Abstract
Simple SummaryPancreatic ductal adenocarcinoma is a devastating disease. Using modern technique of radiotherapy, such as proton therapy, may simultaneously enhance dose to the tumor and decrease dose to surrounding organ, thus limiting toxicity. Moreover, associating drugs to radiotherapy also increases its effectiveness on tumor. The aim of our study was to show the benefit of proton therapy compared to standard radiotherapy with photon, and the benefit of associating different drugs with those particles in vivo. Thus, our results displayed a higher effectiveness of associating proton therapy, gemcitabine and olaparib. Finally, we pointed out that treatment induced significant transcriptomic alterations.Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive cancers [1]
Mice bearing MIA PaCa-2 xenografts were treated with 50 mg/kg olaparib or 40 mg/kg gemcitabine or both associated treatments for two consecutive days (Figure 1)
It is well known that the relative biologic effectiveness (RBE) is defined as the ratio between the dose delivered in photon and proton irradiation, achieving the same specified biologic effect [12]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive cancers [1]. PDAC patients enrolled in RT protocols are commonly treated with photon therapy, X-rays. This method, despite being precise thanks to the intensity-modulated radiotherapy (IMRT), does not allow radiation dose escalation due to the risk of toxicity in the surrounding healthy tissues. With the rise of proton therapy, novel perspectives are expected as they can be better controlled and the dose deposition is more targeted. This advantage of proton over photon enables a potential dose escalation [4]
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