Sirolimus

證據等級: L5

預測適應症: 10 個

Sirolimus: From Organ Transplant Rejection Prophylaxis to Liposarcoma

One-Sentence Summary

Sirolimus is an mTOR inhibitor best known as an immunosuppressant for prevention of renal transplant rejection. The TxGNN model predicts it may be effective for Liposarcoma (notably the myxoid and dedifferentiated subtypes), with 5 clinical trials and 12 publications currently supporting this direction.

Quick Overview

Item	Content
Original Indication	Not documented in the current Germany regulatory dataset (0 licenses on file); sirolimus is historically indicated for prophylaxis of renal transplant rejection (immunosuppressant)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.89%
Evidence Level	L2
Germany Market Status	✗ Not marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this evidence pack. Based on known information, sirolimus is an mTOR (mammalian target of rapamycin) inhibitor, originally developed as an immunosuppressant to prevent renal transplant rejection by blocking mTORC1-driven T-cell proliferation. Its efficacy in that original indication is well established, and the same mTORC1-blocking mechanism is mechanistically transferable to oncology, since mTOR signaling also drives proliferation in several tumor types.

Dedifferentiated liposarcoma (DDLPS) frequently shows activation of the Akt-mTOR and MAPK pathways (PMID 26518767), providing a direct molecular rationale for mTOR inhibition in this tumor. Several rapalog analogs of sirolimus — temsirolimus, everolimus, and ridaforolimus — have already been tested in Phase 2 sarcoma trials, and a dedicated Phase 2 trial of sirolimus combined with cyclophosphamide was completed in metastatic/unresectable myxoid liposarcoma and chondrosarcoma (NCT02821507, n=70), directly supporting biological plausibility.

Interestingly, some of the earliest signals linking sirolimus to reduced tumor risk come from its original transplant population — sirolimus-based immunosuppression has been associated with lower malignancy rates compared with calcineurin inhibitors (PMID 16434506, PMID 20534289) — reinforcing that this drug's antiproliferative mTOR-blocking effect is not confined to the immune system and may extend to tumor cells, including liposarcoma.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02821507	Phase 2	Completed	70	Sirolimus + cyclophosphamide in metastatic/unresectable myxoid liposarcoma and chondrosarcoma; direct on-target trial testing mTOR inhibition in this tumor family
NCT00093080	Phase 2	Completed	216	Ridaforolimus (rapalog analog) once-daily x5 every 2 weeks in advanced sarcoma
NCT01614795	Phase 2	Completed	46	Cixutumumab + temsirolimus (rapalog) in pediatric recurrent/refractory sarcoma
NCT03114527	Phase 2	Active, not recruiting	48	Ribociclib + everolimus (rapalog) in advanced dedifferentiated liposarcoma and leiomyosarcoma
NCT00949325	Phase 1/2	Completed	24	Temsirolimus (rapalog) + liposomal doxorubicin in advanced soft tissue and bone sarcomas

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 and clinical activity
26518767	2016	Cohort/Mechanistic	Tumour Biology	Akt-mTOR and MAPK pathways are activated in dedifferentiated liposarcoma specimens, supporting mTOR inhibitor rationale
39796641	2024	Review	Cancers	Overview of novel FDA-approved and emerging targeted therapeutics in soft tissue sarcoma
37222206	2023	Review	Curr Opin Oncol	Review of molecular-targeted agents and recent clinical trial rationale for advanced sarcomas
37400145	2023	Preclinical	Cancer Genomics Proteomics	Chloroquine + rapamycin combination synergistically inhibits autophagy and is effective against well-differentiated liposarcoma
36309387	2022	Preclinical	In Vivo	Rapamycin + chloroquine arrests tumor growth in a patient-derived orthotopic xenograft model of dedifferentiated liposarcoma
25519700	2015	Preclinical	Mol Cancer Ther	ATP-competitive mTOR kinase inhibitor MLN0128 shows potent antitumor activity in bone/soft-tissue sarcoma, addressing rapalog resistance
20497911	2010	Review	Bull Cancer	Targeted treatment approaches for rare connective tissue tumors and sarcomas, including mTOR-pathway agents
16434506	2006	RCT	J Am Soc Nephrol	Randomized trial: sirolimus after cyclosporine withdrawal reduces cancer risk in adult renal transplant recipients, supporting antitumor properties of sirolimus beyond immunosuppression
20534289	2010	Case series	Transplant Proc	Conversion to rapamycin-based immunosuppression after malignancy diagnosis in kidney transplant recipients, illustrating antitumor rationale of mTOR inhibition

Germany Market Information

Sirolimus is currently not marketed in Germany under this dataset (0 authorizations on file; no product/license records available).

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: A dedicated, completed Phase 2 trial (NCT02821507) directly tested sirolimus in myxoid liposarcoma/chondrosarcoma, and this is reinforced by a broader body of Phase 1/2 trials and mechanistic literature on rapalog-class mTOR inhibitors in sarcoma — meeting L2 evidence (one completed Phase 2/3 trial) rather than the stronger L1 threshold, so guarded rather than unconditional progression is warranted.

To proceed, the following is needed:

TFDA/BfArM-equivalent label data on warnings, contraindications, and drug interactions (currently a Blocking data gap, DG001)
Confirmed mechanism of action documentation from DrugBank (currently a High-severity data gap, DG002)
Published efficacy/safety outcomes from NCT02821507 once fully reported
Route and formulation compatibility assessment for oncology dosing versus the drug's existing immunosuppressant formulations
Disclaimer

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