Sirolimus
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Sirolimus: From Immunosuppression (Organ Transplant Rejection) to Liposarcoma
One-Sentence Summary
Sirolimus (rapamycin) is an mTOR inhibitor best known as an immunosuppressant used to prevent renal transplant rejection. The TxGNN model predicts it may be effective for Liposarcoma, with 5 clinical trials and 12 publications currently supporting this direction — including a completed Phase 2 trial testing sirolimus itself in this tumor type.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Immunosuppression / prevention of organ (renal) transplant rejection — based on known drug-class information; no formal EU label text is on file since the drug is not marketed in the EU per this evidence pack |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.89% |
| Evidence Level | L2 |
| EU Market Status | Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in DrugBank for this evidence pack (flagged as a High-severity data gap, DG002). However, across the supporting evidence, Sirolimus is consistently described as an mTOR (mechanistic target of rapamycin) inhibitor — the same molecular target it engages clinically as an immunosuppressant, where it blocks mTORC1-driven T-cell proliferation to prevent transplant rejection.
Dedifferentiated liposarcoma (DDL) and related soft tissue sarcomas show constitutive activation of the Akt-mTOR and MAPK signaling pathways (PMID 26518767). Because this is the same pathway sirolimus dampens in its immunosuppressive role, there is a plausible mechanistic bridge between its original indication and this oncology application: a pathway that is therapeutically suppressed in transplant patients is aberrantly hyperactivated in this tumor type, providing rationale for an antiproliferative effect.
This is reinforced by direct clinical evidence — NCT02821507 tested sirolimus itself (not an analog) in a completed Phase 2, single-arm trial in myxoid liposarcoma and chondrosarcoma (n=70). Related mTOR-class agents (temsirolimus, everolimus, ridaforolimus) have also been evaluated in overlapping sarcoma populations across several Phase 1/2 trials, further supporting the class-wide mechanistic plausibility.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02821507 | Phase 2 | Completed | 70 | Direct Sirolimus + cyclophosphamide in metastatic/unresectable myxoid liposarcoma and chondrosarcoma; single-arm, mTOR inhibition rationale based on preclinical in vivo data |
| NCT00093080 | Phase 2 | Completed | 216 | Ridaforolimus (mTOR inhibitor) in advanced sarcoma; large sample, completed |
| NCT03114527 | Phase 2 | Active, not recruiting | 48 | Ribociclib + Everolimus (mTOR inhibitor) in advanced dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) |
| NCT01614795 | Phase 2 | Completed | 46 | Cixutumumab + Temsirolimus (sirolimus prodrug) in pediatric recurrent/refractory sarcoma |
| NCT00949325 | Phase 1/2 | Completed | 24 | Temsirolimus + liposomal doxorubicin in advanced soft tissue and bone sarcoma; dosing and efficacy assessment |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37967116 | 2024 | RCT | Clin Cancer Res | SAR-096: Ribociclib + Everolimus in DDL and LMS; synergistic growth inhibition supports mTOR-pathway targeting |
| 39796641 | 2024 | Review | Cancers | Review of novel/targeted therapeutics in soft tissue sarcoma |
| 16434506 | 2006 | Cohort | J Am Soc Nephrol | Sirolimus-based regimen (vs. cyclosporine) reduced malignancy risk in renal transplant recipients, supporting antineoplastic potential of mTOR inhibition |
| 26518767 | 2016 | Preclinical/Mechanism | Tumour Biol | Akt-mTOR and MAPK pathway activation demonstrated in 99 dedifferentiated liposarcoma specimens; in vitro mTOR inhibitor antitumor effect |
| 37400145 | 2023 | Preclinical | Cancer Genomics Proteomics | Chloroquine + rapamycin combination effective against well-differentiated liposarcoma via autophagy inhibition |
| 37222206 | 2023 | Review | Curr Opin Oncol | Review of new molecular-targeted treatments for advanced sarcomas |
| 20497911 | 2010 | Review | Bull Cancer | Review of targeted treatment strategies across molecularly-defined sarcoma subgroups |
| 25519700 | 2015 | Preclinical | Mol Cancer Ther | MLN0128, an ATP-competitive mTOR kinase inhibitor, shows potent antitumor activity in bone/soft-tissue sarcoma models |
| 36309387 | 2022 | Preclinical (PDOX model) | In Vivo | Chloroquine + rapamycin arrests tumor growth in a dedifferentiated liposarcoma patient-derived xenograft mouse model |
| 20534289 | 2010 | Case Series | Transplant Proc | Conversion to rapamycin immunosuppression after malignancy diagnosis in kidney transplant recipients |
EU Market Information
Currently not marketed in the EU — no marketing authorizations are on file for this evidence pack (0 authorizations).
Safety Considerations
Please refer to the SmPC for safety information. Key warnings, contraindications, and drug-drug interaction data are not currently available in this evidence pack (flagged as a Blocking-severity data gap, DG001) — this must be resolved before any safety evaluation can proceed.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: A completed, direct Phase 2 trial of sirolimus itself in liposarcoma (NCT02821507), combined with mechanistic evidence of Akt-mTOR pathway activation in dedifferentiated liposarcoma, supports an L2 evidence rating. However, this rests on a single non-randomized trial rather than a confirmatory RCT, and critical drug-level safety and regulatory data remain unresolved.
To proceed, the following is needed:
- TFDA/EMA product label warnings and contraindications (Blocking gap, DG001)
- Formal mechanism-of-action documentation from DrugBank (High-priority gap, DG002)
- A regulatory access pathway assessment, since Sirolimus currently holds 0 EU marketing authorizations (named-patient import, off-label use, or new authorization)
- Confirmation that oncology dosing/route requirements are compatible with existing formulations approved for transplant indications
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.