Method Profile
Link patient-background intestinal, liver and renal models to tumor spheroids and compare exposure with pharmacodynamic effects.
Exploratory PK–PD comparison and RNA exon-skipping assessment in one NF1-mutant breast-cancer background.
One selected patient’s fibroblast-derived iPSC intestinal and liver organoid derivatives and renal epithelium, plus separately tissue-derived tumor/matched normal spheroids. One healthy fibroblast-derived iPSC background is the main reference.
Four connected compartments maintained structurally for four days. Apical intestinal or metabolism-compartment 10 μM dosing, LC-MS/MS sampling through 72 hours and separate tumor/organ-response experiments.
Disposition and response measurements
Concentration–time profiles, AUC/half-life, tumor IC50, organ viability, electrical barrier resistance and stress-associated markers. Mouse PK is an external comparator, not measured patient plasma PK.
Interventions
Direct and linked-system comparison of PI3K/mTOR-pathway agents; lentiviral U7 small nuclear RNA expression of antisense sequences to induce NF1 exon-2 skipping and restore protein. Paxalisib 10 μM for 72 hours in organ-response experiments.
Compare direct potency with disposition-informed ranking. Keep the direct-screen paxalisib IC50 of 19.4 μM distinct from the separate antisense experiment’s shift from 16 to 1.2 μM.
One personalized patient system and one healthy iPSC background. The initial broader breast-culture effort used fourteen biospecimens and yielded five cultures maintained beyond passage five.
Healthy reference, different dosing routes/agents, control versus NF1 exon skipping, and separate mouse experiments.
The linked system favored paxalisib despite weaker direct tumor potency. NF1 exon skipping strengthened tumor response without a significant intracellular-concentration difference. Preserved organ viability coexisted with lower intestinal/renal TEER and stress signals.
Primary study comparisons of the stated models, treatments and measurements.
An NF1-mutant breast-cancer model links patient-derived intestinal, liver and kidney tissues with tumor and normal spheroids. The system compares drug handling with tumor effects and tests NF1 exon skipping, but lacks human pharmacokinetic or treatment-outcome validation.
