Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma.

We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents-5-FU, irinotecan, and oxaliplatin-of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways. All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples-in both organoids and corresponding matched tumor tissues-uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system. Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.

Farshadi EA ，Chang J ，Sampadi B ，Doukas M ，Van 't Land F ，van der Sijde F ，Vietsch EE ，Pothof J ，Koerkamp BG ，van Eijck CHJ ... -  《-》

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

Labori KJ ，Bratlie SO ，Andersson B ，Angelsen JH ，Biörserud C ，Björnsson B ，Bringeland EA ，Elander N ，Garresori H ，Grønbech JE ，Haux J ，Hemmingsson O ，Liljefors MG ，Myklebust TÅ ，Nymo LS ，Peltola K ，Pfeiffer P ，Sallinen V ，Sandström P ，Sparrelid E ，Stenvold H ，Søreide K ，Tingstedt B ，Verbeke C ，Öhlund D ，Klint L ，Dueland S ，Lassen K ，Nordic Pancreatic Cancer Trial-1 study group ... -  《The Lancet Gastroenterology & Hepatology》

Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6low patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.

Lansbergen MF ，Dings MPG ，Manoukian P ，Fariña A ，Waasdorp C ，Hooijer GKJ ，Verheij J ，Koster J ，Zwijnenburg DA ，Wilmink JW ，Medema JP ，Dijk F ，van Laarhoven HWM ，Bijlsma MF ... -  《-》

Predictors of Resectability and Survival in Patients With Borderline and Locally Advanced Pancreatic Cancer who Underwent Neoadjuvant Treatment With FOLFIRINOX.

Michelakos T ，Pergolini I ，Castillo CF ，Honselmann KC ，Cai L ，Deshpande V ，Wo JY ，Ryan DP ，Allen JN ，Blaszkowsky LS ，Clark JW ，Murphy JE ，Nipp RD ，Parikh A ，Qadan M ，Warshaw AL ，Hong TS ，Lillemoe KD ，Ferrone CR ... -  《-》

A new pancreatic adenocarcinoma-derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms.

Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO. We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness. We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse. To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.

Hadj Bachir E ，Poiraud C ，Paget S ，Stoup N ，El Moghrabi S ，Duchêne B ，Jouy N ，Bongiovanni A ，Tardivel M ，Weiswald LB ，Vandepeutte M ，Beugniez C ，Escande F ，Leteurtre E ，OrgaRES consortium ，Poulain L ，Lagadec C ，Pigny P ，Jonckheere N ，Renaud F ，Truant S ，Van Seuningen I ，Vincent A ... -  《-》