2 research outputs found
Human metastatic cholangiocarcinoma patient-derived xenografts and tumoroids for preclinical drug evaluation
Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30\\%–50\\% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA\_PDX). The CCA\_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA\_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA\_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.This collection of CCA\_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA\_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA\_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA\_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.The authors would like to thank the patients and their families for their support. This work was supported by grants from the Fundaci o Marat o TV3 awarded to T. Macarulla, M. Mel e, and S. Peir o; BeiGene research grant awarded toT. Macarulla and S. Peir o; AECC (INVES20036TIAN), Ram on y Cajal investigator program (RYC2020-029098-I), Proyecto de IþDþi (PID2019-108008RJ-I00), and FERO Foundation grant awarded to T.V. Tian; Proyecto de Investigaci on en Salud from the Instituto de Salud Carlos III (ISCIII) (PI20/00898) awarded to T. Macarulla; FIS/FEDER from the Instituto de Salud Carlos III (ISCIII) (PI12/01250; CP08/00223; PI16/00253 and CB16/12/00449) awarded to S. Peir o; and Ram on y Cajal investigator program (RYC-2017-22249) awarded to M. Mel e. Q. Serra-Camprubà is a recipient of the Ph.D. fellowship from La Caixa Foundation (LCF/PR/PR12/51070001). A. LlopGuevara was supported by the AECC (INVES20095LLOP) and V. Serra by the ISCIII (CPII19/00033). E.J. Arenas was funded by the AECC (POSTD211413AREN).J. Arribas is funded by the Instituto de Salud Carlos III (AC15/00062, CB16/12/00449, and PI22/00001). This publication is based upon the work of COST Action CA18122, European Cholangiocarcinoma Network, supported by the COST (European Cooperation in Science and Technology, www.cost.eu), a funding agency for research and innovation networks. The authors would like to thank Dr. V.A. Raker for manuscript editing and Drs. N. Herranz and J. Mateo for scientific discussions. The authors acknowledge the infrastructure and support of the FERO Foundation, La Caixa Foundation, and the Cellex Foundation.Peer Reviewed"Article signat per 31 autors/es: Queralt Serra-CamprubÃ; Helena Verdaguer; Winona Oliveros; Núria Lupión-Garcia; Núria Lupión-Garcia;Alba Llop-Guevara; Cristina Molina; Maria Vila-Casadesús; Anthony Turpin; Cindy Neuzillet; Joan Frigola; Jessica Querol; Mariana Yáñez-Bartolomé; Florian Castet; Carles Fabregat-Franco; Carmen Escudero-Iriarte; Marta Escorihuela; Enrique J. Arenas; Cristina Bernadó-Morales; Noemà Haro; Francis J. Giles; Óscar J. Pozo; Josep M. Miquel ; Paolo G. Nuciforo; Ana Vivancos; Marta Melé; Violeta Serra ; JoaquÃn Arribas; Josep Tabernero; Sandra Peiró; Teresa Macarulla; Tian V. Tian"Postprint (published version
Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation
Human metastatic cholangiocarcinoma; Xenografts; TumoroidsColangiocarcinoma metastà tic humà ; Xenoempelts; TumoroidesColangiocarcinoma metastásico humano; Xenoinjertos; TumoroidesPurpose:
Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%–50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.
Experimental Design:
We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.
Results:
This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.
Conclusions:
Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.This work was supported by grants from the Fundació Marató TV3 awarded to T. Macarulla, M. Melé, and S. Peiró; BeiGene research grant awarded to T. Macarulla and S. Peiró; AECC (INVES20036TIAN), Ramón y Cajal investigator program (RYC2020-029098-I), Proyecto de I+D+i (PID2019-108008RJ-I00), and FERO Foundation grant awarded to T.V. Tian; Proyecto de Investigación en Salud from the Instituto de Salud Carlos III (ISCIII) (PI20/00898) awarded to T. Macarulla; FIS/FEDER from the Instituto de Salud Carlos III (ISCIII) (PI12/01250; CP08/00223; PI16/00253 and CB16/12/00449) awarded to S. Peiró; and Ramón y Cajal investigator program (RYC-2017-22249) awarded to M. Melé. Q. Serra-Camprubà is a recipient of the Ph.D. fellowship from La Caixa Foundation (LCF/PR/PR12/51070001). A. Llop-Guevara was supported by the AECC (INVES20095LLOP) and V. Serra by the ISCIII (CPII19/00033). E.J. Arenas was funded by the AECC (POSTD211413AREN). J. Arribas is funded by the Instituto de Salud Carlos III (AC15/00062, CB16/12/00449, and PI22/00001). This publication is based upon the work of COST Action CA18122, European Cholangiocarcinoma Network, supported by the COST (European Cooperation in Science and Technology, www.cost.eu), a funding agency for research and innovation networks. The authors would like to thank Dr. V.A. Raker for manuscript editing and Drs. N. Herranz and J. Mateo for scientific discussions. The authors acknowledge the infrastructure and support of the FERO Foundation, La Caixa Foundation, and the Cellex Foundation