Old Drugs, New Battles: How Existing Medications Are Being Repurposed to Fight Triple-Negative Breast Cancer

Table of Contents

• Key Points
• What Is Triple-Negative Breast Cancer?
• Why Drug Repurposing Matters
• How Researchers Find New Uses for Old Drugs
• The Five Faces of TNBC: Why One Treatment Does Not Fit All
• Diabetes Drugs: Metformin as a Cancer Fighter
• Antifungal Drugs: Surprising Anti-Tumor Weapons
• Antiparasitic Drugs: From Worms to Tumors
• Clinical Trials at a Glance
• What This Means for Patients Today
• Limitations: What This Research Could Not Prove
• Recommendations: Practical Takeaways for Patients
• Frequently Asked Questions
• Source Information

Key Points

• TNBC lacks estrogen, progesterone, and HER2 receptors, so hormone and HER2 therapies fail.
• Repurposing FDA-approved drugs can cut development time to 3–5 years and save about $300 million.
• Metformin, itraconazole, ivermectin, propranolol, and other existing drugs show promise against TNBC in early studies.
• TNBC has multiple molecular subtypes; each responds differently to treatments, so tumor profiling matters.
• No repurposed drug is yet FDA-approved for TNBC; standard care remains essential.

What Is Triple-Negative Breast Cancer?

Triple-negative breast cancer (TNBC) accounts for roughly 15% to 20% of all breast cancer cases. It gets its name from what is missing on the cancer cells: they test negative for estrogen receptors (ER), progesterone receptors (PR), and the human epidermal growth factor 2 (HER2) receptor. Because these three "targets" are absent, hormone therapies and HER2-targeted drugs simply do not work.

TNBC is the most aggressive form of breast cancer. It affects younger women and Black women at disproportionately higher rates. The statistics are sobering: approximately 40% of patients with advanced-stage disease die within five years, and the recurrence rate is around 25%, especially in patients with residual microscopic disease after neoadjuvant chemotherapy (treatment given before surgery to shrink tumors).

TNBC frequently spreads to the brain, lungs, and liver. For patients with distant metastases (cancer that has spread beyond the breast), the median survival time is just 13.3 months. Many cases of TNBC are linked to inherited BRCA1 gene mutations, making it a common form of hereditary breast cancer. Researchers have found that TNBC shares a 56% overlap in gene expression patterns with "basal-like" breast tumors.

This aggressive cancer arises from several molecular subtypes, each with distinct characteristics. That heterogeneity helps explain why patients respond so differently to treatment. The biology matters enormously, as you will see in the following section on TNBC subtypes.

Why Drug Repurposing Matters

Cancer remains one of the leading global health challenges. In 2020 alone, there were approximately 19.3 million new cancer cases and 10 million deaths worldwide. Current treatments — including chemotherapy, radiation, and surgery — are limited by severe side effects, drug resistance, and treatment failure in advanced stages. Resistance often develops in cancer stem cells, the small population of cells that drive tumor growth and recurrence.

Developing a brand-new cancer drug is painfully slow and astronomically expensive. The typical timeline spans more than a decade, costs billions of dollars, and carries a success rate of less than 1%. High drug prices and limited accessibility, especially in low- and middle-income countries, make the problem worse. To make matters more challenging, cancer drug spending in Europe has more than tripled between 1995 and 2018, and the global cancer drug market is projected to reach $377 billion by 2027.

Drug repurposing (also called drug repositioning or reprofiling) is a strategy that finds new therapeutic uses for existing FDA-approved drugs beyond their original purpose. Instead of starting from scratch, researchers use medications whose safety profiles are already established in humans. This lets them bypass the earliest, riskiest phases of testing and move drugs directly into Phase II and III clinical trials.

The advantages are substantial:

• Development timeline shrinks dramatically: 3 to 5 years instead of 10 to 17 years for traditional de novo (from-scratch) drug development
• Development costs drop by approximately $300 million
• Safety data in humans already exists, reducing the risk of unexpected toxicities

This concept has deep historical roots. Early chemotherapy itself came from mustard gas research. Today, arsenic trioxide, originally approved for external skin conditions, is an FDA-approved treatment for acute promyelocytic leukemia (APL) when combined with tretinoin. Thalidomide, once infamous for its use against morning sickness, was repurposed to treat refractory multiple myeloma (a blood cancer that does not respond to initial treatment). It is estimated that a remarkable 90% of approved non-cancer drugs — including antidepressants, anticonvulsants, and statins — could have beneficial effects when repurposed, alone or in combination, for cancer therapy.

