Dasatinib
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Dasatinib: From Leukemia (CML) to Ewing Sarcoma
One-Sentence Summary
Dasatinib is a second-generation multi-targeted tyrosine kinase inhibitor (TKI), originally established for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) leukemia through potent inhibition of the BCR-ABL1 oncoprotein. The TxGNN model predicts it may be effective for Ewing Sarcoma, with 3 clinical trials and 9 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic myeloid leukemia (CML) / Ph+ leukemia (no Canadian DIN record available) |
| Predicted New Indication | Ewing Sarcoma |
| TxGNN Prediction Score | 99.90% |
| Evidence Level | L2 |
| Canada Market Status | Not marketed |
| Number of DINs | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available from the Canadian regulatory record. Based on known published information, dasatinib is a small-molecule TKI that inhibits BCR-ABL1, Src family kinases (SFKs), c-KIT, and PDGFR-β at nanomolar concentrations — approximately 325-fold more potent than imatinib against BCR-ABL1 in vitro. Its established role in CML and Ph+ ALL is driven primarily by BCR-ABL1 inhibition; however, the concurrent inhibition of Src family kinases provides a mechanistic bridge to solid tumour indications where SFK signalling is pathologically activated.
Ewing sarcoma is a highly aggressive bone and soft-tissue malignancy most commonly diagnosed in adolescents and young adults. A defining feature of Ewing sarcoma biology is its dependence on Src kinase activation under microenvironmental stress (hypoxia, nutrient deprivation), which drives invadopodia formation, cellular invasion, and metastatic spread. Multiple preclinical studies spanning 2007–2022 directly demonstrate that dasatinib inhibits the Src/FAK signalling complex in Ewing sarcoma cell lines, reducing migration and invasion while inducing apoptosis in cells dependent on SRC for survival. The FAK-Src inhibitory axis has been validated across multiple sarcoma subtypes sharing mesenchymal origin with Ewing sarcoma.
Although dasatinib showed limited activity as a single agent in the completed Phase 2 SARC019 trial (NCT00464620; broad advanced sarcoma population), the mechanistic rationale for combination approaches — particularly with DNA-damaging chemotherapy (ifosfamide, carboplatin, etoposide) — remains scientifically compelling. The early termination of the paediatric Phase I/II combination trial (NCT00788125) was attributable to low enrolment rather than safety signals, leaving the combination hypothesis open for further exploration in relapsed or refractory paediatric Ewing sarcoma.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00464620 | Phase 2 | Completed | 366 | Large-scale multi-sarcoma trial evaluating dasatinib monotherapy for 6-month progression-free survival and response rate; includes Ewing sarcoma patients; results indicate limited single-agent activity in sarcomas overall |
| NCT00788125 | Phase 1/2 | Terminated | 7 | Paediatric sarcoma trial (including Ewing sarcoma) combining dasatinib with ifosfamide, carboplatin, and etoposide; terminated early due to enrolment challenges (7 patients enrolled), not safety concerns; provides preliminary dose and safety reference data |
| NCT06500819 | Phase 1 | Recruiting | 41 | B7-H3 CAR-T cell therapy in relapsed/refractory paediatric solid tumours including Ewing sarcoma; not dasatinib-based — reflects active therapeutic exploration in this indication but provides no direct evidence for dasatinib |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 17363602 | 2007 | Preclinical (in vitro) | Cancer Research | Seminal study demonstrating dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis specifically in bone sarcoma cells dependent on SRC kinase for survival |
| 18202781 | 2008 | Preclinical (in vitro) | Oncology Reports | Direct demonstration of dasatinib antiproliferative and antimigratory activity in Ewing sarcoma and neuroblastoma cell lines; implicates c-KIT and PDGFR inhibition as contributing mechanisms |
| 35655525 | 2022 | Translational Review | Sarcoma | Evaluation of FAK-Src complex targeting in Ewing sarcoma, DSRCT, and rhabdomyosarcoma; single-agent dasatinib failed in Phase 2, but combination strategies with FAK inhibitors show synergistic preclinical activity |
