Patient- Derived Xenografts And Organoid Models

A platform combining patient-derived xenografts (PDXs) and long-term patient-derived organoid (PDxO) cultures that enables renewable, cost-effective, scalable, high molecular fidelity and clinically relevant modeling of breast cancer for drug discovery.

While patient-derived xenografts (PDXs) closely mimic the genomic and phenotypic characteristics of patient tumors, their high cost, low throughput, and maintenance complexity limit their use in large-scale genetic or therapeutic screening. There is a critical need for a complementary model system that retains the biological accuracy of PDXs while enabling high-throughput, reproducible, and cost-efficient drug testing and mechanistic studies.

Patient-derived xenografts (PDX) have several strengths as cancer models. Their close genomic, molecular and phenotypic association with patient tumors makes them well-suited for basic and preclinical studies. However, due to their labor-intensive nature, high cost and low throughput, PDX models are not amenable to large-scale genetic or therapeutic screens. To address this, we established and characterized long-term PDX organoid (PDxO) cultures from breast cancer PDXs and evaluated their application in moderate-throughput drug screening assays. Our study demonstrates that PDxO models generally recapitulate the molecular and genomic features, and exhibit drug response concordance, with their originating PDX. They are cost-efficient, easy to maintain, and renewable - and as a paired resource, PDX and PDxO models have broad application in basic and preclinical cancer research. We are currently establishing 100 paired-PDX/PDxO breast cancer models.
The technology describes reagents and methodologies to establish patient-derived (PDxO) breast cancer models in cell culture (organoids). These can be rapidly expanded in vitro and serve as a renewable resource for downstream commercial applications (1) drug screening (2) preclinical SAR (structure activity relationship) and lead optimization (3) assessment of patient tumors with specific mutation/ genotype profile to targeted therapy, chemotherapy and combination therapies.
The technology has proprietary elements: (1) “organoids” that can be frozen and expanded for use (2) Know-how related to culturing the organoids (media, conditions, protocols) (3) Drug profiling dataset established can be a very valuable asset and further mined for predicting personalized treatment in a specific breast cancer sub-type. The latter may provide areas for future IP protection.

Publication

• Clinically relevant model: Maintains the genomic, molecular, and phenotypic fidelity of patient-derived tumors.
• High-throughput capability: Enables moderate-throughput drug screening and genetic analysis not feasible with in vivo PDX models.
• Renewable and scalable resource: PDxO cultures can be expanded, cryopreserved, and re-derived for repeated studies.
• Cost-effective alternative: Reduces the expense and time associated with traditional PDX studies.
• Bridging translational gap: Provides a complementary in vitro–in vivo system for validating drug response, biomarker discovery, and resistance mechanisms.
• Broad utility: Applicable for drug discovery, structure–activity relationship (SAR) studies, and personalized treatment prediction.
• Proprietary know-how: Includes optimized organoid media, culture protocols, and a unique drug profiling dataset offering future IP and commercialization opportunities.

Guillen, K.P., Fujita, M., Butterfield, A.J. et al. A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology. Nat Cancer 3, 232–250 (2022). https://doi.org/10.1038/s43018-022-00337-6

Lucia Irazabal
lu.irazabal@utah.edu