How Researchers Find New Uses for Old Drugs

Drug repurposing is not a random guessing game. It follows a systematic pathway involving preclinical studies (computer-based in silico modeling, laboratory in vitro testing, and animal in vivo studies), clinical observations, and epidemiological data analysis. Understanding how a drug attacks cancer on a molecular level helps researchers identify promising candidates.

Computational methods are transforming the field. Traditional structure-based techniques such as molecular docking and molecular dynamics — computer simulations that predict how drugs physically bind to their targets — can identify compounds capable of reversing disease-associated gene expression patterns. Modern approaches now integrate genomics, big-data analytics, and artificial intelligence to accelerate hypothesis generation.

A key insight is the concept of "off-target" effects. A drug designed to treat, say, a heart condition might accidentally hit a growth-signaling pathway that cancer cells rely on. These unexpected actions can enhance a drug's anti-tumor activity. Researchers combine multiple data sources, including DrugBank, STITCH, and TCGA (The Cancer Genome Atlas), to match drugs to disease-associated genes and biological pathways.

The benefits are real, but challenges remain. Some repurposed drugs work well as stand-alone treatments (monotherapies), yet drug resistance can emerge over time. Combination therapies — targeting multiple cancer-driving pathways at once — often work better but raise the risk of side effects from drug interactions. Continuous patient monitoring and extensive molecular studies are essential.

The Five Faces of TNBC: Why One Treatment Does Not Fit All

TNBC is not one disease, but a family of diseases. Molecular profiling has revealed four tumor-specific subtypes, each driven by distinct genetic programs. These differences have major implications for which treatments will work best.

The four recognized TNBC subtypes are:

• Basal-like 1 (BL-1): Characterized by abnormal activation of cell cycle and DNA repair genes, including MYC, PIK3CA, BRCA2, and TP53. This subtype responds best to PARP inhibitors and genotoxic agents (drugs that damage DNA).
• Basal-like 2 (BL-2): Shows dysregulated signaling in pathways such as EGFR, MET, NGF, Wnt/β-catenin, and IGF-1R. Potential treatment strategies include mTOR inhibitors and growth factor inhibitors.
• Mesenchymal-like (M): Marked by high cell motility (movement) and differentiation signaling regulated by Wnt, TGF-β, and ALK pathways. These dysregulated pathways contribute to chemotherapy resistance. mTOR inhibitors and EMT-targeting drugs may help here.
• Immunomodulatory (IM): Enriched in immune response pathways, including T-cell receptor signaling, B-cell signaling, and IL-12. This subtype is best treated with immune checkpoint inhibitors (ICIs) such as PD-1, PD-L1, and CTLA-4 inhibitors.
• Luminal androgen receptor (LAR): Despite being ER-negative, this subtype shows high androgen receptor (AR) expression and hormonal pathway activation. Anti-AR therapy (treatments that block male sex hormone receptors) is the most effective approach.

The exact impact of these subtypes on patient outcomes is still under investigation. Intensive research into molecular mechanisms, biomarker identification, and targeted therapies continues. That effort is crucial for personalizing TNBC care.

Diabetes Drugs: Metformin as a Cancer Fighter

Diabetes and cancer share common risk factors, including obesity and aging. These conditions promote insulin resistance, chronic inflammation, and an environment that is permissive to tumor growth. Partly for those reasons, researchers began asking whether diabetes drugs might fight cancer.

Metformin is the leading candidate. It is a first-line drug for type 2 diabetes, and researchers have identified multiple ways it suppresses TNBC:

• Blocks energy production: Metformin inhibits mitochondrial complex I, reducing ATP production (the energy currency of cells) and activating AMPK, which suppresses the mTOR pathway that drives TNBC cell proliferation.
• Attacks fat synthesis: It reduces lipid metabolism by targeting fatty acid synthase (FASN) and cholesterol biosynthesis, both essential for TNBC growth.
• Limits sugar supply: Metformin decreases expression of glucose transporters (GLUT1) in TNBC cells, restricting glucose uptake and cellular energy.
• Prevents metastasis: It impairs cancer stemness and inhibits epithelial-to-mesenchymal transition (EMT), the process by which cancer cells become mobile and invasive.

What the Evidence Shows

In TNBC xenograft models (human tumors grown in mice), metformin significantly decreased tumor size by altering metabolic pathways. Observational studies in patients with diabetes found that those taking metformin have a lower incidence of TNBC and improved survival rates.

