Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Oct 27

PMID 36291768

Authors

Kristin Pape

Anna J Lossner

Doreen William

Tabea Czempiel

Elke Beyreuther

Anna Klimova

Claudia Lehmann

Tim Schmache

Sebastian R Merker

Max Naumann

Anne-Marlen Ada

Franziska Baenke

Therese Seidlitz

Rebecca Butof

Antje Dietrich

Mechthild Krause

Jurgen Weitz

Barbara Klink

Clare von Neubeck

Daniel E Stange

Affiliations

Soon will be listed here.

Abstract

Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient's tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.

Citing Articles

Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors.

Rodland G, Temelie M, Eek Mariampillai A, Hauge S, Gilbert A, Chevalier F Cells. 2024; 13(12.

PMID: 38920686 PMC: 11201490. DOI: 10.3390/cells13121058.

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes.

Pennel K, Dutton L, Melissourgou-Syka L, Roxburgh C, Birch J, Edwards J Expert Rev Mol Med. 2024; 26:e14.

PMID: 38623751 PMC: 11140547. DOI: 10.1017/erm.2024.15.

References

Habr-Gama A, Perez R, Proscurshim I, Campos F, Nadalin W, Kiss D . Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg. 2006; 10(10):1319-28. DOI: 10.1016/j.gassur.2006.09.005. View

Grem J . 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs. 2000; 18(4):299-313. DOI: 10.1023/a:1006416410198. View

Lempiainen H, Halazonetis T . Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J. 2009; 28(20):3067-73. PMC: 2752028. DOI: 10.1038/emboj.2009.281. View

Talevich E, Shain A, Botton T, Bastian B . CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLoS Comput Biol. 2016; 12(4):e1004873. PMC: 4839673. DOI: 10.1371/journal.pcbi.1004873. View

Henriette Tanja L, Guchelaar H, Gelderblom H . Pharmacogenetics in chemotherapy of colorectal cancer. Best Pract Res Clin Gastroenterol. 2009; 23(2):257-73. DOI: 10.1016/j.bpg.2009.02.011. View

Van der Valk M, Hilling D, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets G, Figueiredo N . Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018; 391(10139):2537-2545. DOI: 10.1016/S0140-6736(18)31078-X. View

Alves A, Panis Y, Mathieu P, Kwiatkowski F, Slim K, Mantion G . Mortality and morbidity after surgery of mid and low rectal cancer. Results of a French prospective multicentric study. Gastroenterol Clin Biol. 2005; 29(5):509-14. DOI: 10.1016/s0399-8320(05)82121-9. View

Alexandrov L, Nik-Zainal S, Wedge D, Aparicio S, Behjati S, Biankin A . Signatures of mutational processes in human cancer. Nature. 2013; 500(7463):415-21. PMC: 3776390. DOI: 10.1038/nature12477. View

Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U . Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005; 23(24):5644-50. DOI: 10.1200/JCO.2005.08.144. View

10.

Vaios E, Wo J . Proton beam radiotherapy for anal and rectal cancers. J Gastrointest Oncol. 2020; 11(1):176-186. PMC: 7052774. DOI: 10.21037/jgo.2019.04.03. View

11.

Wilson G, Bentzen S, Harari P . Biologic basis for combining drugs with radiation. Semin Radiat Oncol. 2005; 16(1):2-9. DOI: 10.1016/j.semradonc.2005.08.001. View

12.

Colaco R, Nichols R, Huh S, Getman N, Wei Ho M, Li Z . Protons offer reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer. J Gastrointest Oncol. 2014; 5(1):3-8. PMC: 3904024. DOI: 10.3978/j.issn.2078-6891.2013.041. View

13.

Luhr A, von Neubeck C, Krause M, Troost E . Relative biological effectiveness in proton beam therapy - Current knowledge and future challenges. Clin Transl Radiat Oncol. 2018; 9:35-41. PMC: 5862688. DOI: 10.1016/j.ctro.2018.01.006. View

14.

Hickson I, Zhao Y, Richardson C, Green S, Martin N, Orr A . Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004; 64(24):9152-9. DOI: 10.1158/0008-5472.CAN-04-2727. View

15.

Mayakonda A, Lin D, Assenov Y, Plass C, Koeffler H . Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018; 28(11):1747-1756. PMC: 6211645. DOI: 10.1101/gr.239244.118. View

16.

Suckert T, Nexhipi S, Dietrich A, Koch R, Kunz-Schughart L, Bahn E . Models for Translational Proton Radiobiology-From Bench to Bedside and Back. Cancers (Basel). 2021; 13(16). PMC: 8395028. DOI: 10.3390/cancers13164216. View

17.

Olshen A, Bengtsson H, Neuvial P, Spellman P, Olshen R, Seshan V . Parent-specific copy number in paired tumor-normal studies using circular binary segmentation. Bioinformatics. 2011; 27(15):2038-46. PMC: 3137217. DOI: 10.1093/bioinformatics/btr329. View

18.

Sato T, Stange D, Ferrante M, Vries R, van Es J, van den Brink S . Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology. 2011; 141(5):1762-72. DOI: 10.1053/j.gastro.2011.07.050. View

19.

Chakravarty D, Gao J, Phillips S, Kundra R, Zhang H, Wang J . OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. 2017; 2017. PMC: 5586540. DOI: 10.1200/PO.17.00011. View

20.

Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Vavassori I, Barni S . Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol. 2013; 65(2):350-7. DOI: 10.1016/j.eururo.2013.06.049. View