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Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization

Effective radiation treatment (RT) for recurrent nasopharyngeal cancers (NPC), featuring an intrinsic hypoxic sub-volume, remains a clinical challenge. Lack of disease‐specific in-vitro models of NPC, together with difficulties in establishing patient derived xenograft (PDX) models, have further hin...

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Autores principales: Lucky, Sasidharan Swarnalatha, Law, Martin, Lui, Ming Hong, Mong, Jamie, Shi, Junli, Yu, Sidney, Yoon, Do Kun, Djeng, Shih Kien, Wang, Jiguang, Lim, Chwee Ming, Tan, Min Han
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959730/
https://www.ncbi.nlm.nih.gov/pubmed/33732646
http://dx.doi.org/10.3389/fonc.2021.622244
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author Lucky, Sasidharan Swarnalatha
Law, Martin
Lui, Ming Hong
Mong, Jamie
Shi, Junli
Yu, Sidney
Yoon, Do Kun
Djeng, Shih Kien
Wang, Jiguang
Lim, Chwee Ming
Tan, Min Han
author_facet Lucky, Sasidharan Swarnalatha
Law, Martin
Lui, Ming Hong
Mong, Jamie
Shi, Junli
Yu, Sidney
Yoon, Do Kun
Djeng, Shih Kien
Wang, Jiguang
Lim, Chwee Ming
Tan, Min Han
author_sort Lucky, Sasidharan Swarnalatha
collection PubMed
description Effective radiation treatment (RT) for recurrent nasopharyngeal cancers (NPC), featuring an intrinsic hypoxic sub-volume, remains a clinical challenge. Lack of disease‐specific in-vitro models of NPC, together with difficulties in establishing patient derived xenograft (PDX) models, have further hindered development of personalized therapeutic options. Herein, we established two NPC organoid lines from recurrent NPC PDX models and further characterized and compared these models with original patient tumors using RNA sequencing analysis. Organoids were cultured in hypoxic conditions to examine the effects of hypoxia and radioresistance. These models were then utilized to determine the radiobiological parameters, such as α/β ratio and oxygen enhancement ratio (OER), characteristic to radiosensitive normoxic and radioresistant hypoxic NPC, using simple dose-survival data analytic tools. The results were further validated in-vitro and in-vivo, to determine the optimal boost dose and fractionation regimen required to achieve effective NPC tumor regression. Despite the differences in tumor microenvironment due to the lack of human stroma, RNA sequencing analysis revealed good correlation of NPC PDX and organoid models with patient tumors. Additionally, the established models also mimicked inter-tumoral heterogeneity. Hypoxic NPC organoids were highly radioresistant and had high α/β ratio compared to its normoxic counterparts. In-vitro and in-vivo fractionation studies showed that hypoxic NPC was less sensitive to RT fractionation scheme and required a large bolus dose or 1.4 times of the fractionated dose that was effective against normoxic cells in order to compensate for oxygen deficiency. This study is the first direct experimental evidence to predict optimal RT boost dose required to cause sufficient damage to recurrent hypoxic NPC tumor cells, which can be further used to develop dose-painting algorithms in clinical practice.
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spelling pubmed-79597302021-03-16 Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization Lucky, Sasidharan Swarnalatha Law, Martin Lui, Ming Hong Mong, Jamie Shi, Junli Yu, Sidney Yoon, Do Kun Djeng, Shih Kien Wang, Jiguang Lim, Chwee Ming Tan, Min Han Front Oncol Oncology Effective radiation treatment (RT) for recurrent nasopharyngeal cancers (NPC), featuring an intrinsic hypoxic sub-volume, remains a clinical challenge. Lack of disease‐specific in-vitro models of NPC, together with difficulties in establishing patient derived xenograft (PDX) models, have further hindered development of personalized therapeutic options. Herein, we established two NPC organoid lines from recurrent NPC PDX models and further characterized and compared these models with original patient tumors using RNA sequencing analysis. Organoids were cultured in hypoxic conditions to examine the effects of hypoxia and radioresistance. These models were then utilized to determine the radiobiological parameters, such as α/β ratio and oxygen enhancement ratio (OER), characteristic to radiosensitive normoxic and radioresistant hypoxic NPC, using simple dose-survival data analytic tools. The results were further validated in-vitro and in-vivo, to determine the optimal boost dose and fractionation regimen required to achieve effective NPC tumor regression. Despite the differences in tumor microenvironment due to the lack of human stroma, RNA sequencing analysis revealed good correlation of NPC PDX and organoid models with patient tumors. Additionally, the established models also mimicked inter-tumoral heterogeneity. Hypoxic NPC organoids were highly radioresistant and had high α/β ratio compared to its normoxic counterparts. In-vitro and in-vivo fractionation studies showed that hypoxic NPC was less sensitive to RT fractionation scheme and required a large bolus dose or 1.4 times of the fractionated dose that was effective against normoxic cells in order to compensate for oxygen deficiency. This study is the first direct experimental evidence to predict optimal RT boost dose required to cause sufficient damage to recurrent hypoxic NPC tumor cells, which can be further used to develop dose-painting algorithms in clinical practice. Frontiers Media S.A. 2021-02-23 /pmc/articles/PMC7959730/ /pubmed/33732646 http://dx.doi.org/10.3389/fonc.2021.622244 Text en Copyright © 2021 Lucky, Law, Lui, Mong, Shi, Yu, Yoon, Djeng, Wang, Lim and Tan http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Lucky, Sasidharan Swarnalatha
Law, Martin
Lui, Ming Hong
Mong, Jamie
Shi, Junli
Yu, Sidney
Yoon, Do Kun
Djeng, Shih Kien
Wang, Jiguang
Lim, Chwee Ming
Tan, Min Han
Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization
title Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization
title_full Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization
title_fullStr Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization
title_full_unstemmed Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization
title_short Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization
title_sort patient-derived nasopharyngeal cancer organoids for disease modeling and radiation dose optimization
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959730/
https://www.ncbi.nlm.nih.gov/pubmed/33732646
http://dx.doi.org/10.3389/fonc.2021.622244
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