engl. J. Med, vol.366, pp.883-892, 2012.

R. Fisher, L. Pusztai, and C. Swanton, Cancer heterogeneity: implications for targeted therapeutics, Br. J. Cancer, vol.108, pp.479-485, 2013.

M. Gerlinger and C. Swanton, How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine, Br. J. Cancer, vol.103, pp.1139-1143, 2010.

R. J. Gillies, D. Verduzco, and R. A. Gatenby, Evolutionary dynamics of carcinogenesis and why targeted therapy does not work, Nat. Rev. Cancer, vol.12, pp.487-493, 2012.

R. J. Epstein, The unpluggable in pursuit of the undruggable: tackling the dark matter of the cancer therapeutics universe, Front. Oncol, vol.3, p.304, 2013.

F. Li, C. Zhao, and L. Wang, Molecular-targeted agents combination therapy for cancer: developments and potentials, Int. J. Cancer, vol.134, pp.1257-1269, 2014.

F. E. Vera-badillo, M. Al-mubarak, A. J. Templeton, and E. Amir, Benefit and harms of new anti-cancer drugs, Curr. Oncol. Rep, vol.15, pp.270-275, 2013.

X. Li, Incidence and risk of treatment-related mortality with anti-epidermal growth factor receptor monoclonal antibody in cancer patients: a meta-analysis of 21 randomized controlled trials, PloS One, vol.8, p.81897, 2013.

A. G. Sacher, L. W. Le, and N. B. Leighl, Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non-small-cell lung cancer: the bar is dropping, J. Clin

, Oncol. Off. J. Am. Soc. Clin. Oncol, vol.32, pp.1407-1411, 2014.

L. Amit, I. Ben-aharon, L. Vidal, L. Leibovici, and S. Stemmer, The impact of

. Bevacizumab, Avastin) on survival in metastatic solid tumors--a meta-analysis and systematic review, PloS One, vol.8, p.51780, 2013.

S. Niraula, The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.30, pp.3012-3019, 2012.

B. A. Chabner and T. G. Roberts, Timeline: Chemotherapy and the war on cancer, Nat. Rev. Cancer, vol.5, pp.65-72, 2005.

H. J. Demonaco, A. Ali, E. Hippel, and . Von, The Major Role of Clinicians in the Discovery of Off-Label Drug Therapies, Pharmacother. J. Hum. Pharmacol. Drug Ther, vol.26, pp.323-332, 2006.

R. Parexel-biopharmaceutical and . Statistical, , 2018.

, Streptomycin Treatment of Pulmonary Tuberculosis, Br. Med. J, vol.2, pp.769-782, 1948.

T. R. Pedersen, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Atheroscler. Suppl, vol.5, pp.81-87, 2004.

D. Healy, The Antidepressant Era, 1997.

, Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs -DiMasi -2010 -Clinical Pharmacology &amp

,

J. Langedijk, A. K. Mantel-teeuwisse, D. S. Slijkerman, and M. D. Schutjens,

, Drug repositioning and repurposing: terminology and definitions in literature, Drug Discov. Today, vol.20, pp.1027-1034, 2015.

T. T. Ashburn and K. B. Thor, Drug repositioning: identifying and developing new uses for existing drugs, Nat. Rev. Drug Discov, vol.3, pp.673-683, 2004.

, The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts, Chronic Myeloid Leukemia, vol.121, pp.4439-4442, 2013.

F. S. Collins and H. Varmus, A New Initiative on Precision Medicine, N. Engl. J. Med, vol.372, pp.793-795, 2015.

H. Moses, The Anatomy of Medical Research: US and International Comparisons, JAMA, vol.313, p.174, 2015.

, Drug Development Costs Jump to $2.6 Billion, Cancer Discov, vol.5, pp.2-2, 2015.

J. G. Moffat, J. Rudolph, and D. Bailey, Phenotypic screening in cancer drug discovery -past, present and future, Nat. Rev. Drug Discov, vol.13, pp.588-602, 2014.

B. Vogelstein, Cancer Genome Landscapes. Science, vol.339, pp.1546-1558, 2013.

D. Hanahan and R. A. Weinberg, Hallmarks of Cancer: The Next Generation, Cell, vol.144, pp.646-674, 2011.

C. T. Keith, A. A. Borisy, and B. R. Stockwell, Multicomponent therapeutics for networked systems, Nat. Rev. Drug Discov, vol.4, pp.71-78, 2005.

C. Robert, Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib, N. Engl. J. Med, vol.372, pp.30-39, 2015.

M. J. Keiser, Predicting new molecular targets for known drugs, Nature, vol.462, pp.175-181, 2009.

J. Lamb, The Connectivity Map: a new tool for biomedical research, Nat. Rev. Cancer, vol.7, pp.54-60, 2007.

N. S. Jahchan, A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors, Cancer Discov, vol.3, pp.1364-1377, 2013.

L. F. Zerbini, Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer, Mol. Cancer Ther, vol.13, pp.1929-1941, 2014.

T. T. Talele, S. A. Khedkar, and A. C. Rigby, Successful applications of computer aided drug discovery: moving drugs from concept to the clinic, Curr. Top. Med. Chem, vol.10, pp.127-141, 2010.

Z. Liu, In silico drug repositioning: what we need to know, Drug Discov. Today, vol.18, pp.110-115, 2013.

U. F. Röhrig, Rational design of indoleamine 2,3-dioxygenase inhibitors, J. Med

, Chem, vol.53, pp.1172-1189, 2010.

F. Cheng, Prediction of drug-target interactions and drug repositioning via network-based inference, PLoS Comput. Biol, vol.8, p.1002503, 2012.

D. Brown, Unfinished business: target-based drug discovery, Drug Discov. Today, vol.12, pp.1007-1012, 2007.

L. Zhang, Quantitative High-Throughput Drug Screening Identifies Novel Classes of Drugs with Anticancer Activity in Thyroid Cancer Cells: Opportunities for Repurposing, J. Clin. Endocrinol. Metab, vol.97, pp.319-328, 2012.

R. J. Rickles, Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening, Mol. Cancer Ther, vol.11, pp.1432-1442, 2012.

A. A. Borisy, Systematic discovery of multicomponent therapeutics, Proc. Natl

M. B. Brandl, Computational analysis of image-based drug profiling predicts synergistic drug combinations: applications in triple-negative breast cancer, Mol. Oncol, vol.8, pp.1548-1560, 2014.

J. J. Roix, Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity, PloS One, vol.9, p.101708, 2014.

R. E. Elmslie, P. Glawe, and S. W. Dow, Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in dogs with incompletely resected soft tissue sarcomas, J. Vet. Intern. Med, vol.22, pp.1373-1379, 2008.

M. Campillos, M. Kuhn, A. Gavin, L. J. Jensen, and P. Bork, Drug target identification using side-effect similarity, Science, vol.321, pp.263-266, 2008.

I. Amelio, DRUGSURV: a resource for repositioning of approved and experimental drugs in oncology based on patient survival information, Cell Death Dis, vol.5, p.1051, 2014.

H. A. Ghofrani, I. H. Osterloh, and F. Grimminger, Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond, Nat. Rev. Drug Discov, vol.5, pp.689-702, 2006.

A. M. Carella, G. Beltrami, G. Pica, A. Carella, and G. Catania, Clarithromycin potentiates tyrosine kinase inhibitor treatment in patients with resistant chronic myeloid leukemia, Leuk. Lymphoma, vol.53, pp.1409-1411, 2012.

C. Léauté-labrèze, Propranolol for severe hemangiomas of infancy, N. Engl. J

. Med, , vol.358, pp.2649-2651, 2008.

P. J. Flynn, Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations, Blood, vol.62, pp.1211-1217, 1983.

P. Nygren and R. Larsson, Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer, Acta Oncol. Stockh. Swed, vol.53, pp.427-428, 2014.

