Sirolimus

證據等級: L5

預測適應症: 10 個

Sirolimus: From Organ Transplant Rejection to Liposarcoma

One-Sentence Summary

Sirolimus (rapamycin) is an mTOR inhibitor globally established for prevention of organ rejection in renal transplant recipients, with no current Italy market authorization. The TxGNN model predicts it may be effective for Liposarcoma, with a prediction score of 99.89%. This direction is currently supported by 5 clinical trials and 12 publications, including one completed Phase 2 trial directly using sirolimus in myxoid liposarcoma.

Quick Overview

Item	Content
Original Indication	Organ transplant rejection prevention (no Italy regulatory data available)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.89%
Evidence Level	L2
Italy Market Status	✗ Not marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Sirolimus (rapamycin) is a macrolide compound and the prototype mTOR inhibitor. It functions by binding intracellularly to FKBP12; the resulting complex then binds to and allosterically inhibits mTORC1, blocking downstream effectors S6K1 and 4EBP1. This arrests the cell cycle at G1 phase, suppresses cap-dependent protein translation, and inhibits tumor cell proliferation and angiogenesis. While detailed MOA documentation was not available in the regulatory database queried, sirolimus's mechanism as a direct mTOR inhibitor is extensively characterized in the scientific literature, and all mechanistic rationale below is drawn from published evidence.

Dedifferentiated liposarcoma (DDLPS) is characterized by high-frequency activation of the Akt-mTOR and MAPK signaling pathways, confirmed by immunohistochemical analysis across 99 DDLPS specimens (PMID 26518767). This aberrant pathway activation directly implicates mTORC1 as a therapeutic target. In patient-derived orthotopic xenograft (PDOX) animal models, rapamycin in combination with the autophagy inhibitor chloroquine demonstrated synergistic tumor growth arrest in both well-differentiated and dedifferentiated liposarcoma (PMID 37400145, PMID 36309387), mechanistically linking mTOR inhibition to tumor control in this specific histology.

Most importantly, the completed Phase 2 trial NCT02821507 directly evaluated the combination of sirolimus and cyclophosphamide in 70 patients with metastatic or unresectable myxoid liposarcoma and chondrosarcoma—the most direct available clinical evidence. Four additional trials tested mTOR inhibitor analogs (temsirolimus, ridaforolimus, everolimus) across broader sarcoma populations, consistently demonstrating class-level antiproliferative activity. The convergence of molecular, preclinical, and clinical evidence makes the TxGNN prediction mechanistically sound.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02821507	Phase 2	Completed	70	Direct sirolimus trial: Sirolimus + cyclophosphamide in metastatic/unresectable myxoid liposarcoma and chondrosarcoma; mTOR inhibition shown to prevent tumor growth in in vivo mouse models; highest-grade direct evidence
NCT00093080	Phase 2	Completed	216	Ridaforolimus (mTOR inhibitor) administered 5 days/2-week cycle in advanced sarcoma; largest Phase 2 cohort validating mTOR class efficacy across sarcoma subtypes
NCT01614795	Phase 2	Completed	46	Cixutumumab (anti-IGF-1R) + temsirolimus in pediatric recurrent/refractory sarcoma; dual-pathway mTOR + IGF-1R targeting; provides safety and preliminary efficacy reference
NCT00949325	Phase 1/2	Completed	24	Temsirolimus + liposomal doxorubicin in recurrent sarcoma; established safe dosing and early efficacy signals for mTOR inhibitor combination strategies
NCT03114527	Phase 2	Active, not recruiting	48	Ribociclib + everolimus in advanced dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS); CDK4/6 + mTOR co-inhibition; DDL subtype precisely matches liposarcoma target population

