Abstract
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.
Highlights
Nasopharyngeal carcinoma (NPC) is endemic in the east and southeast Asia, where 95% of the cases are invariably associated with Epstein-Barr virus (EBV) infection [1]
Other part was fixed in 10% neutral buffered formalin (10% NBF) for routine Hematoxylin and Eosin (H&E) staining and remaining tissues were snap frozen in liquid nitrogen for DNA and RNA extraction
Two were lost due to bacterial infections at P2 and P4, and the third could not be maintained beyond P2
Summary
Nasopharyngeal carcinoma (NPC) is endemic in the east and southeast Asia, where 95% of the cases are invariably associated with Epstein-Barr virus (EBV) infection [1]. >50% of the patients present with locally advanced and distant metastasis during initial diagnosis, reducing the 5-year survival rates to 50–70% [2]. Local recurrences are observed in ≈10% of the patients following initial RT, representing a substantial challenge to oncologists [3, 4]. Re-treatment with RT (dose ≥60 Gy) is employed in 70–80% of inoperable advanced recurrent cases [5], often resulting in late complications [6,7,8], further reducing the 5-year survival to ≤50% [9,10,11].
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