Literature Review of Repurposing Antihelmintic Agents in Oncology

Objective in question: The evaluate the literature of related to repurposing antihelmintic agents in the field of oncology.

Background: When treatment options for cancer are broken down there are 3 modalities that offer different approaches to treatment. Typically, it is managed via Irradiation, surgical excision, and lastly chemotherapy. The ladder is the branch in which a significant amount of research and development are heavily invested in. Generally greatest limiting factor in chemotherapy is the ability of refractory tumor cells to develop mechanisms to continue to proliferate, promote their own survival, and spread to other vital organs via metastatic dissemination1. Development of novel anti-neoplastic agents use these same aforementioned mechanisms as targets of interest when they are pushed down the scientific pipeline of drug development. Although there has been significant progress in the field of oncology since the 2000s, with improved survival rates and a decline in incidence, the cost has seen no decline2. Many expensive treatments have become standard of care which has not helped and does not seem to be slowing down any time soon. A systematic review from The Journal of the National Cancer Institute 2016 revealed that of the 300 patients in the study, 62% of patients reported being in debt as a result of treatment3. Similarly, another study including over 4,000 patients showed that over 50% of patients had reported a debt of over $10,000 as a result of treatment4. The conversation then begins to unravel as people desperate for solutions look to other methods and modalities of treatment. Many people begin to look online for solutions and then may easily go down the rabbit hole of “cures” and “treatments” that have not undergone any rigorous scientific testing and are only relying on firsthand accounts.  That being said it is not unheard of for a drug to be repurposed for a secondary repositioned indication. The purpose of this evidence evaluation to look at the available evidence to open up the conversation of antihelmintic medications role -if any- in the field of oncology.

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Antihelmintic agents are medications used for the management and treatment of Enterobius vermicularis (pinworm) and Trichuris trichiura (whipworm). They are the two most common parasitic nematode infections worldwidein humans5. Mebendazole (Emverm) was FDA approved in 2016 for the treatment of pinworms. Albendazole (Albenza) is another agent within the class that is used as second line treatment for whipworms as its efficacy is lower6.

Although Mebendazole was only FDA approved in 2016 for the previously mention indication it had been studied to have a potential avenue for other medical applications before its FDA approval. In 2002 a critical study was done to test for the first time the effect (if any) of mebendazole7. The researchers evaluated the effect of mebendazole in vitro and in vivo in human cancer lines. Specifically, this study was aimed at determining the effect of mebendazole on angiogenesis and solid tumor growth. The results of their in-vitro model revealed that mebendazole had a dose-dependent and time-dependent inhibition on the tumor cell growth. When tested on human lung cancer cell lines there was an inhibition of growth 5-folf compared to control cells. Of note this study also found that in vitro mebendazole inhibited growth in colon, breast and ovarian cancer cells with an IC50­­­ of roughly 0.16 (range) µm. This data prompted to researchers to evaluate the effect in a mouse model. Mice were inoculated with non-small cell lung cancer human cells from the cell line H460. Mice with tumors of > 3 mm were then given mebendazole 1 mg orally every other day which sufficed in marked inhibition of tumor growth in a dose-dependent manner. Mebendazole’s effect on angiogenesis in-vivo showed a significant decrease in vascularity of the mebendazole arm when compared to the control arm. The significance of this study was profound as it was the first study looking at mebendazole as an antitumor agent, and resulted in encouraging findings. It is important to discuss the safety profile of any agent in the field of oncology, as this is a major downside to many treatment options. Mebendazole is metabolized extensively though hepatic metabolism to less toxic byproducts which is thought to be a major reason there is limited or minimal risk of toxicity associated with harm. Since Mebendazole is FDA approved in human, but for another indication extensive knowledge is already known about the safety profile and the maximum tolerated doses. A notable drawback is that since it is indicated for infection there is no long term safety data readily available on chronic therapy.

A study published in 2008 revealed valuable pre-clinical evidence of Mebendazole in adrenocortical cancer8. Using human adrenocortical cancer cell line H295R in 6 week old mice they were able to test the effect of mebendazole on cancer cell line growth in-vitro. Mebendazole has strongly inhibited the growth of these H295R cancer cells at a concentration of 1 µm or greater, while having no effect on the normal fibroblasts. They also tested mebendazole in-vivo by having mice treated with Mebendazole 1 mg and 2 mg orally daily as well as a control equivalent. The anti-tumor activity of mebendazole was found to have significantly inhibit the growth of the established tumors at a dose of 1 mg orally daily; the 2 mg oral daily dose did not seem to provide very distinguishable differences the rate of tumor growth inhibition. The growth metastases inhibition was inhibited by up to 50% to 75% percent compared to the controls with the 1 mg and 2 mg doses, respectively. It is worth noting that in many of the studies the doses that are orally given to the mice are typically 1 mg to 2 mg daily, with many the mice weighing roughly 20 grams, this would equate to a human receiving 500 mg if they weighed 70 kg. Mebendazole is used at a dose of up to 500 mg for its use in roundworm parasitic infections in humans, so the rationale for the dose in mice is appropriate. Since the estimated human equivalent doses that are being tested in mice are showing this level of antitumor and metastatic inhibitory effect it begins to further confirm the broad spectrum of activity this antihelmintic has when used in more debilitating disease states. Metastasis is the main cause of death related to cancer, so taking into consideration that mebendazole inhibited metastasis formation of SW-13 human cancer cell lines in vitro and in vivo there lies more to uncover when looking at mebendazole for metastatic spread prevention and treatment.

