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Published on: December 23, 2022
Multiplex Patient-Based Drug Response Assay in Pancreatic Ductal Adenocarcinoma
Andrew Armstrong1, Muhammad R Haque2, Sina Mirbagheri1
1Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.
Insights
Patient-derived organoids accurately model pancreatic cancer drug response. Transcriptome signatures linked to drug resistance in organoids correlated with poor patient survival, aiding therapeutic selection.
Area of Science:
- Oncology
- Translational Research
- Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDA) presents significant treatment challenges due to ineffective therapies and a lack of predictive biomarkers.
- Current treatment strategies for PDA often yield limited success, necessitating novel approaches for patient stratification and therapeutic selection.
Purpose of the Study:
- To develop and validate a patient-derived organoid (PDO) based high-throughput drug screening assay for modeling PDA treatment response.
- To identify transcriptome signatures associated with drug sensitivity and resistance in PDA.
- To explore the potential of ex vivo drug screening combined with omics data for personalized PDA therapy.
Main Methods:
- Patient biopsies were used to generate fifteen patient-derived organoids (PDOs).
- PDOs underwent high-throughput screening against 18 conventional and investigational drugs using Cell-titer GLO 3D assay.
- Molecular profiling via RNA-seq was performed on PDOs, with comparative analysis against The Cancer Genome Atlas (TCGA) PDA data.
Main Results:
- Reproducible drug response curves were observed across PDOs, with significant inter-patient variability in treatment sensitivity.
- Distinct transcriptome signatures correlated with response to conventional chemotherapeutics.
- Transcriptomic profiles associated with resistance to conventional therapies in PDOs were linked to poorer survival in TCGA PDA patients.
- Pathway analysis identified predictors of response for targeted drugs based on their mechanism of action.
Conclusions:
- The PDO-based drug screening assay effectively models PDA treatment response and can predict clinical outcomes.
- Transcriptome signatures identified ex vivo can serve as biomarkers for therapeutic selection and patient stratification in PDA.
- Integrating organoid drug response with omics data holds promise for advancing personalized medicine in pancreatic cancer.