However, the picture is not entirely bright. Clinical trials evaluating metformin in patients with non-diabetic TNBC have shown mixed results. That suggests a patient's metabolic status — whether diabetes is present — may influence how well the drug works. Metformin also strengthens standard treatments. In laboratory studies, it sensitizes TNBC cells to DNA-damaging chemotherapy agents such as doxorubicin and cisplatin. It also improves the effectiveness of immune checkpoint inhibitors by modulating the tumor microenvironment and reducing immunosuppressive signals. And by targeting cancer stem cells, metformin helps overcome drug resistance.

Safety and Challenges

Metformin has an excellent, well-established safety record. Unlike chemotherapy, it causes minimal systemic toxicity, and its side effects (such as mild gastrointestinal discomfort) are manageable. This makes it a candidate for long-term use. There is one serious concern: lactic acidosis, a dangerous buildup of lactic acid that can occur in patients with kidney impairment. Kidney function must be monitored carefully.

A major scientific hurdle is metformin's low bioavailability. Poor intestinal absorption and reliance on organic cation transporters (OCTs) to enter cells limit how much drug reaches tumor tissue. Researchers are now exploring nanoparticle-based formulations to improve delivery directly to the tumor.

Antifungal Drugs: Surprising Anti-Tumor Weapons

Antifungal medications — designed to kill fungal infections — have shown genuine promise in TNBC because they target key cancer pathways. The imidazole antifungals, including ketoconazole and clotrimazole, induce apoptosis (programmed cell death) and cell cycle arrest in TNBC cells. They also inhibit matrix metalloproteinase 9 (MMP9), an enzyme that helps cancer invade surrounding tissue, reducing TNBC's invasive and metastatic potential.

Itraconazole, another antifungal, works differently. It is a potent inhibitor of the Hedgehog signaling pathway, which is frequently dysregulated in TNBC and contributes to tumor growth and chemotherapy resistance. Itraconazole blocks a protein called SMO (smoothened), preventing the downstream movement of GLI1 and other GLI proteins. Those proteins normally switch on the gene program that promotes TNBC growth.

Preclinical Findings

Laboratory studies show antifungal drugs suppress TNBC proliferation and metastasis. Ketoconazole inhibits tGLI1, a key transcription factor involved in breast cancer brain metastasis. Itraconazole, used alone or with the drug rapamycin, induces G₀/G₁ cell cycle arrest in TNBC cells, significantly reducing their ability to multiply.

Combination approaches look especially promising. Itraconazole enhances chemotherapy by inhibiting drug efflux transporters — the cellular pumps that push chemotherapy out of cancer cells — thereby overcoming multidrug resistance. Ketoconazole sensitizes TNBC cells to radiation therapy by modulating DNA repair pathways. These findings point toward antifungals serving as valuable add-on treatments to standard TNBC care.

Challenges

Itraconazole has poor solubility and bioavailability, which limits its effectiveness throughout the body. Nanoparticle formulations and lipid-based carriers are being explored to enhance drug delivery and tumor targeting. Ketoconazole carries a risk of hepatotoxicity (liver damage), requiring careful monitoring in cancer patients. Large-scale clinical trials remain necessary to validate efficacy in TNBC patients.

Antiparasitic Drugs: From Worms to Tumors

Anthelmintic drugs (anti-worm medications) were originally developed to treat parasitic infections. Researchers now recognize them as promising cancer therapy candidates thanks to their diverse mechanisms of action. Because these drugs have been used in humans for decades, their pharmacokinetic properties (how the body absorbs, distributes, and clears them), pharmacodynamic actions, and toxicity profiles are extensively documented.

Two drugs stand out in this category and are already in clinical testing for TNBC:

• Ivermectin: Preclinical data show it can induce immunogenic cell death — a form of cell death that alerts the immune system to attack the tumor — and enhance T-cell infiltration. Phase II trials are now assessing ivermectin combined with PD-1/PD-L1 checkpoint inhibitors in metastatic TNBC.
• Mebendazole: Strong preclinical evidence from xenograft models demonstrates efficacy, including in brain metastasis models. Early-phase clinical studies in advanced cancers exist, but TNBC-specific clinical data remain limited.

These drugs are also being studied in combination with standard therapies. One promising approach combines antiparasitic agents with immune checkpoint inhibitors, based on the idea that the drug makes the "cold" tumor (one the immune system does not recognize) become "hot" and vulnerable to immune attack.

Clinical Trials at a Glance

Several drug classes are at different stages of clinical investigation for TNBC. The following table, based on data compiled in the review, summarizes the current landscape:

Metformin — Phase III

Registered large randomized trials are evaluating metformin's anti-tumor potential in breast cancer patients. Results are mixed, with varying effects on tumor growth and recurrence. Further combination approaches are under investigation.

