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Chen AM , Farwell DG , Luu Q , Donald PJ , Perks J , Purdy J . [20] Evaluation of the planning target volume in the treatment of head and neck cancer with intensity-modulated radiotherapy: What is the appropriate expansion margin in the setting of daily image guidance? Int J Radiat Oncol Biol Phys 2011 ; 81 : 943 – 9 . Van Herk M , Remeijer P , Rasch C , Lebesque JV . The [21] probability of correct target dosage: Dose-population histograms for deriving treatment margins in radiotherapy . Int J Radiat Oncol Biol Phys 2000 ; 47 : 1121 – 35 . Giske K , Stoiber EM , Schwarz M , Stoll A , Muenter MW [22] Timke C, et al . Local setup errors in image-guided radiotherapy for head and neck cancer patients immobilized with a custom-made device . Int J Radiat Oncol Biol Phys 2011 ; 80 :582 – 9.

normal tissue sparing with IMRT for head-and-neck cancer . Int J Radiat Biol Phys 2001 ; 51 : 1400 – 9 . Van Asselen B , Dehnad H , Raaijmakers CPJ , Roesik JM , [17] Lagendijk JJW , Terhaard CHJ . The dose to the parotid glands with IMRT for oropharyngeal tumors: The effect of reduction of positioning margins . Radiother Oncol 2002 ; 64 : 197 – 204 . Den RB , Doemer A , Kubicek G , Bednarz G , Galvin JM , [18] Keane WM , et al . Daily image guidance with cone-beam computed tomography for head-and-neck cancer intensity-modulated radiotherapy: A prospective study . Int J Radiat Oncol Biol Phys 2010 ; 76 : 1353 – 9 . Hong TS , Tome WA , Chappell RJ , Chinnaiyan P , Mehta MP , [19] Harari P . The impact of daily setup variations on head-and-neck intensity-modulated radiation therapy . Int J Radiat Oncol Biol Phys 2005 ; 61 : 779 – 88 .

Supplementary material available online

Supplementary Figures 1–2 Supplementary Tables I–II

for further treatment at Department of Oncology, Uppsala University Hospital. He had been healthy until emergency surgery after presentation with ileus in 2011. An advanced sigmoid colon cancer was radically resected. Histopathological examination showed a moderately differentiated adenocarcinoma with KRAS mutation. Synchronous multiple bilat-eral lung and paraaortic lymph node metastases were observed and the patient started palliative che-motherapy with a combination of capecitabine, oxaliplatin and bevacizumab. A partial remission was observed at CT evaluations after two and four months of treatment. Following a period of main tenance treatment with capecitabine alone, pro gressive disease was observed in August 2012. Capecitabine, oxaliplatin and bevacizumab was restarted and resulted in stable disease at the fi rst evaluation. However, this treatment was stopped due to intolerable oxaliplatin-induced neuropathy. Sec-ond line treatment with capecitabine and irinotecan was started in December 2012. At fi rst evaluation March 2013, signifi cant progression was observed in

Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer

PETER NYGREN 1 & ROLF LARSSON 2

1 Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala, Sweden and 2 Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, Uppsala, Sweden

To the Editor,

Despite recent progress in the knowledge in cancer biology and considerable expenditure and efforts in the development of new ‘ targeted ’ cancer drugs, prog-ress has been limited in the major cancer types; the newly introduced drugs mostly provide very modest benefi t at high costs, both in terms of healthcare expenditure and patient adverse effects [1]. Drug repo-sitioning, i.e. the fi nding of new indications for drugs in development or use in other diseases is an attractive approach to more effi cient drug development by making use of the preclinical and clinical knowledge already available, allowing for considerable shortcuts in many steps in the drug development process [2].

In an ongoing drug screening project in our labora-tory aiming at repositioning drugs for use in advanced colorectal cancer, we observed high activity in colon cancer models in vitro for several members of the bendazole group of compounds, including the approved antihelmintic drug mebendazole (tradename Vermox).

Shortly following this observation, a 74-year-old man with metastatic colon cancer was considered

Correspondence: P. Nygren, Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, 751 85 Uppsala, Sweden. E-mail: peter.nygren@medsci.uu.se

(Received 7 September 2013 ; accepted 9 September 2013 )

ISSN 0284-186X print/ISSN 1651-226X online © 2014 Informa HealthcareDOI: 10.3109/0284186X.2013.844359

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428 P. Nygren & R. Larsson

the lungs and abdominal lymph nodes and there were new partly poorly defi ned liver metastases up to 8 cm in diameter (Figure 1). Despite the progress the patient was still in excellent performance status and had essentially no disease-related symptoms, except for the therapy-induced neuropathy.

In this situation with no standard therapy left, the drug screen observation in mind, the recent preclin-ical fi nding of antitumour effects of mebendazole in a mice model [3] and a case report indicating anti-tumour effect from mebendazole in a patient with metastatic adrenocortical carcinoma [4], the patient, after informed consent, started mebendazole at the standard antihelmintic dose of 100 mg twice daily, to be continued for six weeks. The patient experi-enced no adverse effects from the treatment and at CT evaluation May 2013 there was near complete remission of the metastases in the lungs and lymph nodes and a good partial remission in the liver (Figure 1). At this stage, the liver enzymes AST and ALT were found elevated up to fi ve and seven times above upper limit of normal and mebendazole was temporarily stopped and then reintroduced at half dose. Liver enzymes slowly decreased and the patient still reported no adverse effects from mebendazole. The disease was stable at a new CT, confi rming the response observed earlier. The patient is now on drug holiday, pending a new CT.

We conclude that mebendazole is seemingly a promising ‘ new ’ drug for treatment of advanced colorectal cancer. A number of pharmacodynamic, clinical trial, drug formulation and dosing issues need to be addressed before mebendazole might become an established drug in this indication. However, the case, together with its preclinical background, illus-trates the potential of drug repositioning to improve the development of new and better cancer therapy.

Declaration of interest: The authors report no confl icts of interest. The authors alone are respon-sible for the content and writing of the paper.

References

Stewart DJ , Kurzrock R . Cancer: The road to Amiens . J Clin [1] Oncol 2009 ; 27 : 328 – 33 . Ashburn TT , Thor KB . Drug repositioning: Identifying and [2] developing new uses for existing drugs . Nature Rev Drug Disc 2004 ; 3 : 673 – 83 . Mukhopadhyay T , Sasaki J , Ramesh R , Roth JA . [3] Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo . Clin Cancer Res 2002 ; 8 : 2963 – 9 . Dobrosotskaya IY , Hammer GD , Schteingart DE , [4] Maturen KE , Worden FP . Mebendazole montherapy and long-term disease control in metastatic adrenocortical carcinoma . Endocrine Practice 2011 ; 17 : e59 – 62 .

Figure 1. Axial computerized tomography at baseline showing multiple liver (A) and lung (C) metastases (arrows) and good regression at fi rst evaluation (B and D), following 6 weeks of treatment with mebendazole.

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