Cargando…

A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response

SIMPLE SUMMARY: Pancreatic cancer (PC) is characterized by an exceptionally aggressive tumor biology, high inter- and intratumor heterogeneity, and resistance to conventional chemotherapy, targeted agents, and immunotherapy. With its rising incidence and dismal prognosis, PC is projected to become t...

Descripción completa

Detalles Bibliográficos
Autores principales: Beutel, Alica K., Schütte, Lena, Scheible, Jeanette, Roger, Elodie, Müller, Martin, Perkhofer, Lukas, Kestler, Annika M. T. U., Kraus, Johann M., Kestler, Hans A., Barth, Thomas F. E., Lemke, Johannes, Kornmann, Marko, Ettrich, Thomas J., Gout, Johann, Seufferlein, Thomas, Kleger, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196829/
https://www.ncbi.nlm.nih.gov/pubmed/34064221
http://dx.doi.org/10.3390/cancers13112539
_version_ 1783706777468010496
author Beutel, Alica K.
Schütte, Lena
Scheible, Jeanette
Roger, Elodie
Müller, Martin
Perkhofer, Lukas
Kestler, Annika M. T. U.
Kraus, Johann M.
Kestler, Hans A.
Barth, Thomas F. E.
Lemke, Johannes
Kornmann, Marko
Ettrich, Thomas J.
Gout, Johann
Seufferlein, Thomas
Kleger, Alexander
author_facet Beutel, Alica K.
Schütte, Lena
Scheible, Jeanette
Roger, Elodie
Müller, Martin
Perkhofer, Lukas
Kestler, Annika M. T. U.
Kraus, Johann M.
Kestler, Hans A.
Barth, Thomas F. E.
Lemke, Johannes
Kornmann, Marko
Ettrich, Thomas J.
Gout, Johann
Seufferlein, Thomas
Kleger, Alexander
author_sort Beutel, Alica K.
collection PubMed
description SIMPLE SUMMARY: Pancreatic cancer (PC) is characterized by an exceptionally aggressive tumor biology, high inter- and intratumor heterogeneity, and resistance to conventional chemotherapy, targeted agents, and immunotherapy. With its rising incidence and dismal prognosis, PC is projected to become the second-leading cause of cancer-related death worldwide in 2030. Tumor heterogeneity induces a considerable variation in responses to antitumor therapies, yet reliable models or biomarkers to predict the effectiveness of treatment strategies for eligible subgroups are not established. Current combination chemotherapeutic regimens are often ineffective and frequently exhibit substantial systemic toxicity impeding longer-term treatment. Patient-derived pancreatic cancer organoids (PDOs) exhibit features of the parental tumor and may thereby represent a powerful preclinical tool to predict drug response. Ex vivo pharmacotyping may enable therapy response prediction and harness personalized treatment in PC patients. In clinical practice, a PDO-guided selection of effective drugs may provide substantial benefit and improve survival outcomes in this heterogeneous disease. ABSTRACT: Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay. Areas under the curves (AUC) are clustered for each drug, and a prediction score is developed for combined regimens. Pharmacotyping profiles are obtained from 28 PDOs (efficacy 63.6%) after a median of 53 days (range 21–126 days). PDOs exhibit heterogeneous responses to the standard-of-care drugs, and are classified into high, intermediate, or low responder categories. Our developed prediction model allows a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimens, respectively. The power of prediction declines in pretreated patients (accuracy 40.0%), particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) is significantly longer in previously treatment-naïve patients receiving a predicted tumor sensitive compared to a predicted tumor resistant regimen (mPFS 141 vs. 46 days; p = 0.0048). In conclusion, generation and pharmacotyping of PDOs is feasible in clinical routine and may provide substantial benefit.
format Online
Article
Text
id pubmed-8196829
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81968292021-06-13 A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response Beutel, Alica K. Schütte, Lena Scheible, Jeanette Roger, Elodie Müller, Martin Perkhofer, Lukas Kestler, Annika M. T. U. Kraus, Johann M. Kestler, Hans A. Barth, Thomas F. E. Lemke, Johannes Kornmann, Marko Ettrich, Thomas J. Gout, Johann Seufferlein, Thomas Kleger, Alexander Cancers (Basel) Article SIMPLE SUMMARY: Pancreatic cancer (PC) is characterized by an exceptionally aggressive tumor biology, high inter- and intratumor heterogeneity, and resistance to conventional chemotherapy, targeted agents, and immunotherapy. With its rising incidence and dismal prognosis, PC is projected to become the second-leading cause of cancer-related death worldwide in 2030. Tumor heterogeneity induces a considerable variation in responses to antitumor therapies, yet reliable models or biomarkers to predict the effectiveness of treatment strategies for eligible subgroups are not established. Current combination chemotherapeutic regimens are often ineffective and frequently exhibit substantial systemic toxicity