Propranolol (a blood pressure drug) — Phase II

Completed window-of-opportunity studies (where patients receive the drug in the short interval between diagnosis and surgery) showed reduced proliferation markers in early breast cancer. This supports further combination trials in TNBC. An active Phase II study is testing propranolol with pembrolizumab and chemotherapy in metastatic PD-L1-positive TNBC, aiming to re-sensitize tumors to treatment.

Ivermectin — Phase II

Registered investigator-initiated trials are combining ivermectin with PD-1/PD-L1 agents in metastatic TNBC. The trials assess safety, dose, and efficacy signals based on the strong preclinical rationale.

Mebendazole — Early Phase/Pilot

Clinical trials in various advanced cancers are underway, with TNBC-specific results still limited despite strong preclinical evidence.

Itraconazole — Early Clinical Use

Small published clinical reports suggest benefits in heavily pre-treated metastatic breast cancer patients (including some TNBC cases). Larger randomized controlled trials (RCTs) are lacking, though the preclinical rationale via Hedgehog/PI3K inhibition is strong.

Statins (cholesterol-lowering drugs) — Observational

Multiple observational studies suggest statin use in TNBC patients improves survival or reduces recurrence. Randomized clinical trial evidence is limited.

NSAIDs (aspirin, indomethacin, naproxen) — Observational

Meta-analyses show long-term low-dose NSAID exposure reduces metastasis and recurrence signals. Randomized trials for TNBC prevention or as adjunct therapy are limited or ongoing.

What This Means for Patients Today

Repurposed drugs offer several practical advantages for TNBC patients. They are readily available, generally affordable, and their known safety profiles mean clinicians already understand their side effects. Metformin's established safety record makes it attractive for long-term maintenance therapy. Propranolol has been prescribed for decades for hypertension, meaning its risks in pregnancy, asthma, and diabetes are well documented.

Because these drugs target different pathways than traditional chemotherapy, they may help overcome resistance — one of the greatest obstacles in TNBC treatment. Combining a repurposed agent with chemotherapy could attack cancer from multiple angles, reducing the odds that tumor cells develop escape routes.

There is genuine excitement around the immune-modulating potential of repurposed drugs. Ivermectin's ability to trigger immunogenic cell death could turn "invisible" tumors into visible targets for the immune system. Used alongside checkpoint inhibitors, these drugs could make immunotherapy more effective for a broader range of patients.

Finally, repurposing is a matter of global health equity. The cost savings in development could translate into more accessible treatments worldwide, especially in low- and middle-income countries where TNBC outcomes remain poorest and expensive targeted therapies are often unavailable.

Limitations: What This Research Could Not Prove

This review is a synthesis of existing studies, not a new clinical trial. The authors identified several significant gaps in the evidence that patients should understand.

Most findings on metformin, antifungals, and statins come from preclinical models or observational studies. Observational data can show associations but cannot prove cause and effect. Patients receiving statins, for example, may have better outcomes for reasons unrelated to the drug itself — such as better overall health monitoring. Randomized controlled trials — the gold standard of medical evidence — are still limited for most of these agents.

Clinical trial results have been mixed, particularly for metformin, where metabolic status may influence drug efficacy. What works in a diabetic patient's metabolic environment may not work in a non-diabetic patient. The review also acknowledges that most diabetes studies involve patients with type 2 diabetes, leaving the distinct hormonal profiles of type 1 diabetes largely unstudied. Some long-acting insulins, such as insulin glargine, have even been associated with an increased risk of pancreatic and colorectal cancers, although evidence on insulin treatment and cancer outcomes remains mixed.

Pharmacological challenges remain under-addressed. Metformin's poor bioavailability limits direct tumor effects. Itraconazole's solubility problems complicate dosing. Ketoconazole's liver toxicity demands monitoring. Each of these constraints affects whether preclinical promise translates into real-world benefit.

The heterogeneity of TNBC further complicates the picture. A drug that works in the BL-1 subtype may fail in the LAR subtype. The exact impact of molecular subtypes on patient outcomes remains under investigation. Finally, long-term safety data for repurposed drugs used at new dose schedules — often at higher doses than their original indications — is incomplete.

