Entinostat as a combinatorial therapeutic for rhabdomyosarcoma

Area of Science:

• Pediatric Oncology
• Cancer Epigenetics
• Soft Tissue Sarcomas

Background:

• Alveolar rhabdomyosarcoma (ARMS) with PAX3::FOXO1 fusion or metastasis has a poor prognosis.
• Metastatic ARMS often relapses with chemotherapy resistance, representing a critical unmet need.
• Chemotherapy resistance is linked to an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit, targetable by HDAC3 inhibition.

Purpose of the Study:

• To investigate the therapeutic efficacy of combining entinostat with chemotherapy in ARMS.
• To evaluate entinostat's potential to overcome chemotherapy resistance in ARMS.

Main Methods:

• Utilized patient-derived xenograft (PDX) models of ARMS.
• Tested combinations of entinostat (HDAC1-3 inhibitor) with relapse-specific chemotherapies.
• Assessed drug interactions as single agent, additive, or synergistic.

Main Results:

• Identified single agent, additive, and synergistic effects between entinostat and chemotherapy in three PAX3::FOXO1+ ARMS models.
• Demonstrated preclinical efficacy of the combination therapy.

Conclusions:

• Preclinical data supports the combination of entinostat with chemotherapy for metastatic ARMS.
• Entinostat, previously shown to be well-tolerated in pediatric trials, warrants further clinical investigation for ARMS treatment.