Abstract
BackgroundFor many cancer types, including colorectal carcinoma (CRC), combined modality treatments have shown to improve outcome, but are frequently associated with significant toxicity, illustrating the need for new therapeutic approaches. Based on preclinical data, TRAIL receptor agonists appeared to be promising agents for cancer therapy especially in combination with DNA damaging regimens. Here, we present the combination of the second-generation TRAIL receptor agonist APG-880 with radiation in a new and clinically relevant 3D model system. MethodsTo investigate the effect of APG-880 in combination with radiation we performed short-term cytotoxicity and long-term clonogenic survival assays in established CRC cell lines, and in tumor organoids derived from colon cancer patients. ResultsAPG-880 is a potent inducer of apoptosis in CRC cell lines and in patient-derived CRC organoids. Furthermore, a supra-additive effect on cytotoxicity was found when APG-880 and radiation were combined simultaneously, with combination indices around 0.7. Lastly, in the long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5. ConclusionsIn a new, clinically relevant CRC-organoid model system we demonstrated a more than additive combined effect between the second-generation TRAIL receptor agonist APG-880 and radiation.
Highlights
Over 50% of all cancer patients receive radiation therapy during the course of their disease and radiotherapy contributes to approximately 40% of all cancer cures [1].Colorectal carcinoma (CRC) is the third most common cancer worldwide with over one million new diagnoses per year and is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030
As TRAIL-receptors are commonly expressed in colorectal tumor tissue [32], we evaluated the efficacy of APG-880 alone and in combination with radiation therapy both in CRC cell lines, and in patient-derived CRC-organoids
Regarding the organoids used in this study, organoid ITO77 was derived from a peritoneal metastasis and organoids ITO17 and ITO60 originated from a primary colorectal carcinoma
Summary
For many cancer types, including colorectal carcinoma (CRC), combined modality treatments have shown to improve outcome, but are frequently associated with significant toxicity, illustrating the need for new therapeutic approaches. We present the combination of the second-generation TRAIL receptor agonist APG-880 with radiation in a new and clinically relevant 3D model system. Methods: To investigate the effect of APG-880 in combination with radiation we performed short-term cytotoxicity and long-term clonogenic survival assays in established CRC cell lines, and in tumor organoids derived from colon cancer patients. In the long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5. Conclusions: In a new, clinically relevant CRC-organoid model system we demonstrated a more than additive combined effect between the second-generation TRAIL receptor agonist APG-880 and radiation.
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