Sirolimus

證據等級: L5

預測適應症: 10 個

Sirolimus: From Renal Transplant Rejection Prophylaxis to Liposarcoma

One-Sentence Summary

Sirolimus (rapamycin) is an mTOR inhibitor originally developed as an immunosuppressant for prophylaxis of renal transplant rejection. The TxGNN model predicts it may be effective for Liposarcoma, with 5 clinical trials (mostly of sirolimus-class analogues) and 12 publications currently supporting this direction. However, a blocking data gap in Finnish/TFDA safety labeling means this candidate cannot yet enter formal safety screening.

Quick Overview

Item	Content
Original Indication	Renal transplant rejection prophylaxis (immunosuppression) — well-established original use; no Finland-specific license text is available in this pack
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.89%
Evidence Level	L2
Finland Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available (DrugBank query returned no MOA field). Based on known pharmacology, sirolimus is an mTOR (mechanistic target of rapamycin) inhibitor, whose efficacy as an immunosuppressant in solid organ transplantation is well established. Mechanistically, this same mTOR-blocking activity is what is being explored for anti-tumour effect in liposarcoma.

Liposarcoma, particularly the dedifferentiated subtype, has demonstrated activation of the Akt-mTOR and MAPK signalling pathways (PMID 26518767), giving a direct mechanistic rationale for mTOR blockade as an anti-proliferative strategy. This is reinforced by class-wide evidence: sirolimus analogues (temsirolimus, ridaforolimus, everolimus) have completed multiple Phase 1/2 trials in advanced soft-tissue sarcoma and liposarcoma, including a single-arm Phase 2 trial of sirolimus itself combined with cyclophosphamide (NCT02821507, n=70, completed).

That said, no Phase 3 confirmatory trial exists for sirolimus (or its analogues) specifically in liposarcoma, and the trial evidence is drawn substantially from related rapalogs rather than sirolimus itself — the mechanistic case is stronger than the direct clinical-trial case.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02821507	Phase 2	Completed	70	Sirolimus + cyclophosphamide, single-arm, in metastatic/unresectable myxoid liposarcoma and chondrosarcoma; based on preclinical mTOR-inhibition tumor-growth-prevention data
NCT00949325	Phase 1/2	Completed	24	Torisel (temsirolimus, a sirolimus prodrug) + liposomal doxorubicin dosing study in recurrent sarcoma
NCT01614795	Phase 2	Completed	46	Cixutumumab + temsirolimus in pediatric recurrent/refractory solid tumors (sarcoma)
NCT00093080	Phase 2	Completed	216	Ridaforolimus (mTOR inhibitor, AP23573) once-daily x5/2-week schedule in advanced sarcoma
NCT03114527	Phase 2	Active, not recruiting	48	Ribociclib (CDK4/6i) + everolimus (mTORi) in advanced dedifferentiated liposarcoma and leiomyosarcoma

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37967116	2024	RCT (Phase 2)	Clin Cancer Res	Ribociclib + everolimus shows synergistic growth inhibition in dedifferentiated liposarcoma/leiomyosarcoma models, supporting combined CDK4/mTOR targeting
16434506	2006	RCT/Cohort	J Am Soc Nephrol	Sirolimus after early cyclosporine withdrawal reduced cancer risk in renal transplant recipients (n=525)
26518767	2016	Mechanistic/Translational	Tumour Biol	Akt-mTOR and MAPK pathway activation demonstrated across 99 dedifferentiated liposarcoma specimens, supporting mTOR-targeted therapy rationale
26093731	2015	Cohort	Transplant Proc	Cancer screening cohort in renal transplant patients on long-term immunosuppression
39796641	2024	Review	Cancers	Review of novel therapeutics (including mTOR-pathway agents) in soft tissue sarcoma
37222206	2023	Review	Curr Opin Oncol	Review of new molecular-targeted treatments for advanced sarcomas
37400145	2023	Preclinical (Xenograft)	Cancer Genomics Proteomics	Chloroquine + rapamycin synergistic autophagy inhibition effective against well-differentiated liposarcoma
36309387	2022	Preclinical (PDX)	In Vivo	Chloroquine + rapamycin arrests tumor growth in a patient-derived orthotopic xenograft model of dedifferentiated liposarcoma
25519700	2015	Preclinical	Mol Cancer Ther	MLN0128, an ATP-competitive mTOR kinase inhibitor, shows potent antitumor activity in bone/soft-tissue sarcoma models
20497911	2010	Review	Bull Cancer	Review of targeted treatment approaches for rare connective tissue tumors and sarcomas

Finland Market Information

Sirolimus is currently not marketed in Finland (0 authorizations on record), so no product/authorization data is available for this section.

Safety Considerations

Please refer to the package insert for safety information. (TFDA/Fimea warnings, contraindications, and DDI data are currently unavailable — see Conclusion for the related blocking data gap.)

Conclusion and Next Steps

Decision: Hold

Rationale: Sirolimus is not currently marketed in Finland, and a blocking data gap (DG001: missing TFDA/Fimea package insert warnings and contraindications) means the candidate cannot yet enter the S1 safety pre-screening stage, regardless of the L2-level clinical/mechanistic evidence supporting liposarcoma as a repurposing target. Note also that this same evidence pack identifies other sirolimus-predicted indications (e.g., PEComa/angiomyolipoma and lymphangioleiomyomatosis) with comparably strong or stronger real-world validation (approved same-class agents everolimus and nab-sirolimus), which may warrant separate prioritization.

To proceed, the following is needed:

TFDA/Fimea package insert (warnings and contraindications) — required to clear the blocking S1 safety gap
Detailed mechanism of action data via DrugBank API
Drug-drug interaction (DDI) data (current query returned no results)
Confirmation of route/dosage-form compatibility for an oncology (liposarcoma) treatment setting, since sirolimus is currently only formulated/dosed for transplant immunosuppression
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.