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37967116	2024	Phase 2 Trial Report	Clinical Cancer Research	SAR-096: Ribociclib + everolimus in advanced DDLPS and LMS; reports anti-tumor activity of mTOR + CDK4/6 dual inhibition in the exact liposarcoma subtype of interest
37400145	2023	Preclinical/Translational	Cancer Genomics & Proteomics	Rapamycin + chloroquine synergistically inhibits autophagy and induces apoptosis in well-differentiated liposarcoma; preclinical validation of sirolimus + autophagy inhibitor strategy
36309387	2022	PDOX Animal Model	In Vivo	Rapamycin + chloroquine arrests tumor growth in a DDLPS patient-derived orthotopic xenograft (PDOX) model; demonstrates translational relevance of mTOR inhibition in DDLPS
26518767	2016	Mechanistic/Molecular	Tumour Biology	Akt-mTOR and MAPK pathway activation confirmed in 99 DDLPS specimens by immunohistochemistry; in vitro antitumor effect of mTOR inhibitor demonstrated; core mechanistic evidence
25519700	2015	Preclinical	Molecular Cancer Therapeutics	MLN0128 (ATP-competitive mTOR kinase inhibitor blocking both mTORC1/2) shows potent in vitro and in vivo antitumor activity in bone and soft-tissue sarcoma models; highlights limitations of first-generation rapalogs
39796641	2024	Review	Cancers	Comprehensive overview of novel therapeutics in soft tissue sarcoma, including FDA-approved TKIs and emerging mTOR inhibitor combination strategies
37222206	2023	Review	Current Opinion in Oncology	Rationale and results of recent clinical trials with molecular-targeted agents for advanced sarcomas; contextualizes mTOR inhibition within the sarcoma treatment landscape
16434506	2006	Clinical Cohort	JASN	Sirolimus after cyclosporine withdrawal in renal transplant patients significantly reduces cancer incidence; demonstrates sirolimus's intrinsic antiproliferative/anti-cancer properties in a clinical population
26093731	2015	Clinical Review	Transplantation Proceedings	Immunosuppressive drug effects on malignancy in long-term transplant patients; sirolimus's differential cancer-protective profile vs. calcineurin inhibitors
20497911	2010	Review	Bulletin du Cancer	Molecular classification of rare connective tissue tumors and sarcomas with specific alterations; provides biological framework for mTOR inhibitor targeting in sarcoma subgroups

Italy Market Information

Sirolimus currently has no marketing authorizations in Italy. There are no approved products, dosage forms, or licensed indications on record with AIFA.

Any use in Italy would require either a compassionate use application (uso compassionevole) under AIFA regulations or enrollment in an authorized clinical trial.

Cytotoxicity

Sirolimus belongs to the rapalog class of targeted antineoplastic agents. Although not a conventional cytotoxic drug, its analogs (temsirolimus, everolimus) are FDA- and EMA-approved antineoplastics, and sirolimus itself is used in oncological contexts (FDA-approved for LAM; nab-sirolimus approved for malignant PEComa). The following applies when used in a cancer treatment setting:

Item	Content
Cytotoxicity Classification	Targeted therapy — mTOR inhibitor (rapalog class); not a conventional cytotoxic agent
Myelosuppression Risk	Low to moderate — anemia and thrombocytopenia reported; leucopenia less common; significantly less myelotoxic than conventional chemotherapy
Emetogenicity Classification	Low
Monitoring Items	CBC with differential, serum creatinine and eGFR, liver function tests (AST/ALT/bilirubin), fasting lipid panel (triglycerides, total cholesterol), fasting glucose, sirolimus whole-blood trough levels
Handling Protection	Standard oncology handling precautions; cytotoxic drug handling protocols recommended in the cancer treatment setting

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: The completed Phase 2 trial NCT02821507 directly testing sirolimus in myxoid liposarcoma (n=70), combined with a strong mechanistic basis (confirmed mTOR pathway activation in DDLPS), extensive mTOR inhibitor class-effect data across sarcoma subtypes, and a TxGNN score of 99.89% (L2 evidence), provides sufficient grounds to advance—but the absence of Italy regulatory authorization and the lack of published trial results from NCT02821507 require protective guardrails before any clinical deployment.

To proceed, the following is needed:

Obtain and review published results from NCT02821507 (sirolimus + cyclophosphamide in myxoid liposarcoma) to confirm efficacy magnitude and safety profile
Retrieve full mechanism of action data from DrugBank API (DG002 remediation) to formalize the MOA rationale section
Assess AIFA pathway for sirolimus authorization in Italy — compassionate use (uso compassionevole, L. 648/96) or investigator-initiated trial (IIT) application
Develop a patient selection protocol specifying liposarcoma histological subtype (myxoid vs. dedifferentiated vs. well-differentiated) and molecular profiling criteria (mTOR pathway activation status)
Design a sirolimus therapeutic drug monitoring (TDM) plan with target trough blood levels and safety stopping rules
Consult with a sarcoma specialist and clinical pharmacologist before initiating any off-label use
Disclaimer

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