Maraviroc
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Maraviroc: From HIV-1 Infection to HER2-Positive Breast Carcinoma
One-Sentence Summary
Maraviroc is a CCR5 antagonist (entry inhibitor) originally developed for HIV-1 infection. Of the 10 TxGNN-predicted repurposing candidates screened in this evidence pack, HER2-positive breast carcinoma stands out as the only one with a specific, testable molecular rationale — a preclinical study shows CCR5 signalling drives trastuzumab resistance in HER2+ tumours — though currently supported by 1 preclinical mechanistic paper and no clinical trials. The other 9 candidates (including the top TxGNN-scored “multiple endocrine neoplasia”) were reviewed and largely rejected for lacking any biological plausibility or supporting evidence.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HIV-1 infection (CCR5 antagonist/entry inhibitor) — not sourced from Australian regulatory data, as maraviroc is not ARTG-listed |
| Predicted New Indication | HER2-positive breast carcinoma |
| TxGNN Prediction Score | 99.22% |
| Evidence Level | L4 (preclinical mechanistic study only) |
| Australia Market Status | Not marketed |
| Number of ARTG Entries | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data for maraviroc is not available in this evidence pack (flagged as a High-severity data gap). Based on known information, maraviroc is a CC-chemokine receptor 5 (CCR5) antagonist used as an entry inhibitor in combination antiretroviral therapy for HIV-1 infection; it blocks the interaction between the HIV-1 envelope glycoprotein gp120 and host CCR5, preventing viral entry.
The repurposing hypothesis for HER2-positive breast carcinoma is more specific than for the other 9 candidates in this pack. A preclinical mechanistic study (PMID 32404410) found that HER2-positive breast cancer cells can autocrine-secrete CCL5 (RANTES), the principal ligand of CCR5, which activates a CCR5→ERK signalling loop that drives resistance to trastuzumab (an anti-HER2 antibody). Since maraviroc directly blocks CCR5, there is a plausible — though not yet directly tested — mechanism by which it could interrupt this autocrine resistance loop and restore or enhance trastuzumab sensitivity.
By contrast, the other candidates in this screening round were reviewed and found weaker: the top TxGNN-ranked prediction (multiple endocrine neoplasia) has no known biological connection to CCR5/chemokine signalling and is assessed in the pack itself as a likely embedding artefact, with zero supporting trials or literature. Two cutaneous T-cell lymphoma variants have only an indirect literature link (a review of ACKR1, a different atypical chemokine receptor, not CCR5/maraviroc specifically). No candidate in this set has advanced past early screening, and HER2-positive breast carcinoma is the only one to reach decision stage S1.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 32404410 | 2020 | Preclinical mechanistic study | Molecular Cancer Therapeutics | Autocrine CCL5 secretion in HER2+ breast cancer activates CCR5→ERK signalling, mediating resistance to trastuzumab |
Australia Market Information
Maraviroc is not currently marketed in Australia — there are no ARTG entries for this drug in the evidence pack, and no Australian Product Information exists to draw on. Overseas-approved labelling (e.g. FDA/EMA) would need to be consulted as a starting reference if this candidate progresses.
Safety Considerations
No specific safety data (key warnings, contraindications, or drug interactions) is available in this evidence pack, and this is flagged as a Blocking data gap (TFDA/TGA-equivalent product information not yet obtained) — meaning safety cannot be formally assessed at this stage. Since maraviroc is not marketed in Australia, there is no local Product Information to fall back on; overseas-approved labelling should be sourced before any further evaluation.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic rationale (CCL5/CCR5/ERK-driven trastuzumab resistance) is specific and testable, but it comes from a single preclinical study that did not test maraviroc itself — no clinical trials exist, the drug is not marketed in Australia, and safety/MOA data gaps are currently blocking (DG001) or high-severity (DG002).
To proceed, the following is needed:
- Resolve the blocking safety data gap: obtain TGA/overseas product information (warnings, contraindications) for maraviroc
- Full mechanism of action profile (currently a documented data gap)
- Direct experimental validation that maraviroc (not just CCR5 blockade generically) reverses trastuzumab resistance in HER2+ models
- Assessment of the Australian regulatory pathway, since maraviroc has no existing ARTG registration
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.