Abstract
Simple SummaryDue to higher precision and consequent sparing of normal tissue, pancreatic cancer patients might profit from proton beam radiotherapy, a treatment modality increasingly used. Since molecular data upon proton irradiation in comparison to standard photon radiotherapy are limited in pancreatic cancer, the aims of our study were to unravel differences in the effectiveness of photon versus proton irradiation and to exploit radiation type-specific molecular changes for radiosensitizing 3D PDAC cell cultures. Although protons showed a slightly higher effectiveness and a stronger induction of molecular alterations than photons, our results revealed a radiation-type independent sensitization of molecular-targeted agents selected according to the discovered molecular, radiation-induced alterations.Pancreatic ductal adenocarcinoma (PDAC) is a highly therapy-resistant tumor entity of unmet needs. Over the last decades, radiotherapy has been considered as an additional treatment modality to surgery and chemotherapy. Owing to radiosensitive abdominal organs, high-precision proton beam radiotherapy has been regarded as superior to photon radiotherapy. To further elucidate the potential of combination therapies, we employed a more physiological 3D, matrix-based cell culture model to assess tumoroid formation capacity after photon and proton irradiation. Additionally, we investigated proton- and photon-irradiation-induced phosphoproteomic changes for identifying clinically exploitable targets. Here, we show that proton irradiation elicits a higher efficacy to reduce 3D PDAC tumoroid formation and a greater extent of phosphoproteome alterations compared with photon irradiation. The targeting of proteins identified in the phosphoproteome that were uniquely altered by protons or photons failed to cause radiation-type-specific radiosensitization. Targeting DNA repair proteins associated with non-homologous endjoining, however, revealed a strong radiosensitizing potential independent of the radiation type. In conclusion, our findings suggest proton irradiation to be potentially more effective in PDAC than photons without additional efficacy when combined with DNA repair inhibitors.
Highlights
Pancreatic cancer, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype, presents one of the top tumor types with unmet needs and only minimal advances in treatment outcome in recent years [1,2]
Sensitivity towards Photon and Proton Irradiation Varies in Human 3D PDAC Cell Cultures
We commenced our study by a comparative tumoroid growth analysis upon photon and proton irradiation in a panel of five human PDAC cell lines grown in physiological laminin-rich extracellular matrix (Figure 1A)
Summary
Pancreatic cancer, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype, presents one of the top tumor types with unmet needs and only minimal advances in treatment outcome in recent years [1,2]. PDAC is the fourth leading cancer in tumor-related deaths and despite extensive research advances, the 5-year survival is still poor, with 7% [2]. Based on its physical properties, treatment with proton beam radiotherapy confers better sparing of organs at risk and is currently discussed as a preferable treatment modality in comparison to standard photon radiotherapy [4]. It is the more optimal dose-depth profile of the proton beam that provides a higher precision. This is characterized by a low entrance dose and an increase at the stop, the so-called Bragg peak. The Bragg peak can be spread out (spread-out Bragg peak, (SOBP)) by combining various beams, each with a different initial energy, over the tumor volume and positioning them precisely [5,6]
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