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Felchle, H.* ; Brunner, V.* ; Groll, T.* ; Walther, C.N.* ; Nefzger, S.M.* ; Zaurito, A.E.* ; Silva, M.G.* ; Gissibl, J.* ; Topping, G.J.* ; Rotgerink, L.L.* ; Saur, D.* ; Steiger, K.* ; Combs, S.E. ; Tschurtschenthaler, M.* ; Fischer, J.C.*

Novel tumor organoid-based mouse model to study image-guided radiation therapy of rectal cancer after non-invasive and precise endoscopic implantation.

Int. J. Radiat. Oncol. Biol. Phys. 118, 1094-1104 (2023)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
PURPOSE: Preoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT) which combines simultaneous radio-chemotherapy with additional courses of chemotherapy (CTx) has emerged as an effective approach. TNT achieves a pathological complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-PD-1 immunotherapy (IT) can induce clinical complete responses in patients with specific genetic alterations. Overall, there is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to IT remain poorly understood. MATERIALS AND METHODS: We developed a novel orthotopic mouse model of rectal cancer which is based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT, and validated rectal tumor growth and response rates to therapy using small animal magnetic resonance imaging and endoscopic follow-up. RESULTS: Rectal tumor formation was successfully induced in all mice following two organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, longterm survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiological tumor staging and histopathological examination. CONCLUSIONS: Our novel mouse model combines orthotopic tumor growth via non-invasive and precise rectal organoid injection and small animal RT. This model holds significant promise for investigating the impact of tumor cell-intrinsic aspects, genetic alterations of the host, or exogenous factors (e.g., nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving CTx, IT or novel targeted therapies.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mouse Model ; Radiation Therapy ; Rectal Cancer ; Translational Research ; Tumor Organoids; Open-label; Preoperative Chemoradiotherapy; Radiotherapy; Chemotherapy; Multicenter; Metabolism; Expression; Blockade
ISSN (print) / ISBN 0360-3016
e-ISSN 0360-3016
Journal International Journal of Radiation Oncology, Biology, Physics
Quellenangaben Volume: 118, Issue: 4, Pages: 1094-1104 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Radiation Medicine (IRM)
Grants TUM School of Medicine
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Else Kroner-Fresenius-Stiftung
German Cancer Aid
Else Kroner Forschungskolleg of the Technical University of Munich
Friedrich Naumann Foundation for Freedom