Recommendations: Practical Takeaways for Patients

For patients currently undergoing TNBC treatment, these findings matter even though no repurposed drug is yet approved specifically for TNBC:

1. Do not self-medicate. Even though these drugs are FDA-approved for other conditions, using them at cancer-fighting doses without oncologist supervision is dangerous. Metformin, for instance, carries a risk of lactic acidosis in patients with kidney problems.
2. Ask your oncologist about ongoing trials. Many of the trials described are actively recruiting. Clinical trial participation can provide access to promising combination strategies that are not otherwise available.
3. Discuss comorbidities openly. If you have diabetes, high blood pressure, or high cholesterol, tell your oncologist about every medication you take. You may already be taking a drug with anticancer potential, and knowing that could affect your treatment plan.
4. Consider your metabolic health. Weight management, blood sugar control, and physical activity — the very factors that link diabetes and cancer — may influence how well repurposed drugs work. Addressing these factors supports your overall treatment.
5. Understand that subtype matters. TNBC is not one disease. Ask whether your tumor has been molecularly profiled. Knowing your subtype helps predict which therapies, repurposed or otherwise, are most likely to work.
6. Stay informed but realistic. The science is moving fast, but no repurposed drug has yet earned FDA approval for TNBC. The most effective strategy remains evidence-based standard care.

The review authors emphasize that further research and personalized approaches are absolutely essential to translate these findings into effective clinical applications. Ongoing research into molecular mechanisms, biomarker identification, and targeted therapies is crucial for improving TNBC outcomes.

Frequently Asked Questions

What is triple-negative breast cancer and why is it so hard to treat?

Triple-negative breast cancer (TNBC) tests negative for estrogen, progesterone, and HER2 receptors, so hormone therapies and HER2-targeting drugs don't work. It makes up about 15% to 20% of breast cancers and is aggressive. Roughly 40% of advanced-stage patients die within five years, and median survival with distant spread is 13.3 months.

What is drug repurposing and how does it differ from developing a new drug?

Drug repurposing finds new medical uses for medications already approved for other conditions. Because their safety in humans is known, these drugs can skip early testing phases. Development takes about 3 to 5 years instead of 10 to 17, and costs around $300 million less. Examples include thalidomide, now used for multiple myeloma.

Which existing medications are being studied against triple-negative breast cancer?

Researchers are testing diabetes drug metformin, antifungals like ketoconazole and itraconazole, antiparasitic drugs ivermectin and mebendazole, blood pressure drug propranolol, statins, and NSAIDs. These are not yet approved for TNBC. They are at various stages of laboratory and clinical investigation, often combined with standard therapies.

Can I take a repurposed drug for TNBC today?

No repurposed drug is FDA-approved for triple-negative breast cancer. Do not self-medicate. Taking these drugs at cancer-fighting doses without oncology supervision is dangerous. Some are being tested in clinical trials, and your oncologist can tell you if you might be eligible for an ongoing trial. Standard evidence-based care remains the most effective approach.

What risks or side effects should I know about these repurposed drugs?

Metformin can cause lactic acidosis, especially with kidney impairment. Ketoconazole carries a risk of liver damage requiring monitoring. Itraconazole has poor solubility and may need special formulations. Long-term safety data for repurposed drugs used at new, higher doses is incomplete. Always tell your oncologist about every medication you take and your full health history.

What should I ask my oncologist about drug repurposing for my TNBC?

Ask about ongoing clinical trials you might join, and disclose all medications for diabetes, blood pressure, or cholesterol. Ask whether your tumor has been molecularly profiled, since subtype affects treatment choices. Also discuss your metabolic health, because conditions like diabetes and obesity may influence how repurposed drugs work. Never start these drugs on your own.

When should I seek a second opinion for triple-negative breast cancer treatment options like repurposed drugs?

A second opinion is useful when your treatment team has not reviewed whether your tumor's molecular subtype affects the plan, or when you want to explore clinical trials of repurposed drugs. TNBC is not one disease; four subtypes respond differently to therapies. Repurposed medications such as metformin, itraconazole, propranolol, or ivermectin are not yet approved for TNBC, so any use must be supervised by an oncologist. A second opinion can confirm your pathology, discuss trial eligibility, and ensure standard care is not delayed. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article: "Old Drugs, New Battles: Unleashing Repurposed Drug Classes in Triple-Negative Breast Cancer Treatment"

Authors: Tshimweneka VS, Mhlanga TV.

Journal: International Journal of Molecular Sciences (IJMS), 2025, Volume 26, Article 11196

DOI: https://doi.org/10.3390/ijms262211196

Publication dates: Received 16 September 2025; Revised 28 October 2025; Accepted 31 October 2025; Published 19 November 2025

Academic Editor: Mi Kyung Park

This patient-friendly article is based on peer-reviewed research. It is an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).