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Drugging the undruggable: early phase trial shows trabectedin and low-dose irinotecan downregulate EWSR1::FLI1 and

David S Shulman1, Katherine A Janeway1

  • 1Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Trends in Cancer
|August 21, 2026
PubMed

Insights

Targeting transcription factor fusion-positive cancers like Ewing sarcoma remains difficult. A study shows that specific doses of trabectedin and irinotecan effectively treat advanced Ewing sarcoma by reducing EWSR1::FLI1 activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Transcription factor fusion-positive cancers, such as Ewing sarcoma, present significant therapeutic challenges.
  • The EWSR1::FLI1 fusion is a hallmark of Ewing sarcoma, driving tumor development.
  • Developing effective targeted therapies for these cancers is a critical unmet need.

Purpose of the Study:

  • To evaluate the efficacy of histology-specific dosing of trabectedin and low-dose irinotecan in advanced Ewing sarcoma.
  • To investigate the impact of this combination therapy on EWSR1::FLI1 activity.
  • To explore novel therapeutic strategies for transcription factor fusion-driven malignancies.

Main Methods:

  • The study involved patients with advanced Ewing sarcoma treated with a specific regimen of trabectedin and irinotecan.
  • Histology-specific dosing was employed based on tumor characteristics.
  • EWSR1::FLI1 activity was assessed to determine the molecular effects of the treatment.

Main Results:

  • The combination of trabectedin and low-dose irinotecan demonstrated clinical activity in advanced Ewing sarcoma.
  • Histology-specific dosing was found to be crucial for treatment efficacy.
  • The regimen successfully downregulated EWSR1::FLI1 activity, indicating a targeted effect.

Conclusions:

  • Trabectedin and low-dose irinotecan, when administered with histology-specific dosing, represent an active treatment for advanced Ewing sarcoma.
  • This approach offers a promising strategy for targeting EWSR1::FLI1 activity in Ewing sarcoma.
  • Further research into targeted therapies for transcription factor fusion-positive cancers is warranted.

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