impeding longer-term treatment. Patient-derived pancreatic cancer organoids (PDOs) exhibit features of the parental tumor and may thereby represent a powerful preclinical tool to predict drug response. Ex vivo pharmacotyping may enable therapy response prediction and harness personalized treatment in PC patients. In clinical practice, a PDO-guided selection of effective drugs may provide substantial benefit and improve survival outcomes in this heterogeneous disease. ABSTRACT: Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay. Areas under the curves (AUC) are clustered for each drug, and a prediction score is developed for combined regimens. Pharmacotyping profiles are obtained from 28 PDOs (efficacy 63.6%) after a median of 53 days (range 21–126 days). PDOs exhibit heterogeneous responses to the standard-of-care drugs, and are classified into high, intermediate, or low responder categories. Our developed prediction model allows a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimens, respectively. The power of prediction declines in pretreated patients (accuracy 40.0%), particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) is significantly longer in previously treatment-naïve patients receiving a predicted tumor sensitive compared to a predicted tumor resistant regimen (mPFS 141 vs. 46 days; p = 0.0048). In conclusion, generation and pharmacotyping of PDOs is feasible in clinical routine and may provide substantial benefit. MDPI 2021-05-21 /pmc/articles/PMC8196829/ /pubmed/34064221 http://dx.doi.org/10.3390/cancers13112539 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Beutel, Alica K.
Schütte, Lena
Scheible, Jeanette
Roger, Elodie
Müller, Martin
Perkhofer, Lukas
Kestler, Annika M. T. U.
Kraus, Johann M.
Kestler, Hans A.
Barth, Thomas F. E.
Lemke, Johannes
Kornmann, Marko
Ettrich, Thomas J.
Gout, Johann
Seufferlein, Thomas
Kleger, Alexander
A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
title A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
title_full A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
title_fullStr A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
title_full_unstemmed A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
title_short A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
title_sort prospective feasibility trial to challenge patient–derived pancreatic cancer organoids in predicting treatment response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196829/
https://www.ncbi.nlm.nih.gov/pubmed/34064221
http://dx.doi.org/10.3390/cancers13112539
work_keys_str_mv AT beutelalicak aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT schuttelena aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT scheiblejeanette aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT rogerelodie aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT mullermartin aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT perkhoferlukas aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT kestlerannikamtu aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT krausjohannm aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT kestlerhansa aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT barththomasfe aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT lemkejohannes aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT kornmannmarko aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT ettrichthomasj aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT goutjohann aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT seufferleinthomas aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT klegeralexander aprospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT beutelalicak prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT schuttelena prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT scheiblejeanette prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT rogerelodie prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT mullermartin prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT perkhoferlukas prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT kestlerannikamtu prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT krausjohannm prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT kestlerhansa prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT barththomasfe prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT lemkejohannes prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT kornmannmarko prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT ettrichthomasj prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT goutjohann prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT seufferleinthomas prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse
AT klegeralexander prospectivefeasibilitytrialtochallengepatientderivedpancreaticcancerorganoidsinpredictingtreatmentresponse