Organoid models and drug screening

Current organoid models of ER+ breast cancer generally suffer from decreased ER expression over time and lack of response to endocrine therapies. I established optimal culturing conditions to support the robust and long-term growth of ER+ PDXOs while preserving tumor heterogeneity. Importantly, PDXOs cultured in BTOM demonstrated stable estrogen receptor (ER) expression over many passages, which overcomes a major technical hurdle in the field. Moreover, PDXOs exhibited responsiveness to estrogen stimulation and sensitivity to endocrine therapies, confirming their suitability for studying ER+ breast cancer progression and drug resistance. These models represent a significant advancement for the field, allowing for more clinically relevant studies that better address both tumor and patient heterogeneity. 

The recently developed Multifunctional Approach to Pharmacologic Screening (MAPS) library combines a sublethal dose of a specific treatment (i.e., CDK4/6i) with a library of more than 300 compounds targeting metabolic pathways and processes such as TCA cycle, glycolysis, reactive oxygen species and nucleotide biosynthesis arrayed across a range of concentrations (20 μM to 1 nM). This platform will allow for rapid and robust identification of metabolic vulnerabilities in multiple different contexts of breast cancer progression and drug resistance. Using PDXOs will allow us to incorporate patient-to-patient variation into my studies so that an identified hit will have a greater chance of being clinically relevant and developed into a therapeutic strategy. We expect this screening platform to open multiple avenues of new investigation that will uncover critical insights into how metabolic reprogramming can be targeted to overcome drug resistance in breast cancer.