Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Targeted therapies offer promise for cancer treatment but require robust efficacy testing.
• Personalized medicine necessitates methods to predict individual patient responses to therapy.
• Patient-derived xenografts (PDX) are valuable preclinical models for cancer research.

Purpose of the Study:

• To develop and validate an integrated approach for testing targeted therapy efficacy.
• To combine next-generation sequencing (NGS) with PDX models for drug response prediction.
• To aid personalized treatment strategies for patients with recurrent or refractory cancers.

Main Methods:

• Utilized mate-pair next-generation sequencing (MPseq) to identify structural and targetable genomic alterations.
• Grew patient-derived tumors in immunocompromised mice to create PDX models.
• Treated PDX models with drugs selected based on genomic analyses and monitored therapeutic response.

Main Results:

• Demonstrated a strong correlation between predicted and observed drug responses in PDX models.
• Successfully identified potentially targetable alterations using MPseq.
• Validated the efficacy testing strategy using ovarian tumors as a model system.

Conclusions:

• The presented integrative approach effectively tests targeted therapy efficacy in a preclinical setting.
• This strategy can guide personalized treatment decisions, including combination therapies and off-label drug use.
• The method holds potential for improving outcomes in patients with difficult-to-treat recurrent cancers.