| 27566104 | 2016 | Preclinical (in vitro/in vivo) | Neoplasia | Microenvironmental stress (hypoxia, nutrient deprivation) activates Src in Ewing sarcoma cells, driving invadopodia formation and migration — a pathway directly targetable by dasatinib |
| 31521948 | 2019 | Preclinical | Neoplasia | Tenascin C and Src cooperate under microenvironmental stress to promote invadopodia formation in Ewing sarcoma; supports Src inhibition as a mechanistically grounded anti-metastatic strategy |
| 26170970 | 2015 | Review | Oncology Letters | Comprehensive review of Src kinase overexpression and activation across sarcoma subtypes; validates Src as a viable therapeutic target and provides mechanistic context for dasatinib repurposing |
| 35190971 | 2022 | Review | Curr Treatment Options Oncol | Systemic therapy review for chondrosarcoma; discusses TKI approaches across mesenchymal tumours and notes the role of antiangiogenic therapy, providing peripheral mechanistic context |
| 29776413 | 2018 | Preclinical | Cell Commun Signal | CXCR4 antagonist plerixafor activates receptor tyrosine kinase signalling in Ewing sarcoma; illustrates complex signalling network cross-talk relevant to understanding combination targeting strategies |
Canada Market Information
Dasatinib currently has no Drug Identification Numbers (DINs) on record and is not approved or marketed in Canada. No regulatory licence data is available for this drug in the Canadian market at this time. Reference to international regulatory filings (FDA, EMA) would be required for safety and indication documentation.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy — multi-targeted tyrosine kinase inhibitor (BCR-ABL1 / Src family kinases / c-KIT / PDGFR-β inhibitor); not a conventional cytotoxic agent |
| Myelosuppression Risk | Moderate to High — neutropenia, thrombocytopenia, and anaemia are commonly reported adverse effects; haematological monitoring is essential |
| Emetogenicity Classification | Low (oral TKI; minimal direct emetogenic potential relative to conventional cytotoxics) |
| Monitoring Items | CBC with differential (baseline and periodic), liver function tests (ALT/AST/bilirubin), renal function, fluid retention assessment, pleural effusion monitoring (chest X-ray or CT), ECG/QTc interval at baseline, pulmonary function if respiratory symptoms arise |
| Handling Protection | Follow institutional oral chemotherapy handling protocols; cytotoxic precautions apply for preparation and disposal per applicable guidelines |
Safety Considerations
Please refer to the package insert for safety information.
Note from published literature: Clinically significant adverse events reported with dasatinib in leukemia populations include pleural effusion (most common fluid-related toxicity), pulmonary hypertension, pericardial effusion, chylothorax (rare), and interstitial pneumonitis. These risks — while characterised primarily in adult CML patients — should be proactively considered when evaluating dasatinib in paediatric Ewing sarcoma populations given the different physiological context. Formal safety data from the Canadian regulatory package insert is not currently available.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: One large-scale completed Phase 2 trial (NCT00464620; n=366) evaluated dasatinib in advanced sarcomas inclusive of Ewing sarcoma, and a convergent body of preclinical evidence (2007–2022) directly validates the Src/FAK pathway as a mechanistically sound target in Ewing sarcoma biology. While single-agent activity appears insufficient, the scientific rationale for combination approaches is compelling and remains incompletely tested clinically.
To proceed, the following is needed:
- Subgroup analysis data for Ewing sarcoma patients from NCT00464620 to quantify dasatinib’s single-agent activity in this specific population
- Formal MOA documentation from DrugBank or a primary regulatory dossier (currently a data gap)
- Canadian regulatory pathway assessment — Health Canada marketing authorisation or Special Access Programme (SAP) eligibility review, given no current DIN
- Design of a prospective combination trial (e.g., dasatinib + ifosfamide/carboplatin/etoposide) with a paediatric-appropriate enrolment strategy and defined safety monitoring plan
- Pharmacokinetic data in paediatric patients to support dosing optimisation in the Ewing sarcoma setting
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.