<< Back to MOTIFvations Blog Home Page

Epigenetic Drug Screening in Patient-derived Organoids Identifies Potential Treatments for Aggressive Breast Cancer

By Stuart P. Atkinson, Ph.D.

July 15, 2024

Tweet

Introduction: Can Advanced Culture Models and Epigenetic Drug Screens Reveal Novel Anti-Cancer Therapeutics?

A general lack of targeted therapies combined with its aggressive nature and subsequent poor prognosis has made the search for effective treatments for triple-negative breast cancer (TNBC) a critically important task (Bianchini et al. and Malorni et al.). Chemotherapy remains the standard treatment approach for TNBC; however, problems such as treatment resistance and disease recurrence (Passalacqua et al. and Mehanna et al.) further highlight the need to efficiently identify effective new drug treatments for aggressive breast cancer cases.

But what is the optimal drug strategy, and which cell culture model would provide an ideal in vitro screening platform? While poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy have exhibited immense promise in TNBC management, researchers guided by Xiaoli Yu and Xiaomao Guo (Fudan University) chose to screen drugs that impact epigenetic processes, given the vital contribution of various epigenetic mechanisms to TNBC tumorigenesis (Zolota et al.) and drug resistance. Furthermore, recent research has highlighted the potential of epigenetic drugs in treating hormone receptor-positive breast cancer (Jiang et al. and Yardley et al.) and TNBC (Chandhasin et al.). The team also chose 3D cellular structures known as organoids (developed from TNBC patient samples) as the culture model for their epigenetic drug screening platform (Sachs et al.) as they recapitulate tumor-associated characteristics to a better degree than the more commonly employed 2D monolayer cell culture model. Overall, patient-derived organoids offer a more physiologically relevant and effective culture model for drug screening (Ranga et al., Tuveson and Clevers, and Li et al.).

The findings of this exciting new study applying this platform, published recently in the journal Pharmaceuticals (Rao and Qiao et al.), underscore the vast potential of epigenetic drugs as advanced therapeutics for aggressive breast cancer and highlight the value of patient-derived organoids in drug discovery.

 Back to Table of Contents

Screening Epigenetic Drugs in Patient-derived Organoids

In their new article, Rao, Qiao, and colleagues described the establishment of the TNBC patient-derived organoids, which they implemented in a high-throughput drug screening system in the hope of identifying novel epigenetic drugs with potent anti-tumor activity and, as such, highlighting potential “epigenetic vulnerabilities” in this aggressive form of breast cancer. The patient-derived organoids - of epithelial origin and varying in size - accurately recapitulated characteristics of the original breast tumor (such as histology and protein expression) and, therefore, provided a robust platform for drug screening purposes. Furthermore, the organoids exhibited stable long-term expansion capacity, further supporting their ongoing implementation in high-throughput drug screenings over long periods of time.

Inspired by previous studies (Mao et al. and Chen et al.), the team next screened a library of epigenetic compounds in the TNBC patient-derived organoids. This approach revealed that organoids more closely mimicked in vivo drug responses than 2D cell-line-based models; furthermore, organoids preserved the inherent heterogeneity in drug sensitivity observed in the original tumor, compared to the consistent responses observed in 2D cell-line models. Overall, these findings underscored the ability of patient-derived organoids to serve as a more reliable platform for predicting clinical responses in TNBC. Additionally, the authors observed similar responses between different organoids to specific drusg, indicating shared epigenetic regulatory-/drug-induced mechanisms in TNBC patients, thereby providing crucial insights for the development of targeted treatments.

They finally assessed the top thirty compounds with the highest drug sensitivity in the initial screening in a secondary screen, which robustly identified Panobinostat (targeting histone deacetylase activity), Pacritinib (targeting JAK/STAT signaling), TAK-901 (targeting aurora kinase signaling), and JIB-04 (targeting histone demethylase activity), as exhibiting potent anti-tumor activity in organoids when compared to paclitaxel, a widely employed chemotherapeutic agent. The authors validated these findings through Calcein-AM/propidium iodide staining and imaging, confirming both the immense potential of the identified epigenetic drugs as effective TNBC treatments and the utility of patient-derived organoids as a screening platform.

 Back to Table of Contents

The Way Forward for Epigenetic Drug Screening in Patient-derived Organoids

This exciting study highlights the potential of patient-derived organoids as an effective platform for anti-cancer drug discovery through high-throughput screening and epigenetic drugs as TNBC treatments; however, the authors note that their findings should act merely as a guide at this stage, as moving these drugs closer to clinical translation will require further in-depth analysis and additional testing in organoids and models of a more complex nature.

For more on how epigenetic drug screening in patient-derived organoids holds the potential to identify effective new treatments for aggressive breast cancers, see Pharmaceuticals, February 2024.

 Back to Table of Contents

About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on Twitter with any questions

Related Articles

<< Back to MOTIFvations Blog Home Page