Sirolimus
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Sirolimus: From Renal Transplant Rejection Prophylaxis to Liposarcoma
One-Sentence Summary
Sirolimus (rapamycin) is an mTOR inhibitor originally developed as an immunosuppressant to prevent organ rejection in renal transplantation. The TxGNN model predicts it may be effective for Liposarcoma, with 5 clinical trials and 12 publications currently supporting this direction — though most of the trial evidence comes from related mTOR inhibitors (temsirolimus, everolimus, ridaforolimus) rather than Sirolimus itself.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Immunosuppression / prophylaxis of renal transplant rejection (well-established use; specific Danish regulatory indication text is not confirmed in the available data) |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.89% |
| Evidence Level | L2 |
| Denmark Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the evidence pack. Based on known pharmacology, Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor (“rapalog”), a drug class whose efficacy in preventing renal transplant rejection is well established, and which mechanistically may be applicable to certain soft-tissue sarcomas.
Dedifferentiated liposarcoma frequently shows activation of the PI3K–Akt–mTOR signalling pathway (PMID 26518767), and mTOR inhibition can block this downstream proliferative signal — giving the prediction a clear molecular biology rationale. However, of the 5 clinical trials identified for this indication, only one (NCT02821507) uses Sirolimus itself directly; the remaining four involve related agents in the same drug class (temsirolimus, everolimus, ridaforolimus). This means the supporting evidence is largely a class-effect inference rather than direct, drug-specific proof for Sirolimus in liposarcoma.
It is also worth noting that among the other candidate indications generated for Sirolimus in this evidence pack (not detailed in this report), lymphangioleiomyomatosis (LAM) and PEComa/angiomyolipoma show substantially more direct, disease-specific Sirolimus evidence — including a completed Phase 3 RCT (NCT00414648, MILES trial) for LAM — and may warrant separate, higher-priority evaluation.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02821507 | Phase 2 | Completed | 70 | Single-arm trial of Sirolimus + cyclophosphamide in metastatic/unresectable myxoid liposarcoma and chondrosarcoma — direct use of Sirolimus itself, indication-matched |
| NCT00093080 | Phase 2 | Completed | 216 | Large trial of ridaforolimus (same-class mTOR inhibitor, not Sirolimus) in advanced sarcoma |
| NCT01614795 | Phase 2 | Completed | 46 | Cixutumumab + temsirolimus (same-class, not Sirolimus) in pediatric recurrent/refractory sarcoma |
| NCT00949325 | Phase 1/2 | Completed | 24 | Torisel (temsirolimus) + liposomal doxorubicin in advanced soft tissue and bone sarcoma |
| NCT03114527 | Phase 2 | Active, not recruiting | 48 | Ribociclib + everolimus (same-class) in advanced dedifferentiated liposarcoma and leiomyosarcoma |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37967116 | 2024 | Single-arm clinical trial report | Clin Cancer Res | Ribociclib + everolimus in dedifferentiated liposarcoma/leiomyosarcoma; synergistic mTOR/CDK4-pathway inhibition |
| 26093731 | 2015 | Cohort | Transplantation Proceedings | Cancer screening in renal transplant patients on long-term immunosuppression, including mTOR inhibitors |
| 16434506 | 2006 | Cohort | J Am Soc Nephrol | Sirolimus after early cyclosporine withdrawal reduced cancer risk vs. cyclosporine in renal transplant recipients |
| 39796641 | 2024 | Review | Cancers | Review of novel therapeutics in soft tissue sarcoma, including mTOR-pathway approaches |
| 37222206 | 2023 | Review | Curr Opin Oncol | Review of new targeted treatments for advanced sarcomas |
| 20497911 | 2010 | Review | Bulletin du Cancer | Review of targeted treatment strategies for rare connective tissue tumours and sarcomas by molecular subgroup |
| 26518767 | 2016 | Mechanism study | Tumour Biology | Analysis of 99 dedifferentiated liposarcoma specimens showing Akt/mTOR and MAPK pathway activation |
| 37400145 | 2023 | Preclinical | Cancer Genomics Proteomics | Chloroquine + rapamycin synergistically inhibits autophagy, effective in well-differentiated liposarcoma models |
| 36309387 | 2022 | Preclinical (PDX model) | In Vivo | Chloroquine + rapamycin arrests tumour growth in a patient-derived xenograft model of dedifferentiated liposarcoma |
| 25519700 | 2015 | Preclinical | Mol Cancer Ther | ATP-competitive mTOR kinase inhibitor MLN0128 shows antitumor activity in bone/soft-tissue sarcoma models |
Denmark Market Information
Sirolimus is not currently marketed in Denmark — no national (Lægemiddelstyrelsen) or centralised (EMA) marketing authorisations are recorded in the evidence pack (0 licenses on file).
Safety Considerations
Please refer to the approved Summary of Product Characteristics (SmPC) for safety information. No drug interaction, warning, or contraindication data were available for review in this evidence pack.
Conclusion and Next Steps
Decision: Hold
Rationale:
- Sirolimus is not currently marketed in Denmark, and a blocking data gap exists for SmPC warnings/contraindications, meaning an initial safety assessment cannot yet be performed.
- Evidence for the liposarcoma indication specifically is class-effect based: only 1 of 5 trials uses Sirolimus itself directly, and the drug’s own original indication/MOA data could not be confirmed from available sources.
To proceed, the following is needed:
- Obtain SmPC / product safety data (warnings, contraindications, drug interactions) from Lægemiddelstyrelsen or EMA
- Confirm the drug’s approved original indication and mechanism of action via DrugBank or regulatory sources
- Clarify access pathway given the drug is not marketed in Denmark (e.g., named-patient/off-label import)
- Consider prioritizing evaluation of related predicted indications (lymphangioleiomyomatosis, PEComa/angiomyolipoma), where Sirolimus has more direct and mature supporting evidence than for liposarcoma
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.