UCLA researchers develop MAESTRO AI platform to identify cancer drug combinations

UCLA researchers developed MAESTRO, an artificial intelligence platform using large language models to identify effective cancer drug combinations. Published in Advanced Science, the platform screened 3,592 natural products to overcome prostate cancer treatment resistance against enzalutamide. MAESTRO identified 150 high-confidence candidates, leading to the discovery that berberine, a plant compound, acts synergistically with enzalutamide across four resistant cancer models by activating AMPK and suppressing mTORC1 pathways.

Development and features of MAESTRO platform

• ▪MAESTRO evaluates potential drug pairings, ranks promising candidates, and generates testable biological explanations without relying on vast amounts of experimental training data.
• ▪The MAESTRO study was published in the journal Advanced Science, with Neil Lin serving as senior author and Chih-Hui Lo as first author.
• ▪UCLA investigators developed MAESTRO, an artificial intelligence platform using large language models to analyze scientific knowledge and identify drug combinations that overcome cancer treatment resistance.

Screening drug combinations with MAESTRO

• ▪MAESTRO evaluated each candidate compound over 100 times to rank candidates based on ranking height and consistency across repeated computational runs.
• ▪MAESTRO evaluated 3,592 natural products to partner with enzalutamide, selecting 150 high-confidence candidates for laboratory testing in 3D prostate cancer spheroids.
• ▪Out of 150 compounds tested in vitro, 23 demonstrated synergy with enzalutamide in prostate cancer models.
• ▪To identify drug candidates, UCLA researchers supplied MAESTRO with scientific data on prostate cancer biology, resistance mechanisms, and known drug actions.

Berberine synergy findings and next steps

• ▪UCLA researchers plan to evaluate the berberine-enzalutamide combination in patient-derived tumor models and animal studies while expanding MAESTRO to other cancer types.
• ▪Adding berberine to enzalutamide increased cellular stress, reduced DNA replication, increased AMPK pathway activity, and suppressed mTORC1 signaling in prostate cancer cells.
• ▪Berberine, a naturally occurring plant compound, demonstrated consistent synergy with enzalutamide across four prostate cancer models featuring different treatment resistance mechanisms.

Prostate cancer and enzalutamide resistance

• ▪Prostate cancer cells often adapt to androgen receptor signaling blockade by activating alternative biological pathways, causing resistance to targeted drugs like enzalutamide.
• ▪Enzalutamide is an advanced prostate cancer medication originally discovered and developed at UCLA.