Dasatinib
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Dasatinib: From Chronic Myeloid Leukemia to Ewing Sarcoma
One-Sentence Summary
Dasatinib is a multi-target tyrosine kinase inhibitor (BCR-ABL, SRC family kinases, c-KIT, PDGFR); the evidence pack's own annotations indicate it is currently approved for chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, though this original-indication field is blank in the source data and should be independently verified. The TxGNN model's top new-indication prediction is Ewing sarcoma, supported by 3 clinical trials and 9 publications, with the strongest clinical trial (Phase 2, n=366) already completed but showing limited single-agent activity.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not provided in evidence pack (drug.original_indications is empty). Contextual notes in the pack's own rationale text describe dasatinib as a BCR-ABL kinase inhibitor used for CML/Ph+ ALL — this needs independent verification against TFDA/DrugBank before use, since it is inconsistent with the "not marketed" status below (see Data Quality Note) |
| Predicted New Indication | Ewing sarcoma |
| TxGNN Prediction Score | 99.90% (score 0.9990, global rank 1,687) |
| Evidence Level | L2 |
| Germany Market Status | Not marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed original mechanism-of-action data is not available in this evidence pack (original_moa: Data Gap). However, the supporting literature and the pack's own repurposing rationale describe dasatinib as a multi-kinase inhibitor that blocks Src-family kinases (SRC/LCK/YES/FYN) in addition to BCR-ABL, c-KIT, and PDGFR.
Ewing sarcoma tumor cells depend heavily on Src signaling — downstream of the disease-defining EWS-FLI1 fusion — for invasion, migration, and invadopodia formation. In vitro studies (PMID 17363602, PMID 18202781) demonstrate that dasatinib inhibits proliferation and migration in bone-sarcoma cell lines through this pathway, giving a plausible mechanistic bridge from dasatinib's known kinase-inhibitory activity to Ewing sarcoma biology.
Clinically, this mechanistic rationale has already been tested: a completed Phase 2 trial in advanced sarcomas (NCT00464620, n=366) included an Ewing sarcoma cohort, but single-agent dasatinib showed limited activity and did not reach the expected response rate. This tempers the otherwise strong mechanistic case and is the main reason the evidence level is capped at L2 rather than higher.
Data Quality Note: The rank-2 prediction (myeloid leukemia) in this same evidence pack flags an internal inconsistency — original_indications is empty and market_status is "not marketed," which does not match dasatinib's well-established approval history for CML. This suggests a possible field-mapping gap in the source database for this drug record. This should be resolved before the "Original Indication" field above is finalized.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00464620 | Phase 2 | Completed | 366 | Response rate and 6-month PFS of dasatinib in advanced sarcomas, including an Ewing sarcoma cohort; single-agent activity was limited and did not meet the expected response rate. |
| NCT00788125 | Phase 1/2 | Terminated | 7 | Pediatric trial of dasatinib combined with ifosfamide/carboplatin/etoposide; terminated with only 7 patients enrolled, limited evidentiary value. |
| NCT06500819 | Phase 1 | Recruiting | 41 | Tests B7-H3 CAR-T cell therapy in relapsed/refractory solid tumors (including Ewing sarcoma population); not a dasatinib trial, only population-level overlap. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 18202781 | 2008 | Preclinical/In vitro | Oncology Reports | Dasatinib shows antiproliferative and antimigratory activity in neuroblastoma and Ewing sarcoma cell lines, consistent with c-KIT/PDGFR/Src involvement. |
| 17363602 | 2007 | Preclinical/In vitro | Cancer Research | Dasatinib inhibits migration/invasion across diverse sarcoma cell lines and induces apoptosis in Src-dependent bone sarcoma cells. |
| 35655525 | 2022 | Preclinical/Mechanistic | Sarcoma | Reviews FAK-Src complex targeting in DSRCT, Ewing sarcoma, and rhabdomyosarcoma; notes dasatinib failed as monotherapy in a Phase 2 study of these subtypes, motivating combination strategies. |
| 31521948 | 2019 | Preclinical/Mechanistic | Neoplasia | Tenascin C and Src cooperate to drive invadopodia formation and invasion in Ewing sarcoma cells under microenvironmental stress. |
| 27566104 | 2016 | Preclinical/Mechanistic | Neoplasia | Microenvironmental stress induces Src-dependent invadopodia activation and migration in Ewing sarcoma. |
| 26170970 | 2015 | Review | Oncology Letters | General review of Src signaling's role in sarcoma biology and its feasibility as a drug target. |
| 35190971 | 2022 | Review (indirect — chondrosarcoma) | Current Treatment Options in Oncology | Systemic therapy review for chondrosarcoma, not Ewing sarcoma specifically; included for background only, low direct relevance. |
Note: 2 additional literature hits returned by the search (PMID 29776413 — plerixafor, not dasatinib; PMID 32999666 — unrelated CML case report) were excluded from this table as not substantively relevant to the dasatinib–Ewing sarcoma question.
Germany Market Information
Dasatinib is currently not marketed in Germany under this evidence pack (0 authorizations on record; market_status: "未上市"). No license records are available to summarize.
Cytotoxicity
Dasatinib is an oncology/antineoplastic agent (tyrosine kinase inhibitor class, referenced in this pack's own rationale as a treatment for CML/Ph+ ALL), so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (BCR-ABL / Src-family kinase inhibitor, tyrosine kinase inhibitor class) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Please refer to the package insert for safety information. (key_warnings, contraindications, and DDI data are all unavailable in this evidence pack — DG001, labeled "Blocking" severity, explicitly prevents proceeding to the S1 safety assessment stage.)
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic rationale (Src-dependent invasion in Ewing sarcoma) is credible and supported by in vitro data, but the only relevant clinical trial (Phase 2, n=366) already showed limited single-agent efficacy, and no dedicated Ewing sarcoma trial data exists. Combined with a Blocking data gap on TFDA labeling/safety information (DG001), the candidate cannot proceed past S1.
To proceed, the following is needed:
- TFDA package insert (warnings, contraindications) — required to clear the S1 safety gate (DG001)
- Confirmed mechanism-of-action data from DrugBank (DG002)
- Resolution of the
original_indications/market_statusdata inconsistency flagged above, so the true original indication and current authorization status can be confirmed - If pursued further, evaluation should focus on combination regimens (e.g., with chemotherapy or FAK inhibitors) rather than dasatinib monotherapy, given the negative single-agent signal in NCT00464620
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.