Drug Repurposing and Off-Label use in Cancer
Drug Repurposing & Off-Label Drug Use in Cancer Care
Drug Repurposing, or drug repositioning, is the study and practice of using existing non-cancer drugs in the treatment of cancer. Both prescription and over-the-counter (OTC) agents have been studied for their anti-cancer potential including aspirin, metformin, curcumin, prochlorperazine, and mebendazole. Since these agents are known and used in other conditions, we have a better understanding of their side effects and how they work in the body as compared to newly developed drugs, which can give researchers a bit of a head start when testing for potential new indications in cancer. Ideally, drug repurposing allows for a less expensive, faster-paced process for drug approval (as compared to traditional R&D and clinical trials for novel agents) by using drugs that already have established safety profiles.
According to a 2016 news feature in Nature, "Getting a drug to market currently takes 13–15 years and between US$2 billion and $3 billion on average... Some estimates suggest that repositioning a drug costs on average $300 million and takes around 6.5 years."
Drug repurposing may ring a bell if you think of Viagra. While the drug (sildenafil) was going through clinical trials for use in cardiology, it was discovered that the drug caused erections and boom, in 1998, Viagra was born for the treatment of erectile dysfunction. More relevantly, thalidomide was developed in the 1950s for use as a sedative, and was later introduced as a treatment for multiple myeloma due to its anti-angiogenic effects.
Off-Label Drug Use
When a drug is approved by the FDA, it is approved for a specific indication, which indicates how, what, and for whom the drug is intended to be used. All prescription drugs must come with a Package Insert (PI), also called the product's label. The label includes information about who the drug is for, what disease it is intended to treat, safety, dosage, etc.. You can easily determine a drug's approved indication by checking the PI. The use of a drug for any purpose beyond it's approved indication is called off-label use.
"Upwards of 30% of all prescriptions written in the US are written off-label, meaning for a purpose other than an FDA-approved indication, dosage, patient group, or route of administration, " according to a 2023 journal article in JACC: Basic to Translational Science.
In the section above on drug repurposing, metformin was mentioned so let's use that for an example. Metformin is a drug indicated for the treatment of type 2 diabetes. In terms of cancer drug repurposing, metformin has been and continues to be studied for its anti-cancer potential, but it is not FDA approved for cancer treatment. If a doctor in the US prescribed metformin for a cancer patient who does not have type 2 diabetes, that would be considered off-label usage because there is not an FDA approved cancer indication for this drug. In this scenario, metformin is both undergoing research for repurposing in cancer AND may be prescribed off-label for use in cancer. Once, or if, metformin receives a cancer-related indication, its use for that cancer type would no longer be experimental or considered off-label. It's legal for doctors to write off-label prescriptions so long as they adhere to responsible medicine practices and document the off-label usage.
"Although the FDA regulates the marketing and safety of drugs and devices, it does not regulate the practice of medicine, and physicians are legally free to use them for purposes other than that for which they were approved, so long as the use is based in “firm scientific rationale and on sound medical evidence” and as long as they “maintain records of the product’s uses and effects.”" (2023 JACC journal article)
The next section discusses specific agents that have been studied for potential repurposing in cancer.
REDUCE (costs & drug approval pace), REUSE (existing drugs), REPURPOSE (for cancer treatment)
Current & Recent Research on Drug Repurposing in Cancer
A 2023 review article in the British Journal of Cancer touches on studies, reviews, and explorations on the following:
- The use of cimetidine, an anti-peptic ulcer drug, as a potential treatment for lung adenocarcinoma
- The use of imipramine, an anti-psychotic, and its ability to improve sensitivity to standard of care treatment in glioblastoma
- The use of aspirin to target TP53 genes to reduce metastatic potential
- The use of curcumin to target MMP9 (matric metalloproteinase-9) to reduce metastatic potential
- The use of metformin, a well-known diabetes medication, to reduce cancer incidence
- The use of curcumin in the prevention of cancer progression in low-risk prostate cancer
- The use of metformin in the prevention of recurrence of endometrial cancer
- The use of nelfinavir, an HIV antiviral, to enhance efficacy of chemoradiotherapy in the treatment of cervical carcinoma
- Niclosamide, metformin, chloroquine and thioridazine have been identified as potential cancer stem cell inhibitors
- Metformin has been shown to both eradicate and radiosensitize cancer cells
- NSAIDs, in particular, COX-2 inhibitors have shown promising anti-cancer activity in previous lab and clinical studies
A 2023 systematic review in Cancers by Ioakeim-Skoufa, A. et al. discusses 7 randomized controlled clinical trials researching the following repurposed drugs:
- Metformin for advanced or metastatic non-squamous non-small cell lung cancer
- Metformin for locally advanced and metastatic hormone-resistant prostate cancer
- Metformin for metastatic or unresectable locally advanced pancreatic adenocarcinoma
- Mebendazole for colorectal cancer
- Low-weight heparin for esophageal squamous cell carcinoma
- Propranolol in autologous hematopoietic stem cell transplantation for multiple myeloma
- Propranolol and etodolac for breast cancer stages 1-3
A 2023 review in Cancers by Hijazi, A. et al. discusses the repurposing of anti-diabetic and anti-hypertensive drugs in cancer care, specifically:
- 6 different anti-diabetic agents have been studied in 52 cancer clinical trials (as of March 2023) including metformin (37 trials), pioglitazone (10 trials), desmopressin (2 trials), and 1 trial each for dapaglifozin, epalrestat, and acarbose.
