# 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.

## Key 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.