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Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing
Published on: September 15, 2023
High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma
Kathleen I Pishas1,2, Karla J Cowley3, Marta Llaurado-Fernandez4,5
1Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.
Abstract:
Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.
Insights
Low grade serous carcinoma (LGSOC) drug screening identified 79 compounds targeting cancer cell cytotoxicity. This research uncovers new therapeutic avenues for this rare, chemo-resistant ovarian cancer subtype.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Low grade serous carcinoma (LGSOC) is a rare ovarian cancer subtype with distinct molecular features.
- Limited LGSOC cases in clinical trials hinder subgroup analysis and treatment extrapolation.
- Existing therapies for relapsed LGSOC are insufficient, necessitating novel treatment strategies.
Purpose of the Study:
- To identify novel therapeutic targets for low grade serous carcinoma (LGSOC).
- To conduct the largest drug screening effort for LGSOC to date.
- To uncover potential drug classes effective against chemo-resistant LGSOC.
Main Methods:
- High-throughput drug screening of 3,436 compounds across 12 patient-derived LGSOC cell lines.
- Utilized high-throughput robotics and high-content imaging for compound assessment.
- Employed novel data analysis pipelines to identify effective compounds.
Main Results:
- Identified 60 high-confidence and 19 moderate-confidence drug candidates.
- Compounds demonstrated cancer cell-specific cytotoxicity at a low dose (0.1 µM).
- Revealed LGSOC cell line susceptibility to known (mTOR/PI3K/AKT) and novel (EGFR, MDM2-p53) drug classes.
Conclusions:
- The study identified promising drug candidates for LGSOC treatment.
- Findings suggest potential efficacy of targeting EGFR and MDM2-p53 pathways in LGSOC.
- This research provides a foundation for developing new therapies for rare ovarian cancers.
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