- 8 different anti-hypertensive drugs had been studied in 40 cancer clinical trials (as of March 2023) including propranolol (18 trials), hydralazine (7 trials), losartan (7 trials), captopril (3 trials), candesartan (2 trials), and 1 trial each for bosentan, minoxidil, and carvedilol.
A 2024 review article in Frontiers in Pharmacology by Fatemi, N. et al. discusses the application of repurposed drugs in gastrointestinal cancers, highlighting some of the following :
- use the use of mebendazole in blocking angiogenesis
- the use of levosimendan, a heart failure drug, in inhibiting several kinases
- the use of spiperone, a schizophrenia drug, in triggering apoptosis in colorectal cancer (CRC) cells
- the use of ebselen as an anti-CRC agent by influencing autophagy and tumor suppression
- oxiconazole, an antifungal, in inducing anti-tumor effects in CRC
- mebendazole, an anti-parasitic, exhibiting a cytotoxic (cell killing) effect in CRC cell lines, reducing metastasis, and the inhibition of Abl and BRAF proteins
- ticonazole, for vaginal yeast infections, in enhancing chemotherapy efficacy in CRC tumor zenografts (in animal studies)
- the use of aspirin with oseltamivir phosphate (OP) to enhance pancreatic cancer cell sensitivity to gemcitabine and hinder the development of chemoresistance
- the anti-tumor and growth suppression effects of ivermectin in gastric cancer
- the use of aspirin to prevent colorectal cancer and pancreatic cancer
Prochlorperazine
A February 2024 publication in the journal of Nanomedicine: Nanotechnology, Biology and Medicine describes research that's being conducted on the use of prochlorperazine (PCZ), a well-known anti-emetic/anti-psychotic medication, in combination with monoclonal antibodies (moAb) like EGFR inhibitors to enhance efficacy. The response rates for moAb treatments are quite low, hovering around 15% and increasing up to 40% when used with other antineoplastic drugs. If this PCZ-moAb combination proves successful it could open the door for a larger population of patients to experience a clinically significant response from monoclonal antibody therapy. A Phase I clinical trial is taking place in Australia, studying the use of prochlorperazine on patients with previously untreated HER2-positive metastatic breast cancer. A 2020 article in Cell describes similar research.
Prochlorperazine (PCZ) has been studied for reducing resistance to radiation therapy in NSCLC (non-small cell lung cancer) populations with KRAS mutations. You can read the 2021 study from the journal of Free Radical Biology and Medicine here.
Prochlorperazine has been studied for its potential to reduce migration and invasion (metastasis) of multiforme glioblastoma cancer cells. You can read the 2022 study in Oncology Letters here.
The Repurposing Drugs in Oncology (ReDO) Database
The Anticancer Fund ReDO_DB is a curated listing of non-cancer drugs which have shown some evidence of anticancer activity. Data comes from peer-reviewed studies, medical case reports, observational studies and clinical trials.
Important note for patients! This list identifies drugs that, based on their scientific properties, warrant further scientific investigation. In most cases the existing scientific evidence for their effects on cancer is very limited. Further scientific and clinical research is needed before any statements regarding their anti-cancer activity can be made. This list is not intended to be used as a source for possible treatment options for patients.
If you'd like to explore the database, you can access it here.
**Note: some of these agents have only been studied in laboratory and/or animal model settings and the findings have not yet been tested in human subjects or applied in clinical studies or settings
