Sirolimus
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Sirolimus: From Renal Transplant Rejection Prophylaxis to Liposarcoma
One-Sentence Summary
Sirolimus (DrugBank DB00877) is an mTOR inhibitor originally developed as an immunosuppressant to prevent renal transplant rejection. The TxGNN model predicts it may also be effective for Liposarcoma, with 5 clinical trials and 12 publications currently informing this direction — though only one trial tests sirolimus itself directly in this indication.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not specified in the available regulatory data; sirolimus was originally developed as an immunosuppressant for renal transplant rejection prophylaxis |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.89% |
| Evidence Level | L2 |
| UK Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for sirolimus is currently a flagged data gap in this evidence pack. Based on established pharmacological knowledge, however, sirolimus is a rapamycin-class mTOR (mechanistic target of rapamycin) inhibitor, originally used to suppress T-cell activation and prevent rejection after kidney transplantation. This mechanism is well documented in the supporting literature — for example, studies of sirolimus in renal transplant recipients show it reduces rather than promotes malignancy risk compared with calcineurin inhibitors (PMID 16434506, PMID 26093731), a finding that first drew attention to its antitumour potential.
Liposarcoma, and particularly its dedifferentiated subtype, has been shown to exhibit constitutive activation of the Akt-mTOR and MAPK signalling pathways (PMID 26518767), providing a plausible mechanistic bridge between an mTOR-inhibiting immunosuppressant and this sarcoma subtype. Preclinical work combining rapamycin with the autophagy inhibitor chloroquine has also demonstrated synergistic antitumour activity in well-differentiated and dedifferentiated liposarcoma models (PMID 37400145, PMID 36309387).
It is important to note that most of the clinical evidence base for mTOR inhibition in liposarcoma involves related rapalogues (temsirolimus, ridaforolimus, everolimus) rather than sirolimus itself. Only one identified trial (NCT02821507) directly tests sirolimus in myxoid liposarcoma, meaning the mechanistic rationale is stronger as a drug-class argument than as sirolimus-specific evidence.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT02821507 | Phase 2 | Completed | 70 | Single-arm trial of sirolimus + cyclophosphamide in metastatic/unresectable myxoid liposarcoma and chondrosarcoma; direct sirolimus intervention (Grade A relevance) |
| NCT01614795 | Phase 2 | Completed | 46 | Cixutumumab + temsirolimus (sirolimus prodrug) in paediatric recurrent/refractory sarcoma |
| NCT00949325 | Phase 1/2 | Completed | 24 | Temsirolimus (Torisel) + liposomal doxorubicin in advanced soft tissue and bone sarcoma |
| NCT00093080 | Phase 2 | Completed | 216 | Ridaforolimus (AP23573), a related mTOR inhibitor, in advanced sarcoma (once-daily x5 every 2 weeks regimen) |
| NCT03114527 | Phase 2 | Active, not recruiting | 48 | Ribociclib + everolimus in advanced dedifferentiated liposarcoma and leiomyosarcoma (mTOR inhibitor is everolimus, not sirolimus) |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 39796641 | 2024 | Review | Cancers | Overview of novel therapeutics in soft tissue sarcoma, including targeted and mTOR-pathway agents |
| 37222206 | 2023 | Review | Current Opinion in Oncology | Rationale and trial results for molecular-targeted agents in advanced sarcomas |
| 26518767 | 2016 | Mechanistic | Tumour Biology | Demonstrates Akt-mTOR and MAPK pathway activation in dedifferentiated liposarcoma specimens, supporting mTOR-targeted therapy rationale |
| 16434506 | 2006 | Cohort | J Am Soc Nephrol | Randomised comparison showing sirolimus-based regimens reduce post-transplant malignancy risk versus cyclosporine |
| 37400145 | 2023 | Preclinical | Cancer Genomics & Proteomics | Chloroquine + rapamycin combination shows synergistic antitumour effect in well-differentiated liposarcoma models |
| 36309387 | 2022 | Preclinical (PDX) | In Vivo | Chloroquine + rapamycin arrests tumour growth in a dedifferentiated liposarcoma patient-derived xenograft model |
| 37967116 | 2024 | Phase 2 trial report | Clin Cancer Res | SAR-096 trial: ribociclib + everolimus in dedifferentiated liposarcoma and leiomyosarcoma |
| 26093731 | 2015 | Cohort | Transplantation Proceedings | Cancer screening outcomes in renal transplant patients on long-term immunosuppressive (incl. mTOR inhibitor) therapy |
| 20497911 | 2010 | Review | Bulletin du Cancer | Targeted treatment approaches for rare connective tissue tumours and sarcomas, including mTOR-directed strategies |
| 25519700 | 2015 | Preclinical | Molecular Cancer Therapeutics | MLN0128, an ATP-competitive mTOR kinase inhibitor, shows antitumour activity in bone and soft-tissue sarcoma models |
Safety Considerations
Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme.
Conclusion and Next Steps
Decision: Hold
Rationale: Evidence specific to sirolimus in liposarcoma is currently limited to a single completed, non-randomised Phase 2 trial (NCT02821507); most other supporting trials and literature involve related rapalogues (temsirolimus, everolimus, ridaforolimus) rather than sirolimus itself. Combined with a Blocking-severity data gap on UK/MHRA warnings and contraindications (preventing any safety pre-assessment) and the absence of any current UK marketing authorisation for sirolimus, the evidence base does not yet support proceeding.
To proceed, the following is needed:
- MHRA-sourced SmPC warnings, contraindications and drug interaction data (resolves blocking data gap DG001)
- Confirmed mechanism of action from DrugBank API (resolves DG002)
- Direct sirolimus (rather than class-analogue) trial data in liposarcoma, ideally randomised
- Clarification of UK regulatory pathway, since sirolimus currently has zero UK marketing authorisations recorded
Note for prioritisation: within this same evidence pack, two other predicted indications for sirolimus show materially stronger, more mature evidence — lymphangiomyoma/lung PEComa (L1, Phase 3 MILES trial NCT00414648 underpinning an existing regulatory approval for LAM) and PEComa (L2, supported by the nab-sirolimus AMPECT precedent). These may warrant evaluation ahead of liposarcoma given their more direct and robust evidentiary support.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.