S. Banavali, Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01420003

J. M. Evans, L. A. Donnelly, A. M. Emslie-smith, D. R. Alessi, and A. D. Morris,

, Metformin and reduced risk of cancer in diabetic patients, BMJ, vol.330, pp.1304-1305, 2005.

P. M. Rothwell, Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials, Lancet Lond. Engl, vol.379, pp.1591-1601, 2012.

J. Cuzick, Estimates of benefits and harms of prophylactic use of aspirin in the general population, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol, vol.26, pp.47-57, 2015.

P. M. Rothwell, Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials, Lancet Lond. Engl, vol.377, pp.31-41, 2011.

E. J. Jacobs, C. C. Newton, S. M. Gapstur, and M. J. Thun, Daily aspirin use and cancer mortality in a large US cohort, J. Natl. Cancer Inst, vol.104, pp.1208-1217, 2012.

X. Liao, Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival

. Engl, J. Med, vol.367, pp.1596-1606, 2012.

E. Domingo, Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer, J. Clin. Oncol. Off. J. Am

. Soc, Clin. Oncol, vol.31, pp.4297-4305, 2013.

R. Nishihara, Aspirin use and risk of colorectal cancer according to BRAF mutation status, JAMA, vol.309, pp.2563-2571, 2013.

A. T. Chan, S. Ogino, and C. S. Fuchs, Aspirin use and survival after diagnosis of colorectal cancer, JAMA, vol.302, pp.649-658, 2009.

S. P. Fink, Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD), Sci. Transl. Med, vol.6, pp.233-235, 2014.

H. Nan, Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants, JAMA, vol.313, pp.1133-1142, 2015.

M. Yin, J. Zhou, E. J. Gorak, and F. Quddus, Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and metaanalysis, The Oncologist, vol.18, pp.1248-1255, 2013.

S. Gandini, Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders, Cancer Prev. Res. Phila. Pa, vol.7, pp.867-885, 2014.

N. Gronich and G. Rennert, Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates, Nat. Rev. Clin. Oncol, vol.10, pp.625-642, 2013.

G. Blandino, Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC, Nat. Commun, vol.3, p.865, 2012.

A. Janzer, Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells, Proc. Natl

S. Orecchioni, The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells, Int. J. Cancer, vol.136, pp.534-544, 2015.

S. Kordes, Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial, Lancet Oncol, vol.16, pp.839-847, 2015.

L. C. Sakoda, Metformin use and lung cancer risk in patients with diabetes, Cancer Prev. Res. Phila. Pa, vol.8, pp.174-179, 2015.

S. Orecchioni, Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer, Cancer Res, vol.73, pp.5880-5891, 2013.

K. Birsoy, Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides, Nature, vol.508, pp.108-112, 2014.

I. Pernicova and M. Korbonits, Metformin--mode of action and clinical implications for diabetes and cancer, Nat. Rev. Endocrinol, vol.10, pp.143-156, 2014.

H. A. Hirsch, D. Iliopoulos, and K. Struhl, Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth, Proc. Natl. Acad. Sci. U

S. , , vol.110, pp.972-977, 2013.

S. Eikawa, Immune-mediated antitumor effect by type 2 diabetes drug, metformin

, Proc. Natl. Acad. Sci. U. S. A, vol.112, pp.1809-1814, 2015.

C. Hart, Anakoinosis: Communicative Reprogramming of Tumor Systems -for Rescuing from Chemorefractory Neoplasia, Cancer Microenviron. Off. J. Int. Cancer Microenviron. Soc, vol.8, pp.75-92, 2015.

S. Prost, Erosion of the chronic myeloid leukaemia stem cell pool by PPAR? agonists, Nature, vol.525, pp.380-383, 2015.

K. G. Roberts, Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia, N. Engl. J. Med, vol.371, pp.1005-1015, 2014.

K. R. Schultz, Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study

, Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.27, pp.5175-5181, 2009.

M. G. Kris, Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs, JAMA, vol.311, 1998.

A. Tsimberidou, Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses, Clin. Cancer Res. Off

, J. Am. Assoc. Cancer Res, vol.20, pp.4827-4836, 2014.

M. Schwaederle, Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.33, pp.3817-3825, 2015.

L. Tourneau and C. , Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-ofconcept, randomised, controlled phase 2 trial, Lancet Oncol, vol.16, pp.1324-1334, 2015.

A. M. Tsimberidou and R. Kurzrock, Precision medicine: lessons learned from the SHIVA trial, Lancet Oncol, vol.16, pp.579-580, 2015.

R. A. Kyle and S. V. Rajkumar, Multiple myeloma, N. Engl. J. Med, vol.351, pp.1860-1873, 2004.
URL : https://hal.archives-ouvertes.fr/hal-00557757

S. Singhal, Antitumor activity of thalidomide in refractory multiple myeloma

. Engl, J. Med, vol.341, pp.1565-1571, 1999.

M. A. Dimopoulos, A. Anagnostopoulos, and D. Weber, Treatment of plasma cell dyscrasias with thalidomide and its derivatives, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.21, pp.4444-4454, 2003.

M. A. Dimopoulos, Thalidomide and dexamethasone combination for refractory multiple myeloma, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol, vol.12, pp.991-995, 2001.

A. Anagnostopoulos, D. Weber, K. Rankin, K. Delasalle, and R. Alexanian, Thalidomide and dexamethasone for resistant multiple myeloma, Br. J. Haematol, vol.121, pp.768-771, 2003.

R. García-sanz, The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma, Hematol. J. Off. J. Eur. Haematol. Assoc, vol.3, pp.43-48, 2002.

N. Mitsiades, Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications, Blood, vol.99, pp.4525-4530, 2002.

P. G. Richardson, Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma, Blood, vol.100, pp.3063-3067, 2002.

J. B. Zeldis, R. Knight, M. Hussein, R. Chopra, and G. Muller, A review of the history, properties, and use of the immunomodulatory compound lenalidomide, Ann. N. Y. Acad. Sci, vol.1222, pp.76-82, 2011.

A. Lopez-girona, Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide, Leukemia, vol.26, pp.2326-2335, 2012.

P. P. Chamberlain, Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs, Nat. Struct. Mol. Biol, vol.21, pp.803-809, 2014.

A. Ali, Propranolol attenuates hemorrhage and accelerates wound healing in severely burned adults, Crit. Care Lond. Engl, vol.19, p.217, 2015.

E. R. Peskind, Propranolol for disruptive behaviors in nursing home residents with probable or possible Alzheimer disease: a placebo-controlled study, Alzheimer Dis. Assoc. Disord, vol.19, pp.23-28, 2005.

R. M. Greendyke, D. R. Kanter, D. B. Schuster, S. Verstreate, and J. Wootton, Propranolol treatment of assaultive patients with organic brain disease. A double-blind crossover, placebo-controlled study, J. Nerv. Ment. Dis, vol.174, pp.290-294, 1986.

R. Fogari, Beta-blocker effects on plasma lipids in antihypertensive therapy: importance of the duration of treatment and the lipid status before treatment, J. Cardiovasc. Pharmacol, vol.16, issue.5, pp.76-80, 1990.

D. G. Shand, Pharmacokinetics of propranolol: a review, Postgrad. Med. J, vol.52, pp.22-25, 1976.

T. Walle, Food-induced increase in propranolol bioavailability--relationship to protein and effects on metabolites, Clin. Pharmacol. Ther, vol.30, pp.790-795, 1981.

S. L. Bowman, S. A. Hudson, G. Simpson, J. F. Munro, and J. A. Clements, A comparison of the pharmacokinetics of propranolol in obese and normal volunteers, Br. J. Clin. Pharmacol, vol.21, pp.529-532, 1986.

