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 to prevent organ rejection after 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 strongest trial data comes from sirolimus analogs (temsirolimus, everolimus, ridaforolimus) rather than sirolimus itself.

Quick Overview

Item	Content
Original Indication	Prophylaxis of renal transplant rejection (immunosuppressant) — not captured in Norway regulatory data, inferred from the drug's established clinical use and supporting literature in this evidence pack
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.89%
Evidence Level	L2
Norway 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 in DrugBank for this candidate. Based on the supporting literature in this evidence pack, Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor — it binds FKBP12 and blocks mTORC1 signaling, which regulates cell growth, proliferation, and survival. Its efficacy in preventing renal transplant rejection is well established, and several of the included publications (e.g., studies on renal transplant recipients, PMID 16434506, 26093731) note that sirolimus-based immunosuppression is associated with a reduced incidence of malignancy compared with calcineurin inhibitors, pointing toward antiproliferative activity beyond immune suppression.

Liposarcoma, particularly the dedifferentiated subtype, has been shown to exhibit aberrant activation of the Akt-mTOR and MAPK pathways (PMID 26518767), providing a direct mechanistic rationale for mTOR blockade as an antitumor strategy. This is mechanistically distinct from sirolimus's original transplant indication but converges on the same molecular pathway (mTORC1 inhibition), which is the core biological link supporting this repurposing hypothesis.

Importantly, the bulk of clinical evidence in liposarcoma comes from sirolimus analogs (temsirolimus, everolimus, ridaforolimus) rather than sirolimus itself. Only one trial (NCT02821507) directly tests sirolimus in this population, and it was a single-arm Phase 2 study rather than a randomized controlled trial. This class-level extrapolation strengthens the biological plausibility but leaves a gap in drug-specific efficacy and safety evidence.

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
NCT00949325	Phase 1/2	Completed	24	Torisel (temsirolimus, sirolimus analog) + liposomal doxorubicin in advanced soft tissue and bone sarcomas
NCT01614795	Phase 2	Completed	46	Cixutumumab + temsirolimus in pediatric recurrent/refractory sarcoma
NCT00093080	Phase 2	Completed	216	Ridaforolimus (mTOR inhibitor analog) in advanced sarcoma; largest trial in this indication but not sirolimus itself
NCT03114527	Phase 2	Active, not recruiting	48	Ribociclib + everolimus in advanced dedifferentiated liposarcoma and leiomyosarcoma

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37967116	2024	RCT (Phase 2)	Clin Cancer Res	Ribociclib + everolimus showed synergistic growth inhibition in dedifferentiated liposarcoma and leiomyosarcoma models, supporting mTOR-pathway targeting
16434506	2006	Cohort (transplant population)	J Am Soc Nephrol	Sirolimus after cyclosporine withdrawal reduced cancer risk in renal transplant recipients, suggesting antitumor activity of sirolimus beyond immunosuppression
39796641	2024	Review	Cancers	Overview of novel therapeutics in soft tissue sarcoma, including mTOR-pathway-targeted agents
37400145	2023	Preclinical	Cancer Genomics Proteomics	Combination of chloroquine and rapamycin (sirolimus) synergistically inhibited autophagy and was effective against well-differentiated liposarcoma models
26518767	2016	Mechanism study	Tumour Biol	Demonstrated activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcoma specimens, providing the mechanistic basis for mTOR inhibition
37222206	2023	Review	Curr Opin Oncol	Summary of recent clinical trials on molecular-targeted agents, including mTOR inhibitors, in advanced sarcomas
26093731	2015	Cohort (transplant population)	Transplant Proc	Evaluated effects of immunosuppressive drugs, including sirolimus, on malignancy development in long-term transplant patients
36309387	2022	Preclinical (PDOX model)	In Vivo	Chloroquine combined with rapamycin arrested tumor growth in a patient-derived orthotopic xenograft model of dedifferentiated liposarcoma
25519700	2015	Preclinical	Mol Cancer Ther	Described dysregulation of the PI3K/Akt/mTOR pathway across multiple sarcoma subtypes and limitations of first-generation rapalogues
20497911	2010	Review	Bull Cancer	Discussed targeted treatment approaches, including mTOR-pathway inhibition, for rare connective tissue tumors and sarcomas

Norway Market Information

Sirolimus currently holds no market authorizations in Norway (total licenses: 0). No product-level dosage form or approved indication data is available for this drug in the Norwegian regulatory dataset.

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: While the mechanistic rationale (mTOR pathway activation in liposarcoma) is biologically plausible and supported by class-level evidence (L2), sirolimus itself has only one completed single-arm Phase 2 trial in this indication, most efficacy data comes from analog compounds, and the drug is not currently marketed in Norway. Critically, TFDA/Norway package insert data (warnings, contraindications) are entirely unavailable, which blocks even a preliminary safety assessment.

To proceed, the following is needed:

TFDA/Norwegian package insert data (warnings, contraindications, DDI) to complete a baseline safety review
DrugBank-confirmed mechanism of action data for sirolimus
A sirolimus-specific (not analog) randomized controlled trial in liposarcoma to upgrade evidence level beyond single-arm Phase 2
Route of administration and formulation compatibility assessment for an oncology treatment setting
Consideration of related higher-confidence candidates in this same evidence pack (e.g., lung PEComa, rank 9, "Proceed with Guardrails") which may warrant parallel evaluation given stronger direct sirolimus trial support (MIDAS, RESULT, MILES trials)
Disclaimer

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