Dasatinib

證據等級: L5

預測適應症: 10 個

Dasatinib: From Chronic Myeloid Leukemia to Ewing Sarcoma

One-Sentence Summary

Dasatinib (Sprycel®) is a second-generation tyrosine kinase inhibitor (TKI) originally approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, working by blocking the BCR-ABL fusion kinase that drives these blood cancers.

The TxGNN model predicts it may be effective for Ewing Sarcoma, with 3 clinical trials and 9 publications currently supporting this direction. However, most evidence remains at the preclinical stage, and the single completed sarcoma trial enrolled all advanced sarcoma subtypes rather than Ewing sarcoma exclusively.

Quick Overview

Item	Content
Original Indication	Chronic Myeloid Leukemia (CML), Ph+ Acute Lymphoblastic Leukemia
Predicted New Indication	Ewing Sarcoma
TxGNN Prediction Score	99.90%
Evidence Level	L2
Singapore Market Status	✗ Not Registered
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available from this Evidence Pack. Based on known pharmacological information, Dasatinib is a small-molecule, orally bioavailable multi-kinase inhibitor that potently blocks BCR-ABL, Src family kinases (SFKs), c-KIT, and PDGFR-β. Its primary clinical approval is built on BCR-ABL inhibition in CML, but its Src kinase inhibitory activity creates a compelling mechanistic bridge to Ewing sarcoma biology.

Ewing sarcoma is a highly aggressive bone and soft tissue malignancy predominantly driven by the EWS-FLI1 fusion oncoprotein, which dysregulates downstream signaling pathways including the Src/FAK axis. Multiple preclinical studies from 2007 to 2022 have demonstrated that Ewing sarcoma cells are heavily dependent on Src kinase activity for migration, invasion, and survival — particularly under tumor microenvironmental stress conditions such as hypoxia and nutrient deprivation. Dasatinib has been shown to block invadopodia formation, inhibit Src-dependent cell migration, reduce proliferation, and induce apoptosis in Ewing sarcoma cell lines. The EWS-FLI1 fusion protein may additionally upregulate Src signaling, further reinforcing this mechanistic rationale.

Although CML and Ewing sarcoma are fundamentally different diseases (hematologic vs. bone/soft tissue malignancy), their shared dependency on Src-family kinase signaling provides a biologically plausible basis for repurposing. The TxGNN model's high prediction score (99.90%) likely reflects this Src-axis convergence captured within the knowledge graph. Notably, the largest sarcoma-specific dasatinib trial (NCT00464620, n=366) included Ewing sarcoma patients as part of an advanced sarcoma cohort, and Ewing sarcoma-specific subgroup results have not been separately published — representing the key evidence gap to resolve.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00464620	Phase 2	Completed	366	Dasatinib monotherapy in advanced sarcomas (all subtypes including Ewing); evaluated response rate and 6-month progression-free survival — the largest single dasatinib sarcoma trial to date, but Ewing-specific subgroup data not separately reported
NCT00788125	Phase 1/2	Terminated	7	Pediatric trial of dasatinib combined with ICE chemotherapy (ifosfamide/carboplatin/etoposide); terminated early with only 7 patients enrolled, yielding limited safety data for the combination and no efficacy conclusions
NCT06500819	Phase 1	Recruiting	41	B7-H3 CAR-T cell therapy in pediatric relapsed/refractory solid tumors including Ewing sarcoma; not a dasatinib trial — included to reflect the broader landscape of novel agents being tested in this indication