W. J. Leahey, J. D. Neill, M. P. Varma, and R. G. Shanks, Comparison of the efficacy and pharmacokinetics of conventional propranolol and a long acting preparation of propranolol

, Br. J. Clin. Pharmacol, vol.9, pp.33-40, 1980.

J. Olesen, K. Hougård, and M. Hertz, Isoproterenol and propranolol: ability to cross the blood-brain barrier and effects on cerebral circulation in man, Stroke, vol.9, pp.344-349, 1978.

L. Filippi, Successful Propranolol Treatment of a Kaposiform Hemangioendothelioma Apparently Resistant to Propranolol. Pediatr, Blood Cancer, vol.63, pp.1290-1292, 2016.

E. Mutschler, H. Spahn, and W. Kirch, The interaction between H2-receptor antagonists and beta-adrenoceptor blockers, Br. J. Clin. Pharmacol, vol.17, pp.51-57, 1984.

M. D. Winniford, R. L. Huxley, and L. D. Hillis, Randomized, double-blind comparison of propranolol alone and a propranolol-verapamil combination in patients with severe angina of effort, J. Am. Coll. Cardiol, vol.1, pp.492-498, 1983.

T. J. Martin, Characterization of beta-adrenergic receptor linked to adenylate cyclase in a human cancer cell line (COLO 16), Clin. Sci. Mol. Med, vol.55, pp.23-29, 1978.

H. Schmitt and R. Pochet, In vivo labelling of beta-adrenergic receptors on rat glioma cells, FEBS Lett, vol.76, pp.302-305, 1977.

C. Delavier-klutchko, J. Hoebeke, and A. D. Strosberg, The human carcinoma cell line A431 possesses large numbers of functional beta-adrenergic receptors, FEBS Lett, vol.169, pp.151-155, 1984.

A. Ramu, R. Spanier, H. Rahamimoff, and Z. Fuks, Restoration of doxorubicin responsiveness in doxorubicin-resistant P388 murine leukaemia cells, Br. J. Cancer, vol.50, pp.501-507, 1984.

T. Tsuruo, Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells, Cancer Res, vol.44, pp.4303-4307, 1984.

N. Shiraishi, S. Akiyama, M. Kobayashi, and M. Kuwano, Lysosomotropic agents reverse multiple drug resistance in human cancer cells, Cancer Lett, vol.30, pp.251-259, 1986.

F. Hajighasemi and A. Mirshafiey, In vitro sensitivity of leukemia cells to propranolol

, J. Clin. Med. Res, vol.1, pp.144-149, 2009.

D. M. Lamkin, Chronic stress enhances progression of acute lymphoblastic leukemia via ?-adrenergic signaling, Brain. Behav. Immun, vol.26, pp.635-641, 2012.

F. Hajighasemi and S. Hajighasemi, Effect of propranolol on angiogenic factors in human hematopoietic cell lines in vitro, Iran. Biomed. J, vol.13, pp.223-228, 2009.

G. Shakhar and S. Ben-eliyahu, In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats, J. Immunol. Baltim. Md, vol.160, pp.3251-3258, 1950.

M. Benish, Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis, Ann. Surg. Oncol, vol.15, pp.2042-2052, 2008.

P. H. Thaker, Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma, Nat. Med, vol.12, pp.939-944, 2006.

E. K. Sloan, The sympathetic nervous system induces a metastatic switch in primary breast cancer, Cancer Res, vol.70, pp.7042-7052, 2010.

K. Lang, Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs, Int. J. Cancer, vol.112, pp.231-238, 2004.

C. Strell, Norepinephrine promotes the ?1-integrin-mediated adhesion of MDA

, MB-231 cells to vascular endothelium by the induction of a GRO? release, Mol. Cancer Res. MCR, vol.10, pp.197-207, 2012.

E. Pasquier, Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment, Oncotarget, vol.2, pp.797-809, 2011.

D. Liu, ?2-AR signaling controls trastuzumab resistance-dependent pathway, Oncogene, vol.35, pp.47-58, 2016.

J. P. Campbell, Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice, PLoS Biol, vol.10, p.1001363, 2012.

H. Hasegawa and I. Saiki, Psychosocial stress augments tumor development through beta-adrenergic activation in mice, Jpn. J. Cancer Res. Gann, vol.93, pp.729-735, 2002.

M. Dal-monte, Functional involvement of ?3-adrenergic receptors in melanoma growth and vascularization, J. Mol. Med. Berl. Ger, vol.91, pp.1407-1419, 2013.

L. J. Wrobel and F. A. Le-gal, Inhibition of human melanoma growth by a noncardioselective ?-blocker, J. Invest. Dermatol, vol.135, pp.525-531, 2015.

A. Glasner, 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. Baltim. Md, vol.184, pp.2449-2457, 1950.

S. K. Lutgendorf, Vascular endothelial growth factor and social support in patients with ovarian carcinoma, Cancer, vol.95, pp.808-815, 2002.

S. K. Lutgendorf, Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.9, pp.4514-4521, 2003.

A. K. Sood, Stress hormone-mediated invasion of ovarian cancer cells, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.12, pp.369-375, 2006.

J. Lee, Surgical stress promotes tumor growth in ovarian carcinoma, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.15, pp.2695-2702, 2009.

K. M. Chisholm, ?-Adrenergic receptor expression in vascular tumors

, Pathol. Off. J. U. S. Can. Acad. Pathol. Inc, vol.25, pp.1446-1451, 2012.

J. M. Stiles, Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma, PloS One, vol.8, p.60021, 2013.

E. Pasquier, Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study, EBioMedicine, vol.6, pp.87-95, 2016.

E. Pasquier, ?-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma, Br. J. Cancer, vol.108, pp.2485-2494, 2013.

T. Xu, Antiangiogenic effect of propranolol on the growth of the neuroblastoma xenografts in nude mice, J. Pediatr. Surg, vol.48, pp.2460-2465, 2013.

J. K. Wolter, Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma, Oncotarget, vol.5, pp.161-172, 2014.

D. Palm, The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers, Int. J. Cancer, vol.118, pp.2744-2749, 2006.

K. Guo, Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol, Oncol. Rep, vol.22, pp.825-830, 2009.

D. Zhang, Q. Ma, S. Shen, and H. Hu, Inhibition of pancreatic cancer cell proliferation by propranolol occurs through apoptosis induction: the study of beta-adrenoceptor antagonist's anticancer effect in pancreatic cancer cell, Pancreas, vol.38, pp.94-100, 2009.

D. Zhang, Q. Ma, H. Hu, and M. Zhang, ?2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF?B and AP-1, Cancer Biol. Ther, vol.10, pp.19-29, 2010.

C. Kim-fuchs, Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment, Brain. Behav. Immun, vol.40, pp.40-47, 2014.

L. I. Partecke, Chronic stress increases experimental pancreatic cancer growth, reduces survival and can be antagonised by beta-adrenergic receptor blockade

, J. Int. Assoc. Pancreatol. IAP Al, vol.16, pp.423-433, 2016.

K. Masur, B. Niggemann, K. S. Zanker, and F. Entschladen, Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers, Cancer Res, vol.61, pp.2866-2869, 2001.

M. Coelho, Antiproliferative effects of ?-blockers on human colorectal cancer cells, Oncol. Rep, vol.33, pp.2513-2520, 2015.

C. Chin, Selective ?2-AR Blockage Suppresses Colorectal Cancer Growth Through Regulation of EGFR-Akt/ERK1/2 Signaling, G1-Phase Arrest, and Apoptosis, J. Cell. Physiol, vol.231, pp.459-472, 2016.

Q. Lin, Effect of chronic restraint stress on human colorectal carcinoma growth in mice, PloS One, vol.8, p.61435, 2013.

E. V. Yang, Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells, Cancer Res, vol.66, pp.10357-10364, 2006.

B. Annabi, M. Lachambre, K. Plouffe, R. Moumdjian, and R. Béliveau, Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion, Pharmacol. Res, vol.60, pp.438-445, 2009.

