Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy

Hirt, Christian; Booij, Tijmen H.; Grob, Linda; Simmler, Patrik; Toussaint, Nora C.; Keller, David L.; Taube, Doreen; Ludwig, Vanessa; Goryachkin, Alexander; Pauli, Chantal; Lenggenhager, Daniela; Stekhoven, Daniel J.; Stirnimann, Christian U.; Endhardt, Katharina; Ringnalda, Femke; Villiger, Lukas; Siebenhüner, Alexander; Karkampouna, Sofia; Menna, Marta De; Beshay, Janette; Klett, Hagen; Julio, Marianna Kruithof-de; Schüler, Julia; Schwank, Gerald

doi:10.1016/j.xgen.2022.100095

Cited by 40 publications

(41 citation statements)

References 64 publications

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“…For instance, alterations affecting the FGFR3 gene in NMIBC or cell cycle regulators in MIBC that have been proposed in previous studies were confirmed in our cohort (15,20). The concordance of the genomic profiles between PDO and PT has been already demonstrated in previous studies for BLCa (33,54) and upper urinary tract urothelial cancer (UTUC) (55) as well as for other cancer types such as breast (37), ovarian (31), rectal (40), gastrointestinal (39), pancreatic (38,56,57) and prostate cancers (29,32). Marker analyses confirm that organoids retain the main tumor phenotype.…”

Section: Discussionsupporting

confidence: 87%

Bladder cancer organoids as a functional system to model different disease stages and therapy response

Minoli

Cantore

Kiener

et al. 2022

Preprint

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Bladder Cancer (BLCa) inter-patient heterogeneity is considered the primary cause of tumor reoccurrence and treatment failure, suggesting that BLCa patients could benefit from a more personalized treatment approach. Patient-derived organoids (PDOs) have been successfully used as a functional model for predicting drug response in different cancer types. In our study, we established BLCa PDO cultures from different BLCa stages. BLCa PDOs preserve the histological and molecular heterogeneity of the parental tumors, including their multiclonal genetic landscapes. BLCa PDOs consistently share key genetic alterations detected in parental tumors, mirroring tumor evolution in longitudinal sampling. Our drug screening pipeline was implemented using BLCa PDOs, testing both standard-of-care and additional FDA-approved compounds for other solid tumors. Integrative analysis of drug response profiles with matched PDO genomic analysis was used to determine enrichment thresholds for candidate markers of therapy resistance and sensitivity. By assessing the clinical history of longitudinally sampled cases, the clonal evolution of the disease could be determined and matched with drug response profiles. In conclusion, we have developed a clinically relevant pipeline for drug response profile assessment and discovery of candidate markers of therapy resistance.

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Section: Discussionsupporting

confidence: 87%

Bladder cancer organoids as a functional system to model different disease stages and therapy response

Minoli

Cantore

Kiener

et al. 2022

Preprint

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“…PDOs can be generated from surgical resection specimens and ultrasound-guided fine needle aspirations (EUS-FNAs) within weeks, with high efficiency. PDOs can be used to delineate drug response and resistance as they harbor most of the genetic alterations present in the original tumors [17][18][19][20][21][22][23]. The first study to correlate PDO response to treatment outcome was performed in gastrointestinal cancer, and other studies have provided additional evidence that patient response may be predicted by ex vivo testing [24,25].…”

Section: Introductionmentioning

confidence: 99%

Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment

Hennig

Baenke

Klimová

et al. 2022

The Journal of Pathology

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Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor‐free margins were significantly more frequent when full‐dose neoCTx was applied. We determined if patient‐derived organoids (PDOs) can be used to personalize poly‐chemotherapy regimens by pharmacotyping of treatment‐naïve and post‐neoCTx PDAC PDOs. Five out of ten CTx‐naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx‐naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly‐chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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“…Since PDOs recapitulated patient- and disease-specific features, several drug-screening approaches on such biobanks have been reported. 180 In a very recent study by the group of Gerald Schwank, they used PDOs from pancreatic cancer (PDAC) patients to demonstrate that organoids can be used for precision oncology, not only to allow drug screening, but also for the identification of novel candidates for drug repurposing via genome editing. 180 In line with previous studies they observed a high diversity in PDOs phenotypes, which correlated strongly with in vivo morphology of primary PDAC tumours.…”

Section: Introductionmentioning

confidence: 99%

“… 180 In a very recent study by the group of Gerald Schwank, they used PDOs from pancreatic cancer (PDAC) patients to demonstrate that organoids can be used for precision oncology, not only to allow drug screening, but also for the identification of novel candidates for drug repurposing via genome editing. 180 In line with previous studies they observed a high diversity in PDOs phenotypes, which correlated strongly with in vivo morphology of primary PDAC tumours. To enable high-throughput compound screening in these organoid lines, they established a fully automated drug screening platform and compared different approaches that have been used in previous drug screening assays.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the success of these initial studies and scope of application in personalised medicine, several additional studies, focusing on various different tumour entities, soon followed. All studies impressively demonstrated that PDOs recapitulate the mutational landscape of their primary tumours and can be generated from the respective GI cancer entity including colorectal cancer,161 163 166–170 gastric cancer,32 164 171–175 oesophageal cancer,176–179 pancreatic cancer,10 90 180 181 gastroenteropancreatic neuroendocrine neoplasms,182 and liver cancer 183–185. Of particular interest for precision medicine, the molecular subtypes of cancers are maintained during PDO cultures, indicating that the culture conditions do not foster outgrowth of certain subtypes.…”

Section: Introductionmentioning

confidence: 99%

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Organoids in gastrointestinal diseases: from experimental models to clinical translation

Günther

Winner

Stappenbeck

2022

Gut

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We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut–brain axis or gut–liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.

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Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy

Cited by 40 publications

References 64 publications

Bladder cancer organoids as a functional system to model different disease stages and therapy response

Bladder cancer organoids as a functional system to model different disease stages and therapy response

Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment

Organoids in gastrointestinal diseases: from experimental models to clinical translation

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