In 2013 a study was conducted to evaluate the in-vitro effect in chemoresistant breast cancer cell lines (SKBr-3)9,13. The purpose of this study was to look at the effect of the chemotherapy agent gemcitabine combined with a benzimidazole (albendazole, flubendazole, and mebendazole) compared to gemcitabine alone in regards to anti-neoplastic activity. The study found that mebendazole was the most cytotoxic of the antihelmintic agents by producing cytotoxic activity by reducing cell survival by up to 63.1% with a concentration dose of 0.5 µm.

It is important to be aware that no clinical trials in humans have been completed to date evaluating mebendazole’s role in cancer, however there are a few ongoing phase 1 trials that are estimated to be completed in 2020 10. Although the human data is lacking case reports do add value when looking at the total clinical picture potential of mebendazole.

 In 2011 there was a case report of an individual who had adrenocortical cancer who had tried and failed multiple systemic therapies.11 The patient was seeing continued disease progression on 5-FU, bevacizumab, streptozotocin, and irradiation therapy. The patient subsequently tried the human approved dose of mebendazole 100 mg PO twice daily and did not have disease progression for 19 months, and did see some regression in the metastases. Unfortunately, the patient began to see progression return after 2 years of starting on the monotherapy of mebendazole.

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A second case report published in 2013 regarding mebendazole’s role in metastatic colon cancer12. The patient had metastatic spread to multiple sites including the liver and lungs. Similar to the previous case report in 2011, the patient received mebendazole 100 mg orally twice daily which is the antihelmintic treatment approved dose. Following 6 weeks of mebendazole treatment, a CT scan revealed that the colon cancer had resulted in almost complete remission in the metastatic lesions in the lungs and partial remission of metastatic lesions in their liver.

While the evidence is promising in many aspects for mebendazole’s use in different forms of cancer, there are also some drawbacks that must be considered when placing this drug as a candidate for repurposing. Because of the lack of data in human clinical trials is it difficult to begin to determine where mebendazole would be introduced in the timeline of managing cancer. In the two case reports previously mentioned, mebendazole was initiated later in the disease course once progression was seen on other agents. It is reasonable to question the effect that mebendazole would have earlier on in the disease course. Another question to keep in mind is he dosing regimen, as there is not long term data with particular doses that would be needed if mebendazole were to be repositioned for use in maintenance. One major barrier not related to the drug mechanism is cost. Mebendazole is already an FDA approved drug in humans and its low cost does not make it an attractive drug for pharmaceutical companies to go after as it does not present with valuable return on investment. The low cost gives companies and the industry little incentive to go after mebendazole as a commercial product. So mebendazole is then placed in limbo for large scale randomized controlled clinical testing. Academic research or federal funding could provide mebendazole with a breakthrough it would need to reposition this drug in the field of oncology.

The current data available does place mebendazole as a favorable candidate for repositioning the drug in oncology as its low cost, ideal safety profile in vivo, in vitro, and humans via case reports. As the results of the current ongoing studies are completed a clearer picture and potential trajectory of its use in human will become more evident. Given the fact that it has shown benefit in patient with cancer refractory to first line treatment, mebendazole should not be tossed to the wind in regards to providing a new inclusion in therapy as a means to provide a better quality of life for those suffering from terminal illnesses with poor prognosis. Using the data reviewed mebendazole seems to be a strong candidate for repurposing, and a new introduction outside its’ indication in the clinical setting of oncology treatment.

References:

1. Shord SS, Cordes LM. Cancer Treatment and Chemotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146074145. Accessed October 29, 2019.
2. Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103(2):117–128.
3. Cheryl K. A, Matthew P. B, Reginald D. T-S, et al.  Financial Hardships Experienced by Cancer Survivors: A Systematic Review. Journal of the National Cancer Institute. 2017;(2):1.
4. Banegas MP, Guy GP Jr, de Moor JS, et al. For Working-Age Cancer Survivors, Medical Debt And Bankruptcy Create Financial Hardships. Health Affairs (Project Hope). 2016;35(1):54-61. doi:10.1377/hlthaff.2015.0830.
5. Jourdan PM, Lamberton PH, Fenwick A, Addiss DG. Soil‐transmitted helminth infections. Lancet 2018;391(10117):252–65.
6. Steinmann P, Utzinger J, Du Z-W, et al. Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: a randomized controlled trial. Plos One. 2011;6(9):e25003.
7. Mukhopadhyay T, Sasaki J, Ramesh R, et al.  Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2002; 8(9) 2963–9.
8. Martarelli D, Pompei P, Baldi C, Mazzoni G. Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice. Cancer Chemother Pharmacol. 2008;61(5):809-817.
9. C. P. Coyne, T. Jones, 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 (Spec. Iss. Cancer Prev. Ther.) 2013; 2(1).
10. ClinicalTrials.gov Identifier: NCT02644291, NCT03628079, NCT01837862
11. Irina Y. D, Gary D. H, David E. S, et al. Mebendazole Monotherapy and Long-Term Disease Control in Metastatic Adrenocortical Carcinoma. Endocr Pract.  2011;(3):e59.
12. Nygren P, Larsson R. Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncologica (Stockholm, Sweden). 2014;53(3):427-428.
13. Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. Repurposing Drugs in Oncology (ReDO)--mebendazole as an anti-cancer agent. Ecancermedicalscience. 2014;8(413-446):1-16.

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