D. G. Bernabé, A. C. Tamae, É. R. Biasoli, and S. H. Oliveira, Stress hormones increase cell proliferation and regulates interleukin-6 secretion in human oral squamous cell carcinoma cells, Brain. Behav. Immun, vol.25, pp.574-583, 2011.

N. E. Wolter, J. K. Wolter, D. J. Enepekides, and M. S. Irwin, Propranolol as a novel adjunctive treatment for head and neck squamous cell carcinoma, J. Otolaryngol. -Head Neck Surg. J. Oto-Rhino-Laryngol. Chir. Cervico-Faciale, vol.41, pp.334-344, 2012.

R. Grzanna, C. G. Frondoza, G. L. Hung, and A. Sastre, In vivo administration of propranolol delays development of a murine plasmacytoma tumor, J. Auton. Nerv. Syst, vol.14, pp.397-401, 1985.

P. Bomber, R. Mccready, and P. Hammersley, Propranolol hydrochloride enhancement of tumor perfusion and uptake of gallium-67 in a mouse sarcoma, J. Nucl. Med. Off. Publ. Soc. Nucl. Med, vol.27, pp.243-245, 1986.

M. A. Burton and B. N. Gray, Redistribution of blood flow in experimental hepatic tumours with noradrenaline and propranolol, Br. J. Cancer, vol.56, pp.585-588, 1987.

X. Liao, The ?-adrenoceptor antagonist, propranolol, induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor ?B signaling, Oncol. Rep, vol.24, pp.1669-1676, 2010.

X. Liao, Effects of propranolol in combination with radiation on apoptosis and survival of gastric cancer cells in vitro, Radiat. Oncol. Lond. Engl, vol.5, p.98, 2010.

H. A. Al-wadei, M. H. Al-wadei, and H. M. Schuller, Cooperative regulation of nonsmall cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention, PloS One, vol.7, p.29915, 2012.

M. H. Al-wadei, H. A. Al-wadei, and H. M. Schuller, Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors ?3, ?5, and ?7, Mol. Cancer Res. MCR, vol.10, pp.239-249, 2012.

I. Kozanoglu, New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma, J. Cancer Res. Clin. Oncol, vol.139, pp.327-335, 2013.

A. A. Abdin, N. A. Soliman, and E. M. Saied, Effect of propranolol on IL-10, visfatin, Hsp70, iNOS, TLR2, and survivin in amelioration of tumor progression and survival in Solid Ehrlich Carcinoma-bearing mice, Pharmacol. Rep. PR, vol.66, pp.1114-1121, 2014.

W. Wei, C. Shen, H. Song, Z. Qiu, and Q. Luo, Propranolol sensitizes thyroid cancer cells to cytotoxic effect of vemurafenib, Oncol. Rep, vol.36, pp.1576-1584, 2016.

V. Albiñana, Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients, Orphanet J. Rare Dis, vol.10, p.118, 2015.

L. Perron, I. Bairati, F. Harel, and F. Meyer, Antihypertensive drug use and the risk of prostate cancer (Canada), Cancer Causes Control CCC, vol.15, pp.535-541, 2004.

G. Nkontchou, Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis, Cancer Prev. Res. Phila. Pa, vol.5, pp.1007-1014, 2012.

P. Chang, Propranolol Reduces Cancer Risk: A Population-Based Cohort Study, Medicine (Baltimore), vol.94, p.1097, 2015.

S. Zhong, ?-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies, Eur. J. Cancer Prev. Off. J. Eur. Cancer Prev. Organ. ECP, vol.25, pp.440-448, 2016.

T. I. Barron, R. M. Connolly, L. Sharp, K. Bennett, and K. Visvanathan, Beta blockers and breast cancer mortality: a population-based study, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.29, pp.2635-2644, 2011.

W. K. Childers, C. S. Hollenbeak, and P. Cheriyath, Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis, Clin. Breast Cancer, vol.15, pp.426-431, 2015.

D. C. Galván, A. P. Ayyappan, and B. A. Bryan, Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment, Oncoscience, vol.5, pp.264-268, 2018.

W. Chow, Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated ?-Blockade, JAMA Dermatol, vol.151, pp.1226-1229, 2015.

J. Daguzé, Visceral metastatic angiosarcoma treated effectively with oral cyclophosphamide combined with propranolol, JAAD Case Rep, vol.2, pp.497-499, 2016.

J. Daguzé, M. Saint-jean, and B. Dréno, Large nose angiosarcoma treated effectively with oral cyclophosphamide combined with propranolol, J. Eur. Acad. Dermatol. Venereol, vol.32, pp.52-54, 2018.

G. S. Bhattacharyya, Continuous metronomic temozolamide with propranolol and etodolac in recurrent globlastoma: A pilot study, J. Clin. Oncol, vol.32, pp.13005-13005, 2014.

T. Shahid, Continuous low dose temozolamide with or without VT-122 in glioblastoma, J. Clin. Oncol, vol.33, pp.13010-13010, 2015.

G. S. Bhattacharyya, Effect of coadministered beta blocker and COX-2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) paclitaxel, J. Clin. Oncol, vol.33, pp.302-302, 2015.

A. N. De-la-torre, Effect of coadministration of propranolol and etodolac

, plus sorafenib for patients with advanced hepatocellular carcinoma (HCC), J. Clin. Oncol, vol.33, pp.390-390, 2015.

T. Aoyagi, K. P. Terracina, A. Raza, H. Matsubara, and K. Takabe, Cancer cachexia, mechanism and treatment, World J. Gastrointest. Oncol, vol.7, pp.17-29, 2015.

A. Hyltander, U. Körner, and K. G. Lundholm, Evaluation of mechanisms behind elevated energy expenditure in cancer patients with solid tumours, Eur. J. Clin. Invest, vol.23, pp.46-52, 1993.

A. Hyltander, P. Daneryd, R. Sandström, U. Körner, and K. Lundholm, Betaadrenoceptor activity and resting energy metabolism in weight losing cancer patients, Eur. J. Cancer Oxf. Engl, vol.36, pp.330-334, 1990.

M. E. Lindgren, Beta-blockers may reduce intrusive thoughts in newly diagnosed cancer patients, Psychooncology, vol.22, pp.1889-1894, 2013.

H. Selye, R. Veilleux, and M. Cantin, Excessive stimulation of salivary gland growth by isoproterenol, Science, vol.133, pp.44-45, 1961.

T. Barka, . Induced, and . Proliferation, THE EFFECT OF ISOPROTERENOL. Exp. Cell Res, vol.37, pp.662-679, 1965.

H. Iwata, K. Kariya, and S. Fujimoto, Effect of compounds affecting the adrenergic mechanism on cell growth and division of Tetrahymena pyriformis W, Jpn. J. Pharmacol, vol.19, pp.275-281, 1969.

J. T. Bijman, Modulation of placental alkaline phosphatase activity and cytokeratins in human HN-1 cells by butyrate, retinoic acid, catecholamines and histamine

, J. Cancer, vol.56, pp.127-132, 1987.

H. M. Schuller and B. Cole, Regulation of cell proliferation by beta-adrenergic receptors in a human lung adenocarcinoma cell line, Carcinogenesis, vol.10, pp.1753-1755, 1989.

X. Lin, K. Luo, Z. Lv, and J. Huang, Beta-adrenoceptor action on pancreatic cancer cell proliferation and tumor growth in mice, Hepatogastroenterology, vol.59, pp.584-588, 2012.

O. D. I?eri, beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration, Pharm. Biol, vol.52, pp.1374-1381, 2014.

S. L. Valles, Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6-and glutathione-dependent mechanism, J. Transl. Med, vol.11, p.72, 2013.

