Personalized pharmacokinetic–pharmacodynamic guided therapy via an induced pluripotent stem cell–derived multi-organoid platform in NF1-mutant breast cancer

TL;DR

A new personalized cancer treatment model uses organoids from stem cells to guide drug therapy for NF1-mutant breast cancer.

Contribution

A multi-organoid platform integrating PK/PD and genomic data enables personalized therapy for NF1-mutant breast cancer.

Findings

The NOCS platform enabled individualized assessment of drug metabolism and excretion.

Paxalisib combined with exon skipping therapy showed synergistic anticancer effects in tumor models.

The approach integrates PK/PD modeling with genotype-driven strategies for precision oncology.

Abstract

Effective precision oncology demands integration of pharmacokinetics/pharmacodynamics (PK/PD) profiling with tumor-specific genomic features. Here, we present a personalized treatment model using a patient-derived Networking Organoid Culture System (NOCS) composed of intestinal, liver, and kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of an NF1-mutant breast cancer patient. This multi-organoid system enabled individualized assessment of drug absorption, distribution, metabolism, and excretion. Integrative genomic and pathway analyses uncovered therapeutic vulnerabilities, including responsiveness to a novel exon skipping therapy targeting NF1. PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts.

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