Ex vivo drug sensitivity profiling to complement molecular profiling in pediatric precision oncology

Area of Science:

• Oncology
• Pharmacology
• Translational Medicine

Background:

• High-risk pediatric extra-cranial solid tumors have poor prognoses with survival rates below 50%.
• Molecular profiling alone is often insufficient for guiding treatment decisions during tumor relapse.
• Novel strategies are needed to rapidly assess drug sensitivities in pediatric cancers.

Purpose of the Study:

• To evaluate short-term ex vivo drug screening as a rapid and reliable method for assessing drug sensitivities in pediatric solid tumors.
• To determine the feasibility and consistency of ex vivo drug screening across multiple institutions.
• To identify effective compounds and therapeutic strategies for pediatric solid tumors, particularly in cases lacking targetable alterations.

Main Methods:

• Utilized ex vivo cultures derived from established patient-derived xenograft (PDX) models of pediatric solid tumors.
• Performed drug screening within 14 days of sample receipt, testing 77-224 compounds per sample.
• Ensured consistency and reproducibility by conducting experiments across two institutes and using replicate models.

Main Results:

• Ex vivo drug screening demonstrated consistent drug responses across institutes and reproducibility in replicate models.
• Observed tumor type-specific drug sensitivities, with neuroblastoma showing correlations between transcriptomic changes and ALK-inhibitor response, independent of ALK-mutation status.
• Identified effective drug 'hits' in 94% of screens, expanding treatment options for 88% of cases lacking targetable alterations and refining compound choices when targetable events were present.

Conclusions:

• Ex vivo drug screening is a fast, feasible, and reliable method for assessing compound efficacy in pediatric solid tumors.
• This approach provides valuable insights for identifying functional treatment suggestions, especially for tumors without known targetable alterations.
• Recommends integrating ex vivo drug screening into future next-generation diagnostic platforms for pediatric solid tumors, alongside genomics and transcriptomics.