G. Shay, C. C. Lynch, and B. Fingleton, Moving targets: Emerging roles for MMPs in cancer progression and metastasis, Matrix Biol. J. Int. Soc. Matrix Biol, pp.200-206, 2015.

L. Yadav, Matrix metalloproteinases and cancer -roles in threat and therapy. Asian Pac, J. Cancer Prev. APJCP, vol.15, pp.1085-1091, 2014.

K. Guo, Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol, Oncol. Rep, vol.22, pp.825-830, 2009.

S. Moretti, ?-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines, Lab. Investig. J. Tech. Methods Pathol, vol.93, pp.279-290, 2013.

A. Barbieri, The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo, Int. J. Oncol, vol.47, pp.527-534, 2015.

B. Annabi, E. Vaillancourt-jean, A. G. Weil, and R. Béliveau, Pharmacological targeting of ?-adrenergic receptor functions abrogates NF-?B signaling and MMP-9 secretion in medulloblastoma cells, OncoTargets Ther, vol.3, pp.219-226, 2010.

S. Wu, Clinical efficacy of propranolol in the treatment of hemangioma and changes in serum VEGF, bFGF and MMP-9, Exp. Ther. Med, vol.10, pp.1079-1083, 2015.

S. Thaivalappil, Propranolol-mediated attenuation of MMP-9 excretion in infants with hemangiomas, Head Neck Surg, vol.139, pp.1026-1031, 2013.

C. K. Pon, J. R. Lane, E. K. Sloan, and M. L. Halls, The ?2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion, FASEB J. Off

, Publ. Fed. Am. Soc. Exp. Biol, vol.30, pp.1144-1154, 2016.

B. N. Smith and N. A. Bhowmick, Role of EMT in Metastasis and Therapy Resistance

, J. Clin. Med, vol.5, 2016.

T. Shan, Novel regulatory program for norepinephrine-induced epithelialmesenchymal transition in gastric adenocarcinoma cell lines, Cancer Sci, vol.105, pp.847-856, 2014.

J. Zhang, Norepinephrine induced epithelial-mesenchymal transition in HT-29 and A549 cells in vitro, J. Cancer Res. Clin. Oncol, vol.142, pp.423-435, 2016.

A. Jacob and R. Prekeris, The regulation of MMP targeting to invadopodia during cancer metastasis. Front, Cell Dev. Biol, vol.3, p.4, 2015.

S. J. Creed, ?2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion, Breast Cancer Res. BCR, vol.17, p.145, 2015.

J. Linden, Adenosine promotes tumor metastasis, Sci. Signal, vol.6, p.20, 2013.

E. Ntantie, An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering, Sci. Signal, vol.6, p.39, 2013.

B. Psaila and D. Lyden, The metastatic niche: adapting the foreign soil, Nat. Rev. Cancer, vol.9, pp.285-293, 2009.

M. H. Barcellos-hoff, D. Lyden, and T. C. Wang, The evolution of the cancer niche during multistage carcinogenesis, Nat. Rev. Cancer, vol.13, pp.511-518, 2013.

S. Karaman and M. Detmar, Mechanisms of lymphatic metastasis, J. Clin. Invest, vol.124, pp.922-928, 2014.

C. P. Le, Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination, Nat. Commun, vol.7, p.10634, 2016.

M. Ozeki, Propranolol as an alternative treatment option for pediatric lymphatic malformation, Tohoku J. Exp. Med, vol.229, pp.61-66, 2013.

A. Asano, M. Morimatsu, H. Nikami, T. Yoshida, and M. Saito, Adrenergic activation of vascular endothelial growth factor mRNA expression in rat brown adipose tissue: implication in cold-induced angiogenesis, Biochem. J, vol.328, pp.179-183, 1997.

C. Tonello, Role of sympathetic activity in controlling the expression of vascular endothelial growth factor in brown fat cells of lean and genetically obese rats, FEBS Lett, vol.442, pp.167-172, 1999.

J. Lee, Surgical stress promotes tumor growth in ovarian carcinoma, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.15, pp.2695-2702, 2009.

E. V. Yang, Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression, Brain. Behav. Immun, vol.23, pp.267-275, 2009.

N. E. Wolter, J. K. Wolter, D. J. Enepekides, and M. S. Irwin, Propranolol as a novel adjunctive treatment for head and neck squamous cell carcinoma, J. Otolaryngol. -Head Neck Surg. J. Oto-Rhino-Laryngol. Chir. Cervico-Faciale, vol.41, pp.334-344, 2012.

S. Lamy, M. Lachambre, S. Lord-dufour, and R. Béliveau, Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells, Vascul. Pharmacol, vol.53, pp.200-208, 2010.

J. J. Kum and Z. A. Khan, Mechanisms of propranolol action in infantile hemangioma

, Dermatoendocrinol, vol.6, p.979699, 2014.

B. Annabi, M. Lachambre, K. Plouffe, R. Moumdjian, and R. Béliveau, Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion, Pharmacol. Res, vol.60, pp.438-445, 2009.

S. Y. Park, Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1? protein-dependent mechanism, Int. J. Cancer, vol.128, pp.2306-2316, 2011.

C. Muraki, Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells, Int. J. Cancer, vol.130, pp.59-70, 2012.

M. A. Iñiguez, A. Rodríguez, O. V. Volpert, M. Fresno, and J. Redondo,

, Cyclooxygenase-2: a therapeutic target in angiogenesis, Trends Mol. Med, vol.9, pp.73-78, 2003.

M. Ciccarelli, Impaired neoangiogenesis in ??-adrenoceptor gene-deficient mice: restoration by intravascular human ??-adrenoceptor gene transfer and role of NF?B and CREB transcription factors, Br. J. Pharmacol, vol.162, pp.712-721, 2011.

J. M. Zamora, H. L. Pearce, and W. T. Beck, Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells, Mol. Pharmacol, vol.33, pp.454-462, 1988.

T. Bando, Stimulation of beta-adrenoceptor enhances sensitivity to cisplatin in non-small cell lung cancer cell lines, Int. J. Oncol, vol.10, pp.1197-1201, 1997.

E. Pasquier, Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study, EBioMedicine, vol.6, pp.87-95, 2016.

Y. Akutsu, COX2 expression predicts resistance to chemoradiotherapy in esophageal squamous cell carcinoma, Ann. Surg. Oncol, vol.18, pp.2946-2951, 2011.

S. Xia, Y. Zhao, S. Yu, and M. Zhang, Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells, Cancer Biother. Radiopharm, vol.25, pp.317-323, 2010.

H. J. Yang, N. Kim, K. M. Seong, H. Youn, and B. Youn, Investigation of radiationinduced transcriptome profile of radioresistant non-small cell lung cancer A549 cells using RNA-seq, PloS One, vol.8, p.59319, 2013.

L. Brohée, Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment, Oncotarget, vol.6, pp.11264-11280, 2015.

J. Liu, The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models, Psychoneuroendocrinology, vol.52, pp.130-142, 2015.

P. Green-mcdonald, M. O'connell, and S. K. Lutgendorf, Psychoneuroimmunology and cancer: a decade of discovery, paradigm shifts, and methodological innovations, Brain. Behav. Immun, vol.30, pp.1-9, 2013.

H. Teshima, Prevention of immunosuppression in stressed mice by neurotropin(NSP), Life Sci, vol.47, pp.869-876, 1990.

V. V. Kalinichenko, M. B. Mokyr, L. H. Graf, R. L. Cohen, and D. A. Chambers,

, Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression, J. Immunol. Baltim. Md, vol.163, pp.2492-2499, 1950.

W. Wu, Social isolation stress enhanced liver metastasis of murine colon 26-L5

, carcinoma cells by suppressing immune responses in mice, Life Sci, vol.66, pp.1827-1838, 2000.