Literature Evidence

PMID	Year	Type	Journal	Key Findings
18202781	2008	Preclinical (In vitro/In vivo)	Oncology Reports	Direct demonstration of dasatinib antiproliferative and antimigratory activity in Ewing sarcoma cell lines; c-KIT and PDGFR identified as relevant molecular targets in this tumor type
17363602	2007	Preclinical (In vitro)	Cancer Research	Dasatinib inhibits migration and invasion across diverse human sarcoma cell lines and induces apoptosis specifically in bone sarcoma cells that are Src-kinase dependent for survival
35655525	2022	Preclinical (Translational)	Sarcoma	Targeting the FAK-Src complex in Ewing sarcoma and related round cell sarcomas; dasatinib single-agent activity was insufficient, supporting combination strategies as the next step
31521948	2019	Preclinical (In vitro)	Neoplasia	Tenascin C and Src kinase cooperate under microenvironmental stress to drive invadopodia formation and invasion in Ewing sarcoma — dasatinib-targetable mechanism
27566104	2016	Preclinical (In vitro)	Neoplasia	Microenvironmental stress (hypoxia, nutrient deprivation) induces Src-dependent invadopodia activation and cell migration in Ewing sarcoma, identifying a stress-response vulnerability
26170970	2015	Review	Oncology Letters	Comprehensive review of Src signaling biology in sarcoma subtypes; positions Src inhibition — and by extension dasatinib — as a rational therapeutic strategy
29776413	2018	Preclinical (In vitro)	Cell Communication and Signaling	CXCR4 antagonist plerixafor activates receptor tyrosine kinase signaling in Ewing sarcoma cells, highlighting crosstalk between microenvironmental pathways and Src-related signaling axes
35190971	2022	Clinical Review	Current Treatment Options in Oncology	Review of systemic therapy approaches in sarcomas, including discussion of antiangiogenic and TKI strategies; provides contextual framing for dasatinib's role in the broader sarcoma landscape

Singapore Market Information

Dasatinib is currently not registered with the Health Sciences Authority (HSA) of Singapore. No product authorizations or approved indications are on record.

Dasatinib (Sprycel®, Bristol-Myers Squibb) is approved in major markets globally — including the US (FDA, 2006), EU (EMA), and Japan (PMDA) — for CML and Ph+ ALL. Access in Singapore would require an HSA Special Access Route (SAR) application under the Therapeutic Products Act for unregistered medicinal products.

Cytotoxicity

Item	Content
Cytotoxicity Classification	Targeted therapy — BCR-ABL / Src family kinase inhibitor (second-generation TKI); not a conventional cytotoxic agent
Myelosuppression Risk	Moderate — cytopenias (neutropenia, thrombocytopenia, anemia) are common class effects; Grade 3/4 neutropenia reported in approximately 21–36% of CML patients in pivotal trials
Emetogenicity Classification	Low — oral TKI with minimal intrinsic emetogenic potential; nausea is typically mild and manageable without prophylactic antiemetics
Monitoring Items	Complete blood count with differential (weekly for the first 2 months, then monthly thereafter), liver function tests, renal function, serum electrolytes, ECG for QTc assessment, and chest imaging for pleural effusion surveillance
Handling Protection	Standard oral cytotoxic handling precautions apply; closed-system transfer devices recommended if tablets require manipulation; disposal according to local cytotoxic waste regulations

Safety Considerations

Please refer to the package insert for safety information.

No Singapore/Taiwan regulatory package insert data, contraindications, or drug interaction records were available in this Evidence Pack. Known class-associated concerns for dasatinib — based on global regulatory labels — include pleural effusion (occurring in approximately 20–35% of patients), pulmonary arterial hypertension, QTc prolongation, hepatotoxicity, and embryofetal toxicity (Pregnancy Category D). Consultation of the FDA-approved Sprycel® Prescribing Information or EMA Summary of Product Characteristics is strongly recommended prior to any clinical use.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: The TxGNN prediction for dasatinib in Ewing sarcoma is mechanistically coherent and supported by a consistent body of preclinical evidence spanning 15 years (2007–2022), all pointing to Src/FAK-axis dependency as a therapeutically exploitable vulnerability. A completed Phase 2 trial (n=366) has evaluated dasatinib in advanced sarcomas including Ewing patients, reaching L2 evidence level — but Ewing sarcoma-specific efficacy outcomes have not been separately reported, which represents the primary bottleneck before any clinical translation decision can be made.

To proceed, the following is needed:

Obtain subgroup efficacy data from NCT00464620 specifically for the Ewing sarcoma patient cohort (contact investigators or review conference abstracts)
Retrieve the full Sprycel® prescribing information (FDA USPI or EMA SmPC) for complete contraindications, black box warnings, and drug interaction profile
Query DrugBank API to formally confirm mechanism of action and target binding profile (flagged as a high-severity data gap)
Evaluate HSA Singapore Special Access Route eligibility if clinical use is contemplated
Consider designing a Ewing sarcoma-specific biomarker-selected pilot study or basket trial incorporating Src phosphorylation status and EWS-FLI1 fusion confirmation as stratification criteria
Assess potential combination partners — preclinical data suggest dasatinib as monotherapy may be insufficient; synergistic combinations with standard-of-care VDC/IE backbone or emerging agents warrant exploration
Disclaimer

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