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Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients

There is a high clinical unmet need to improve outcomes for pancreatic ductal adenocarcinoma (PDAC) patients, either with the discovery of new therapies or biomarkers that can track response to treatment more efficiently than imaging. We report an innovative approach that will generate renewed inter...

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Autores principales: Freed, Ian M., Kasi, Anup, Fateru, Oluwadamilola, Hu, Mengjia, Gonzalez, Phasin, Weatherington, Nyla, Pathak, Harsh, Hyter, Stephen, Sun, Weijing, Al-Rajabi, Raed, Baranda, Joaquina, Hupert, Mateusz L., Chalise, Prabhakar, Godwin, Andrew K., A. Witek, Malgorzata, Soper, Steven A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526802/
https://www.ncbi.nlm.nih.gov/pubmed/37759489
http://dx.doi.org/10.3390/cells12182266
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author Freed, Ian M.
Kasi, Anup
Fateru, Oluwadamilola
Hu, Mengjia
Gonzalez, Phasin
Weatherington, Nyla
Pathak, Harsh
Hyter, Stephen
Sun, Weijing
Al-Rajabi, Raed
Baranda, Joaquina
Hupert, Mateusz L.
Chalise, Prabhakar
Godwin, Andrew K.
A. Witek, Malgorzata
Soper, Steven A.
author_facet Freed, Ian M.
Kasi, Anup
Fateru, Oluwadamilola
Hu, Mengjia
Gonzalez, Phasin
Weatherington, Nyla
Pathak, Harsh
Hyter, Stephen
Sun, Weijing
Al-Rajabi, Raed
Baranda, Joaquina
Hupert, Mateusz L.
Chalise, Prabhakar
Godwin, Andrew K.
A. Witek, Malgorzata
Soper, Steven A.
author_sort Freed, Ian M.
collection PubMed
description There is a high clinical unmet need to improve outcomes for pancreatic ductal adenocarcinoma (PDAC) patients, either with the discovery of new therapies or biomarkers that can track response to treatment more efficiently than imaging. We report an innovative approach that will generate renewed interest in using circulating tumor cells (CTCs) to monitor treatment efficacy, which, in this case, used PDAC patients receiving an exploratory new therapy, poly ADP-ribose polymerase inhibitor (PARPi)—niraparib—as a case study. CTCs were enumerated from whole blood using a microfluidic approach that affinity captures epithelial and mesenchymal CTCs using anti-EpCAM and anti-FAPα monoclonal antibodies, respectively. These antibodies were poised on the surface of two separate microfluidic devices to discretely capture each subpopulation for interrogation. The isolated CTCs were enumerated using immunophenotyping to produce a numerical ratio consisting of the number of mesenchymal to epithelial CTCs (denoted “Φ”), which was used as an indicator of response to therapy, as determined using computed tomography (CT). A decreasing value of Φ during treatment was indicative of tumor response to the PARPi and was observed in 88% of the enrolled patients (n = 31). Changes in Φ during longitudinal testing were a better predictor of treatment response than the current standard CA19-9. We were able to differentiate between responders and non-responders using ΔΦ (p = 0.0093) with higher confidence than CA19-9 (p = 0.033). For CA19-9 non-producers, ΔΦ correctly predicted the outcome in 72% of the PDAC patients. Sequencing of the gDNA extracted from affinity-selected CTC subpopulations provided information that could be used for patient enrollment into the clinical trial based on their tumor mutational status in DNA repair genes.
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spelling pubmed-105268022023-09-28 Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients Freed, Ian M. Kasi, Anup Fateru, Oluwadamilola Hu, Mengjia Gonzalez, Phasin Weatherington, Nyla Pathak, Harsh Hyter, Stephen Sun, Weijing Al-Rajabi, Raed Baranda, Joaquina Hupert, Mateusz L. Chalise, Prabhakar Godwin, Andrew K. A. Witek, Malgorzata Soper, Steven A. Cells Article There is a high clinical unmet need to improve outcomes for pancreatic ductal adenocarcinoma (PDAC) patients, either with the discovery of new therapies or biomarkers that can track response to treatment more efficiently than imaging. We report an innovative approach that will generate renewed interest in using circulating tumor cells (CTCs) to monitor treatment efficacy, which, in this case, used PDAC patients receiving an exploratory new therapy, poly ADP-ribose polymerase inhibitor (PARPi)—niraparib—as a case study. CTCs were enumerated from whole blood using a microfluidic approach that affinity captures epithelial and mesenchymal CTCs using anti-EpCAM and anti-FAPα monoclonal antibodies, respectively. These antibodies were poised on the surface of two separate microfluidic devices to discretely capture each subpopulation for interrogation. The isolated CTCs were enumerated using immunophenotyping to produce a numerical ratio consisting of the number of mesenchymal to epithelial CTCs (denoted “Φ”), which was used as an indicator of response to therapy, as determined using computed tomography (CT). A decreasing value of Φ during treatment was indicative of tumor response to the PARPi and was observed in 88% of the enrolled patients (n = 31). Changes in Φ during longitudinal testing were a better predictor of treatment response than the current standard CA19-9. We were able to differentiate between responders and non-responders using ΔΦ (p = 0.0093) with higher confidence than CA19-9 (p = 0.033). For CA19-9 non-producers, ΔΦ correctly predicted the outcome in 72% of the PDAC patients. Sequencing of the gDNA extracted from affinity-selected CTC subpopulations provided information that could be used for patient enrollment into the clinical trial based on their tumor mutational status in DNA repair genes. MDPI 2023-09-13 /pmc/articles/PMC10526802/ /pubmed/37759489 http://dx.doi.org/10.3390/cells12182266 Text en © 2023 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
Freed, Ian M.
Kasi, Anup
Fateru, Oluwadamilola
Hu, Mengjia
Gonzalez, Phasin
Weatherington, Nyla
Pathak, Harsh
Hyter, Stephen
Sun, Weijing
Al-Rajabi, Raed
Baranda, Joaquina
Hupert, Mateusz L.
Chalise, Prabhakar
Godwin, Andrew K.
A. Witek, Malgorzata
Soper, Steven A.
Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients
title Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients
title_full Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients
title_fullStr Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients
title_full_unstemmed Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients
title_short Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients
title_sort circulating tumor cell subpopulations predict treatment outcome in pancreatic ductal adenocarcinoma (pdac) patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526802/
https://www.ncbi.nlm.nih.gov/pubmed/37759489
http://dx.doi.org/10.3390/cells12182266
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