O. Kanemi, X. Zhang, Y. Sakamoto, M. Ebina, and R. Nagatomi, Acute stress reduces intraparenchymal lung natural killer cells via beta-adrenergic stimulation, Clin. Exp. Immunol, vol.139, pp.25-34, 2005.

A. J. Tarr, ?-Adrenergic receptor mediated increases in activation and function of natural killer cells following repeated social disruption, Brain. Behav. Immun, vol.26, pp.1226-1238, 2012.

S. Ben-eliyahu, Can we really know if a stressor increases or decreases natural killer cell activity?, Brain. Behav. Immun, vol.26, pp.1224-1225, 2012.

G. Sonnenfeld, J. E. Cunnick, A. V. Armfield, P. G. Wood, and B. S. Rabin, Stressinduced alterations in interferon production and class II histocompatibility antigen expression, Brain. Behav. Immun, vol.6, pp.170-178, 1992.

A. Khalili, Long acting propranolol and HSP-70 rich tumor lysate reduce tumor growth and enhance immune response against fibrosarcoma in Balb/c mice, Iran. J. Immunol. IJI, vol.10, pp.70-82, 2013.

H. Huang, J. Tang, X. Han, Y. Peng, and Y. Qiu, Lymphocyte-derived catecholamines induce a shift of Th1/Th2 balance toward Th2 polarization, Neuroimmunomodulation, vol.20, pp.1-8, 2013.

H. Huang, X. Fang, X. Wang, Y. Peng, and Y. Qiu, Regulation of differentiation and function of helper T cells by lymphocyte-derived catecholamines via ??-and ??-adrenoceptors, Neuroimmunomodulation, vol.22, pp.138-151, 2015.

P. Panina-bordignon, Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12, J. Clin. Invest, vol.100, pp.1513-1519, 1997.

Y. S. Khaled, B. J. Ammori, and E. Elkord, Myeloid-derived suppressor cells in cancer: recent progress and prospects, Immunol. Cell Biol, vol.91, pp.493-502, 2013.

M. Motallebnezhad, The immunobiology of myeloid-derived suppressor cells in cancer, Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med, vol.37, pp.1387-1406, 2016.

J. Jin, Chronic psychological stress induces the accumulation of myeloid-derived suppressor cells in mice, PloS One, vol.8, p.74497, 2013.

Y. Mao, Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity, Clin. Cancer Res. Off

, J. Am. Assoc. Cancer Res, vol.20, pp.4096-4106, 2014.

L. Zhou, Propranolol Attenuates Surgical Stress-Induced Elevation of the

, Regulatory T Cell Response in Patients Undergoing Radical Mastectomy, J. Immunol. Baltim. Md, pp.3460-3469, 2016.

N. Normanno, Epidermal growth factor receptor (EGFR) signaling in cancer, Gene, vol.366, pp.2-16, 2006.

J. S. Rush, L. M. Quinalty, L. Engelman, D. M. Sherry, and B. P. Ceresa, Endosomal accumulation of the activated epidermal growth factor receptor (EGFR) induces apoptosis, J. Biol. Chem, vol.287, pp.712-722, 2012.

Y. Mosesson, G. B. Mills, and Y. Yarden, Derailed endocytosis: an emerging feature of cancer, Nat. Rev. Cancer, vol.8, pp.835-850, 2008.

R. Shaughnessy, Epidermal growth factor receptor endocytic traffic perturbation by phosphatidate phosphohydrolase inhibition: new strategy against cancer, FEBS J, vol.281, pp.2172-2189, 2014.

A. Norambuena, Phosphatidic acid induces ligand-independent epidermal growth factor receptor endocytic traffic through PDE4 activation, Mol. Biol. Cell, vol.21, pp.2916-2929, 2010.

Y. Lavie, O. Piterman, and M. Liscovitch, Inhibition of phosphatidic acid phosphohydrolase activity by sphingosine. Dual action of sphingosine in diacylglycerol signal termination, FEBS Lett, vol.277, pp.7-10, 1990.

F. Kang, Propranolol inhibits glucose metabolism and 18F-FDG uptake of breast cancer through posttranscriptional downregulation of hexokinase-2, J. Nucl. Med. Off. Publ. Soc. Nucl. Med, vol.55, pp.439-445, 2014.

M. Nakanishi and D. W. Rosenberg, Multifaceted roles of PGE2 in inflammation and cancer, Semin. Immunopathol, vol.35, pp.123-137, 2013.

A. S. Nagaraja, Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis, Oncogene, vol.35, pp.2390-2397, 2016.

L. J. Gay and B. Felding-habermann, Contribution of platelets to tumour metastasis, Nat. Rev. Cancer, vol.11, pp.123-134, 2011.

B. B. Su, J. H. Chen, H. Shi, Q. Q. Chen, and J. Wan, Aspirin may modify tumor microenvironment via antiplatelet effect, Med. Hypotheses, vol.83, pp.148-150, 2014.

S. A. Mousa and L. J. Petersen, Anti-cancer properties of low-molecular-weight heparin: preclinical evidence, Thromb. Haemost, vol.102, pp.258-267, 2009.

D. B. Pfankuchen, D. P. Stölting, M. Schlesinger, H. Royer, and G. Bendas, Low molecular weight heparin tinzaparin antagonizes cisplatin resistance of ovarian cancer cells

, Biochem. Pharmacol, vol.97, pp.147-157, 2015.

D. Spano, Dipyridamole prevents triple-negative breast-cancer progression, Clin. Exp. Metastasis, vol.30, pp.47-68, 2013.

T. N. Bonten, Effect of ?-blockers on platelet aggregation: a systematic review and meta-analysis, Br. J. Clin. Pharmacol, vol.78, pp.940-949, 2014.

A. Punda, Effects of atenolol and propranolol on platelet aggregation in moderate essential hypertension: randomized crossover trial, Croat. Med. J, vol.46, pp.219-224, 2005.

K. Aschbacher, Good stress, bad stress and oxidative stress: insights from anticipatory cortisol reactivity, Psychoneuroendocrinology, vol.38, pp.1698-1708, 2013.

L. Cao, Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition, Cell, vol.142, pp.52-64, 2010.

R. W. Ammann, A. Fleiner-hoffmann, F. Grimm, and J. Eckert, Long-term mebendazole therapy may be parasitocidal in alveolar echinococcosis, J. Hepatol, vol.29, pp.994-998, 1998.

R. L. Rausch, J. F. Wilson, B. J. Mcmahon, and M. A. O'gorman, Consequences of continuous mebendazole therapy in alveolar hydatid disease--with a summary of a ten-year clinical trial, Ann. Trop. Med. Parasitol, vol.80, pp.403-419, 1986.

S. Reuter, B. Jensen, K. Buttenschoen, W. Kratzer, and P. Kern, Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature, J. Antimicrob. Chemother, vol.46, pp.451-456, 2000.

G. J. Münst, G. Karlaganis, and J. Bircher, Plasma concentrations of mebendazole during treatment of echinococcosis: preliminary results, Eur. J. Clin. Pharmacol, vol.17, pp.375-378, 1980.

P. A. Braithwaite, M. S. Roberts, R. J. Allan, and T. R. Watson, Clinical pharmacokinetics of high dose mebendazole in patients treated for cystic hydatid disease

, J. Clin. Pharmacol, vol.22, pp.161-169, 1982.

M. Dawson and T. R. Watson, The effect of dose form on the bioavailability of mebendazole in man, Br. J. Clin. Pharmacol, vol.19, pp.87-90, 1985.

A. M. Shcherbakov and A. A. Lur'e,

, Med. Parazitol. (Mosk.), vol.46, p.49, 1989.

C. Liu, Enhanced bioavailability and cysticidal effect of three mebendazole-oil preparations in mice infected with secondary cysts of Echinococcus granulosus, Parasitol. Res, vol.111, pp.1205-1211, 2012.

