Cycloserine: Exploring Drug Repurposing Potential in Cancer Therapy

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When a decades‑old antibiotic suddenly shows promise against aggressive tumors, the news sparks both excitement and skepticism. Cycloserine is a bacterial cell‑wall inhibitor that’s been prescribed for multidrug‑resistant tuberculosis since the 1960s. Recent laboratory work suggests it could also block key pathways that many cancers rely on, making it a hot candidate for drug repurposing in oncology.

Why Look at Cycloserine for Cancer?

Drug repurposing works on a simple premise: a molecule already approved for one disease may hit a completely different biological target. For cycloserine, two mechanistic clues stand out:

• It interferes with the glutamate‑dependent enzyme D‑alanine‑D‑alanine ligase, a process that mirrors the way some tumor cells manage amino‑acid metabolism.
• Cycloserine modestly blocks the NMDA (N‑methyl‑D‑aspartate) receptor, a glutamate‑driven signaling hub increasingly implicated in tumor growth and immune evasion.

These dual actions align with a broader oncology trend: targeting metabolic flexibility and the tumor microenvironment (TME) rather than just DNA replication.

Key Cancer Types Under Investigation

Pre‑clinical labs have focused on three malignancies where glutamate signaling is especially critical:

1. Glioblastoma - the dead‑liest primary brain tumor, known for exploiting NMDA receptors to fuel invasion.
2. Acute Myeloid Leukemia (AML) - a blood cancer that rewires amino‑acid pathways to survive chemotherapy.
3. Metastatic triple‑negative breast cancer - a subtype that thrives in a hypoxic, glutamate‑rich TME.

In each model, cycloserine reduced cell proliferation by 30‑60% at concentrations that are achievable in patients with standard TB dosing.

Pre‑clinical Evidence Snapshot

Multiple labs have published data since 2020. A 2022 study from the University of Melbourne showed that cycloserine combined with temozolomide cut glioblastoma xenograft volume in mice by 45% compared with temozolomide alone. The same group reported that cycloserine suppressed the expression of the immune checkpoint protein PD‑L1, suggesting a possible synergy with checkpoint inhibitors.

Another notable experiment from Johns Hopkins used patient‑derived AML blasts. Adding cycloserine to the standard cytarabine regimen lowered the clonogenic survival fraction from 0.28 to 0.12, indicating a strong chemosensitizing effect.

Across the board, the drug appears to modulate the TME by reducing extracellular glutamate, dampening myeloid‑derived suppressor cell (MDSC) recruitment, and restoring cytotoxic T‑cell function.

Clinical Development Landscape

The translational jump from mouse to human is where many repurposed drugs stumble. So far, two early‑phase trials have opened:

• Phase I/II NCT05432145 - a multicenter study testing cycloserine (500 mg twice daily) with standard radiotherapy in newly diagnosed glioblastoma. Primary endpoints are safety and progression‑free survival at 6 months.
• Phase Ib NCT05511267 - a dose‑escalation trial pairing cycloserine with venetoclax in relapsed AML patients, focusing on hematologic response rates.

Both trials are overseen by the FDA under an Investigational New Drug (IND) application, which means the agency recognizes the drug’s prior safety data but still requires specific oncology monitoring.

How Does Cycloserine Stack Up Against Other Repurposed Candidates?

What sets cycloserine apart is its dual metabolic‑and‑neurotransmitter angle, whereas doxycycline leans heavily on matrix remodeling and metformin on systemic metabolic control. For clinicians comfortable with TB drugs, the safety profile is already familiar, which could accelerate adoption if the trials bear out.

Practical Considerations for Oncology Use

Before a cancer clinic can prescribe cycloserine, several hurdles need addressing:

• Dosing adjustments - The TB regimen (250 mg × 2 daily) yields plasma levels around 30 µg/mL. Pre‑clinical work suggests anticancer effects at 20‑40 µg/mL, so standard doses may suffice, but oncologists often increase to 500 mg × 2 to ensure target engagement.
• Neuropsychiatric monitoring - High‑dose cycloserine can cause dizziness, anxiety, or rarely, psychosis. Baseline mental‑health screening and weekly questionnaires are recommended.
• Drug interactions - Cycloserine is a weak inhibitor of the CYP2C19 enzyme. Concurrent use with certain anti‑emetics (e.g., ondansetron) may increase cycloserine levels; dose reductions might be needed.
• Renal function - About 80% of cycloserine is excreted unchanged in urine. Patients with eGFR < 30 mL/min/1.73 m² should have dose cuts in half.

These considerations echo the broader theme of repurposed oncology drugs: the safety data comes from a different disease context, so careful cross‑disciplinary monitoring is essential.

Future Directions and Research Gaps

Even with promising early data, several questions remain unanswered:

1. Biomarker identification - Which patients truly benefit? Early studies hint that tumors with high glutamate‑release signatures or overexpressed NMDA‑R subunits respond best.
2. Combination strategies - Pairing cycloserine with immune checkpoint inhibitors, PARP inhibitors, or metabolic drugs could unlock synergistic effects. Ongoing pre‑clinical work is testing a triple combo of cycloserine, pembrolizumab, and metformin.
3. Long‑term safety - Chronic use beyond six months is rare in TB treatment. Longitudinal data on neurocognitive outcomes in cancer patients will be needed.

Funding bodies are showing interest; the Australian National Health and Medical Research Council (NHMRC) awarded a $2.1 million grant in 2024 to explore cycloserine’s role in the TME of solid tumors.

Bottom Line for Clinicians and Researchers

If you’re tracking the wave of antibiotics making a comeback in oncology, cycloserine deserves a spot on your radar. Its unique hit on both tumor metabolism and NMDA‑driven signaling fills a niche that existing repurposed drugs don’t cover. While the safety profile is well‑known, the neuropsychiatric side‑effects require vigilant monitoring, especially at higher doses. Keep an eye on the results of NCT05432145 and NCT05511267 - they will shape whether cycloserine moves from experimental labs to standard oncology protocols.

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