Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical...

Area of Science:

• Pharmacology and Oncology
• Pediatric Cancer Research
• Drug Discovery and Development

Background:

• Volasertib (BI 6727) is a potent Polo-like kinase 1 (Plk1) inhibitor.
• Plk1 is overexpressed in various childhood cancers, making it a therapeutic target.
• Volasertib was evaluated using the Pediatric Preclinical Testing Program (PPTP) due to its novel mechanism.

Purpose of the Study:

• To assess the in vitro and in vivo efficacy of volasertib against a panel of childhood cancer models.
• To determine the anti-cancer activity of volasertib in solid tumors and acute lymphoblastic leukemia (ALL) models.
• To evaluate the potential clinical relevance of volasertib based on preclinical data.

Main Methods:

• In vitro testing of volasertib against PPTP cell lines across a concentration range (0.1 nM to 1.0 microM).
• In vivo xenograft studies in solid tumor and ALL models using specific dosing and schedules (IV, 30 mg/kg or 15 mg/kg, q7dx3).
• Evaluation of efficacy based on median relative IC50, event-free survival (EFS), tumor growth inhibition (T/C ratio), and objective responses (CRs).

Main Results:

• Volasertib exhibited potent in vitro cytotoxic activity with a median relative IC50 of 14.1 nM.
• Significant EFS differences were observed in 59% of solid tumor and 50% of ALL xenografts.
• Tumor growth inhibition and objective responses (complete regressions) were noted in several solid tumor and ALL models, including neuroblastoma and glioblastoma.

Conclusions:

• Volasertib demonstrates significant in vitro and in vivo anti-cancer activity against a broad range of childhood cancer models without histotype selectivity.
• Observed tumor regressions in vivo suggest therapeutic potential.
• Pharmacokinetic data indicate higher drug exposure in mice than humans, potentially overestimating clinical efficacy in pediatric cancers.