Y. Chiba, N. Kohri, K. Iseki, and K. Miyazaki, Improvement of dissolution and bioavailability for mebendazole, an agent for human echinococcosis, by preparing solid dispersion with polyethylene glycol, Chem. Pharm. Bull. (Tokyo), vol.39, pp.2158-2160, 1991.

A. Bekhti and J. Pirotte, Cimetidine increases serum mebendazole concentrations

, Implications for treatment of hepatic hydatid cysts, Br. J. Clin. Pharmacol, vol.24, pp.390-392, 1987.

S. Deva and M. Jameson, Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer, Cochrane Database Syst. Rev, vol.007814, 2012.

R. Bai, Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.21, pp.3462-3470, 2015.

T. Mukhopadhyay, J. Sasaki, R. Ramesh, and J. A. Roth, Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.8, pp.2963-2969, 2002.

J. Sasaki, The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells, Mol. Cancer Ther, vol.1, pp.1201-1209, 2002.

D. Martarelli, P. Pompei, C. Baldi, and G. Mazzoni, Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice, Cancer Chemother. Pharmacol, vol.61, pp.809-817, 2008.

N. Doudican, A. Rodriguez, I. Osman, and S. J. Orlow, Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells, Mol. Cancer Res. MCR, vol.6, pp.1308-1315, 2008.

N. A. Doudican, S. A. Byron, P. M. Pollock, and S. J. Orlow, XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts, Anticancer. Drugs, vol.24, pp.181-188, 2013.

R. Bai, V. Staedtke, C. M. Aprhys, G. L. Gallia, and G. J. Riggins, Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme, Neuro-Oncol, vol.13, pp.974-982, 2011.

P. Nygren, M. Fryknäs, B. Agerup, and R. Larsson, Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer, J. Cancer Res. Clin. Oncol, vol.139, pp.2133-2140, 2013.

C. P. Coyne, T. Jones, and R. Bear, Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicity in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma, J. Clin. Exp. Oncol, vol.2, 2013.

I. Y. Dobrosotskaya, G. D. Hammer, D. E. Schteingart, K. E. Maturen, and F. Worden,

P. , Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma, Endocr. Pract. Off. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol, vol.17, pp.59-62, 2011.

J. P. Laclette, G. Guerra, and C. Zetina, Inhibition of tubulin polymerization by mebendazole, Biochem. Biophys. Res. Commun, vol.92, pp.417-423, 1980.

P. A. Friedman and E. G. Platzer, Interaction of anthelmintic benzimidazoles with Ascaris suum embryonic tubulin, Biochim. Biophys. Acta, vol.630, pp.271-278, 1980.

A. A. Argyriou, A. P. Kyritsis, T. Makatsoris, and H. P. Kalofonos, Chemotherapyinduced peripheral neuropathy in adults: a comprehensive update of the literature, Cancer Manag. Res, vol.6, pp.135-147, 2014.

J. P. Cata, H. R. Weng, B. N. Lee, J. M. Reuben, and P. Dougherty, Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy, Minerva Anestesiol, vol.72, pp.151-169, 2006.

S. Dakshanamurthy, Predicting new indications for approved drugs using a proteochemometric method, J. Med. Chem, vol.55, pp.6832-6848, 2012.

M. H. Pourgholami, Potent inhibition of tumoral hypoxia-inducible factor 1alpha by albendazole, BMC Cancer, vol.10, p.143, 2010.

S. W. Chu, S. Badar, D. L. Morris, and M. H. Pourgholami, Potent inhibition of tubulin polymerisation and proliferation of paclitaxel-resistant 1A9PTX22 human ovarian cancer cells by albendazole, Anticancer Res, vol.29, pp.3791-3796, 2009.

E. Pasquier, S. Honore, and D. Braguer, Microtubule-targeting agents in angiogenesis: Where do we stand?, Drug Resist. Updat, vol.9, pp.74-86, 2006.

R. Stupp, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N. Engl. J. Med, vol.352, pp.987-996, 2005.

A. Peón, S. Naulaerts, and P. J. Ballester, Predicting the Reliability of Drug-target Interaction Predictions with Maximum Coverage of Target Space, Sci. Rep, vol.7, p.3820, 2017.

P. Pantziarka, G. Bouche, L. Meheus, V. Sukhatme, and V. P. Sukhatme, Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent, Ecancermedicalscience, vol.8, p.443, 2014.

S. R. Lai, S. A. Castello, A. C. Robinson, and J. W. Koehler, In vitro anti-tubulin effects of mebendazole and fenbendazole on canine glioma cells, Vet. Comp. Oncol, vol.15, pp.1445-1454, 2017.

D. S. Tyler, Click chemistry enables preclinical evaluation of targeted epigenetic therapies, Science, vol.356, pp.1397-1401, 2017.

O. Bounedjah, Free mRNA in excess upon polysome dissociation is a scaffold for protein multimerization to form stress granules, Nucleic Acids Res, vol.42, pp.8678-8691, 2014.
URL : https://hal.archives-ouvertes.fr/hal-02292175

C. M. Dewey, TDP-43 aggregation in neurodegeneration: are stress granules the key?, Brain Res, vol.1462, pp.16-25, 2012.

O. D. King, A. D. Gitler, and J. Shorter, The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease, Brain Res, vol.1462, pp.61-80, 2012.

M. Ramaswami, J. P. Taylor, and R. Parker, Altered ribostasis: RNA-protein granules in degenerative disorders, Cell, vol.154, pp.727-736, 2013.

Y. R. Li, O. D. King, J. Shorter, and A. D. Gitler, Stress granules as crucibles of ALS pathogenesis, J. Cell Biol, vol.201, pp.361-372, 2013.

J. Papakrivos, Regulatory Strategy for the Development of Known Drugs in New Therapeutic Areas, 2011.

S. Balogh, Extensions of indication in the European Union -a regulatory overview, 2016.

, Abraxane assessment report -EMA, European Medicines Agency, 2013.

, European Medicines Agency, 2015.

, European Medicines Agency 2019 a. European Medicines Agency post-authorisation procedural advice for users of the centralised procedure -EMEA-H-19984/03 Rev, vol.82, 2019.

, concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures, European Commission, vol.56, pp.1-79, 2008.

, Lysodren (mitotane): EPAR summary for the public, European Medicines Agency, vol.423898, 2013.

A. M. Vogel, Hybrid or Mixed Marketing Authorization Application in the European Union: Not a Trivial Decision in New Development Programs for Established Drugs

, J, vol.46, pp.479-484, 2012.

P. Pantziarka, M. Pirmohamed, and N. Mirza, New uses for old drugs, BMJ k2701, 2018.

R. R. Shah and P. D. Stonier, Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead, J. Clin. Pharm. Ther, vol.44, pp.6-22, 2019.

J. Langedijk, Extensions of indication throughout the drug product lifecycle: a quantitative analysis, Drug Discov. Today, vol.21, pp.348-355, 2016.

G. Nayroles, Unlocking the potential of established products: toward new incentives rewarding innovation in Europe, J. Mark. Access Health Policy, vol.5, p.1298190, 2017.

, European Commission (2007a). an extended (11-year) marketing protection period, 2007.

, Guidance on a new therapeutic indication for a wellestablished substance, European Commission, 2007.

, Study on the economic impact of supplementary protection certificates, pharmaceutical incentives and rewards in, Copenhagen Economics, 2018.

R. B. Smith, Repositioned drugs: integrating intellectual property and regulatory strategies, Drug Discov. Today Ther. Strateg, vol.8, pp.131-137, 2011.

N. Novac, Challenges and opportunities of drug repositioning, Trends Pharmacol. Sci, vol.34, pp.267-272, 2013.

S. J. Dilly and G. S. Morris, Pimping up Drugs Recovered, Superannuated and Under Exploited Drugs -An Introduction to the Basics of Drug Reprofiling, Curr. Drug Discov

. Technol, , vol.14, pp.121-126, 2017.

