Drug repurposing involves finding new uses for older medications that are currently on the market and approved for other indications. However, in some cases, drug repurposing can also refer to taking a new look at drugs that may have failed clinical trials for other indications and may now be given a new life to treat a different condition.
Drug repurposing can lead to quicker access to medications as the time to FDA approval is significantly shortened, use of medications with well-defined pharmacokinetic and adverse event profiles, and lower costs since the expense of bringing a repurposed drug to market is substantially reduced compared with a new drug molecular entity.
There are several strategies for drug repurposing, including activity-based drug repurposing in which a drug candidate is found to be structurally similar and share biological properties and indications with other drugs for breast cancer (BC), and in silico drug repurposing or network-based drug repurposing in which an association has been identified in the disease-gene-drug paradigm.
A recent review article examined clinically approved drugs that were originally used to treat conditions other than BC that are now being used in this type of malignancy. The classes of medications discussed are alkylating agents, anthracyclines, antimetabolites, CDK4/6 inhibitors, hormone therapy or endocrine therapy, mechanistic target of rapamycin (mTOR) kinase inhibitors, and mitotic inhibitors.
A deeper dive into several of the above-mentioned drug classes finds that among the alkylating agents, cyclophosphamide is typically used with docetaxel, paclitaxel, or doxorubicin. However, in repurposed chemotherapy regimens, the alkylating agent is now paired with methotrexate and fluorouracil for six cycles or with doxorubicin for four cycles. Thiotepa, another alkylating agent, is being studied for use with vinblastine, doxorubicin, and fluoxymesterone.
Doxorubicin is an example of a repurposed anthracycline that took 20 years after its original discovery and indication to be tried in BC. Now, it is a mainstay of numerous BC regimens, including AC (e.g., doxorubicin, cyclophosphamide), TAC (e.g., taxotere, doxorubicin, cyclophosphamide), and FAC (5-fluorouracil, doxorubicin, and cyclophosphamide).
Antimetabolites that have been repurposed in BC include 5-fluorouracil, methotrexate, capecitabine, and gemcitabine. 5-fluorouracil was initially approved in 1962 for the treatment of a type of squamous cell skin cancer called keratoacanthomas. 5-fluorouracil was first used along with methotrexate in the management of BC in 1985. Since then, the antimetabolite has been used in combination with doxorubicin, cisplatin, cyclophosphamide, and epirubicin. It is also used in high-dose regimens along with paclitaxel and doxorubicin.
Although methotrexate was discovered in the 1940s, it was not until the 1960s that it was used as monotherapy in BC. As mentioned previously, it is used in the repurposed regimen of cyclophosphamide, methotrexate, and 5-fluorouracil in BC. Capecitabin, a pro-drug of 5-fluorouracil that was approved in 1998 for colon cancer, is used to treat paclitaxel- or docetaxel-resistant advanced and metastatic BC. It is used either as monotherapy or in combination with cabazitaxel, vinorelbine, or ixabepilone.
Gemcitabine, a prodrug that acts as an analogue of cytidine, was approved as an antiviral agent in 1980. It has been studied in HIV, hepatitis C, influenza, and even MERS-CoV. It was initially approved for pancreatic and non-small cell lung cancer in the 1990s, but it was not until 2004 that it received the nod as first-time treatment for metastatic disease BC in combination with paclitaxel. Gemcitabine is also used in BC in combination with vinorelbine, cisplatin, and capecitabine.
mTOR kinase inhibitors have antiprofilerative and antiangiogenic properties. The mTOR kinase inhibitor everolimus was first approved for renal cancer in 2009, and in the following year as an immunosuppressant in renal transplants. In 2011, everolimus was approved for pancreatic cancer. The next year, it was approved for advanced metastatic BC in women who failed letrozole or anastrozole treatment.
Mitotic inhibitors include docetaxel, paclitaxel, and vinblastine. Paclitaxel, which was discovered in 1971, comes from the pacific yew and was originally used to manage arterial restenosis. It was approved in the 1990s for the treatment of ovarian cancer. Docetaxel was initially indicated for prostate cancer. It was not until later that docetaxel and paclitaxel regimens were repositioned for use as neoadjuvant or adjuvant monotherapy or in combination with other chemotherapeutic agents for the treatment of early, advanced, and metastatic BC in both pre- and postmenopausal women.
Vinblastine, another mitotic inhibitor, was being investigated a hypoglycemic agent in the 1950s when its effects on the hematological profile were observed. In 1965, it was approved for lymphoma. It was not until the 1980s that vinblastine was approved in combination with mitomycin with/out cisplatin for advanced and metastatic BC.
While this paper reviewed chemotherapeutic drugs that were repurposed for use in BC, there are nonantineoplastic agents that are also being studied for this indication. Among these are metformin, mebendazole, cimetidine, nitroglycerin, itraconazole, and diclofenac, to name a few.
Pharmacists should be cognizant of the use of repurposed drugs as these medications may be administered off-label before they acquire official FDA-approval status. Doses and treatment courses may vary from their original indication and may not be recognized by computerized provider order-entry systems.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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