S. Murteira, A. Millier, Z. Ghezaiel, and M. Lamure, Drug reformulations and repositioning in the pharmaceutical industry and their impact on market access: regulatory implications, J. Mark. Access Health Policy, vol.2, 2014.

P. Norman, Repurposing as a strategy for orphan drug development, evidence from European approvals, Expert Opin. Orphan Drugs, vol.1, pp.473-480, 2013.

E. H. Davies, E. Fulton, D. Brook, and D. A. Hughes, Affordable orphan drugs: a role for not-for-profit organizations: Non-profit orphan drug development, Br. J. Clin. Pharmacol, vol.83, pp.1595-1601, 2017.

, Thalidomide Celgene : EPAR -Public assessment report, European Medicines Agency, 2008.

, State of paediatric medicines in the EU -10 years of the EU Paediatric Regulation, 2017.

, Hemangiol : EPAR -Public assessment report, European Medicines Agency, 2014.

J. Blatt and S. J. Corey, Drug repurposing in pediatrics and pediatric hematology oncology, Drug Discov. Today, vol.18, pp.4-10, 2013.

M. M. Rumore, Medication Repurposing in Pediatric Patients: Teaching Old Drugs New Tricks, J. Pediatr. Pharmacol. Ther, vol.21, pp.36-53, 2016.

S. Murteira, A. Millier, and M. Toumi, Drug repurposing in pharmaceutical industry and its impact on market access: market access implications, J. Mark. Access Health Policy, vol.2, p.22814, 2014.

P. Minghetti, From Off-Label to Repurposed Drug in Non-Oncological Rare Diseases: Definition and State of the Art in Selected EU Countries, Med. Access Point Care, vol.1, p.16, 2017.

D. W. Shineman, Overcoming obstacles to repurposing for neurodegenerative disease, Ann. Clin. Transl. Neurol, vol.1, pp.512-518, 2014.

M. Toumi and C. Rémuzat, Value added medicines: what value repurposed medicines might bring to society?, J. Mark. Access Health Policy, vol.5, p.1264717, 2017.

, Repurposing of established medicines/active substances -Ad hoc session with invited stakeholders -STAMP 6/31, 2017.

S. Simoens, E. Picavet, D. Cassiman, and M. Dooms, PHP15 What Price do we Pay for Repurposing Medicines for Rare Diseases?, Value Health, vol.15, pp.15-16, 2012.

M. Dooms, H. Pincé, and S. Simoens, Do we need authorized orphan drugs when compounded medications are available?: Unnecessary authorization of some orphan drugs, J. Clin. Pharm. Ther, vol.38, pp.1-2, 2013.

A. Van-bossuyt, Parliamentary questions: the sharp price increase of the drug CDCA (chenodeoxycholic acid), 2018.

T. Sheldon, Dutch hospital makes own drug for rare condition after manufacturer hikes price to ?170 000, BMJ k2103, 2018.

A. Breckenridge and R. Jacob, Overcoming the legal and regulatory barriers to drug repurposing, Nat. Rev. Drug Discov, vol.18, pp.1-2, 2019.

, Explanatory note on general fees payable to the European Medicines Agency as of 1, European Medicines Agency, 2019.

R. E. Sachs, P. B. Ginsburg, and D. P. Goldman, Encouraging New Uses for Old Drugs, JAMA, vol.318, p.2421, 2017.

S. Pushpakom, Drug repurposing: progress, challenges and recommendations, Nat. Rev. Drug Discov, vol.18, pp.41-58, 2019.

V. P. Sukhatme, K. Fang, A. Lo, and V. &-ukhatme, Financial orphan therapies looking for adoption, 2014.

P. Polamreddy and N. Gattu, The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions, Drug Discov. Today, vol.24, pp.789-795, 2019.

, Association of Medical Research Charities. Facilitating adoption of off-patent, repurposed medicines into NHS clinical practice, 2017.

S. J. Weir, L. J. Degennaro, and C. P. Austin, Repurposing Approved and Abandoned Drugs for the Treatment and Prevention of Cancer through Public-Private Partnership, Cancer Res, vol.72, pp.1055-1058, 2012.

T. I. Oprea and J. Mestres, Drug Repurposing: Far Beyond New Targets for Old Drugs

, AAPS J, vol.14, pp.759-763, 2012.

V. T. Devita, Off-label use of approved drugs, Nat. Rev. Clin. Oncol, vol.6, pp.181-181, 2009.

M. Weda, Study on off-label use of medicinal products in the European Union, 2017.

C. Vannieuwenhuysen, Towards a better managed off-label use of drugs -KCE Reports 252. KCE Rep. 252 Belg, Health Care Knowl. Cent. KCE, 2015.

A. Persidis, Drug Repositioning and Off-Label Use-Finding the Balance and Understanding the Differences: Interview with David Cavalla, MA, PhD, Founder, Numedicus. Drug Repurposing Rescue Repositioning, vol.1, pp.5-7, 2015.

A. P. Abernethy, Systematic Review: Reliability of Compendia Methods for Off-Label Oncology Indications, Ann. Intern. Med, vol.150, p.336, 2009.

A. K. Green, W. A. Wood, and E. M. Basch, Time to Reassess the Cancer Compendia for Off-label Drug Coverage in Oncology, JAMA, vol.316, p.1541, 2016.

C. Lenk and G. Duttge, Ethical and legal framework and regulation for off-label use: European perspective, Ther. Clin. Risk Manag, vol.537, 2014.

T. Eguale, Association of Off-label Drug Use and Adverse Drug Events in an Adult Population, JAMA Intern. Med, vol.176, p.55, 2016.

C. Verbaanderd, L. Meheus, I. Huys, and P. Pantziarka, Repurposing Drugs in Oncology: Next Steps, Trends Cancer, vol.3, pp.543-546, 2017.

F. Pammolli, L. Magazzini, and M. Riccaboni, The productivity crisis in pharmaceutical R&D, Nat. Rev. Drug Discov, vol.10, pp.428-438, 2011.

M. J. Waring, An analysis of the attrition of drug candidates from four major pharmaceutical companies, Nat. Rev. Drug Discov, vol.14, pp.475-486, 2015.

N. Nosengo, Can you teach old drugs new tricks?, Nature, vol.534, pp.314-316, 2016.

. Ycharts, Pfizer's Expiring Viagra Patent Adversely Affects Other Drugmakers Too

L. Urquhart, Market watch: Top drugs and companies by sales in 2017, Nat. Rev. Drug Discov, vol.17, p.232, 2018.

, Repurposed drugs: second time lucky, vol.388

M. Allison, NCATS launches drug repurposing program, Nat. Biotechnol, vol.30, pp.571-572, 2012.

D. E. Frail, Pioneering government-sponsored drug repositioning collaborations: progress and learning, Nat. Rev. Drug Discov, vol.14, pp.833-841, 2015.

J. K. Prague, Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial, Lancet Lond. Engl, vol.389, pp.1809-1820, 2017.

D. H. Drewry, T. M. Willson, and W. J. Zuercher, Seeding collaborations to advance kinase science with the GSK Published Kinase Inhibitor Set (PKIS), Curr. Top. Med. Chem, vol.14, pp.340-342, 2014.

S. Knapp, A public-private partnership to unlock the untargeted kinome, Nat. Chem. Biol, vol.9, pp.3-6, 2013.

A. N. Billin, Discovery of Novel Small Molecules that Activate Satellite Cell Proliferation and Enhance Repair of Damaged Muscle, ACS Chem. Biol, vol.11, pp.518-529, 2016.

J. M. Elkins, Comprehensive characterization of the Published Kinase Inhibitor Set, Nat. Biotechnol, vol.34, pp.95-103, 2016.