Tumour Organoids from Multifocal Metastatic Colorectal Cancers for Personalised Oncology - European Medical Journal

Tumour Organoids from Multifocal Metastatic Colorectal Cancers for Personalised Oncology

1 Mins
Oncology
Authors:
Kushtrim Kryeziu,1 Solveig K. Klokkerud,1 Kaja C.G. Berg,1 Max Z. Totland,1 Christian H. Bergsland,1,2 Barbara Niederdorfer,1 Seyed H. Moosavi,1,2 Trygve Syversveen,3 Eva Hofsli,4 Morten Brændengen,5 Kristoffer Lassen,6 Arild Nesbakken,1,2,7 Sheraz Yaqub,2,6 Tormod Guren,8 Anita Sveen,1,2 *Ragnhild A. Lothe1,2
Disclosure:

Kryeziu has received a travel grant to attend European Society for Medical Oncology (ESMO) 2022 from Hydros Fond. Yaqub has received funds from Bayer and a grant from South-Eastern Norway Regional Health Authority. Guren has received honoraria from Pierre Fabre; and served on the Safety Monitoring Board for three academic studies. Sveen has received research grants from The Research Council of Norway, The Norwegian Cancer Society, and the South-Eastern Norway Regional Health Authorities. Lothe has received research grants from The Research Council of Norway, The Norwegian Cancer Society, and the South-Eastern Norway Regional Health Authorities. The other authors have declared no conflicts of interest.

Acknowledgements:

The authors would like to express their very great appreciation to the patients that donated the tissues, and their family members for their support. The authors also thank the study nurses and their technical staff for their valuable contribution to this study.

Citation:
EMJ Oncol. ;10[1]:30-31. DOI/10.33590/emjoncol/10088513. https://doi.org/10.33590/emjoncol/10088513.
Keywords:
Chemotherapy, colorectal cancer (CRC), functional oncology, genomics, heterogeneity, liver metastasis, living biobank, patient-derived organoids (PDO), personalised oncology, pharmacogenomics.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

Patients with colorectal cancer (CRC) have limited systemic treatment options compared to other major cancer types.1 Tumour heterogeneity is a major cause of treatment failure.

MATERIALS AND METHODS

The authors have generated a living biobank of 208 patient-derived organoids (PDO) from liver metastases of 100 patients treated by hepatic resection for advanced CRC at Oslo University Hospital, Norway. The biobank includes multiple synchronous lesions (n=2–6) from 66 of the patients, and recurrent lesions sampled at hepatic re-resections of four patients. All PDOs have been screened for sensitivity to custom-made and clinically relevant drug libraries for CRC (n=40–47 drugs).2,3 Subsets of PDOs and corresponding tumour tissue samples have been analysed by multi-omics approaches.4 The study design is illustrated in Figure 1.

Figure 1: Study design.
Single or multiple metastases were resected from patients with advanced CRC and ex vivo PDOs established. Tumour organoids were seeded to pre-drugged plates, followed by cell viability measurements (3D CellTiter-Glo) after 96 hours. Drug Sensitivity Scores were calculated for each drug as a measure of reduced viability. In parallel, gene expression and sequencing of clinically relevant mutations were conducted for pharmacogenomic analyses. Short tandem repeat profiling was performed for all PDOs and their corresponding tissues for authentication.
Chemo: chemotherapy; CRC: colorectal cancer; mCRC: metastatic colorectal cancer; mIHC: multiplexed immunohistochemistry; MSI: microsatellite instability; PDO: patient-derived organoids; STR: short tandem repeat.

RESULTS

Metastatic lesions from individual patients showed only modest heterogeneity in drug sensitivities with distribution of mean Euclidean distances skewed towards lower intra-patient heterogeneity. Also, there was no correlation between the number of PDOs analysed per patient and their mean Euclidean distances. TP53 mutated PDOs were generally multidrug-resistant, and TP53 wild-type PDOs were sensitive to several chemotherapies, including 5-FU, SN-38, TAS-102, and gemcitabine. Furthermore, sensitivity to the PARP inhibitor talazoparib was significantly higher in TP53 wild-type PDOs, which supports the authors’ previous study suggesting wild-type TP53 activity as a mechanism of response to PARP inhibition in CRC cell lines.5 A TP53 mutated PDO harbouring an ATM mutation was hypersensitive to PARP inhibition, suggesting that other mechanisms of poly adenosine diphosphate-ribose polymerase inhibitor sensitivity are also involved. Among patients with a lack of sensitivity to standard-of-care drugs for CRC, 7% and 4% presented strong sensitivities towards conventional chemotherapies methotrexate and gemcitabine, respectively. Ex vivo drug vulnerabilities from the living biobank are currently being used as a reference basis for an interventional Phase II umbrella clinical study for patients with advanced CRC.

CONCLUSION

PDOs from multifocal liver metastases model pharmacogenomic heterogeneity of advanced CRCs and have strong potential for personalised oncology.

References
Sveen A et al. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol. 2020;17(1):11-32. Bruun J et al. Patient-derived organoids from multiple colorectal cancer liver metastases reveal moderate intra-patient pharmacotranscriptomic heterogeneity. Clin Cancer Res. 2020;26(15):4107-19. Kryeziu K et al. Increased sensitivity to SMAC mimetic LCL161 identified by longitudinal ex vivo pharmacogenomics of recurrent, KRAS mutated rectal cancer liver metastases. J Transl Med. 2021;19(1):384. Berg KCG et al. Multi-omics of 34 colorectal cancer cell lines – a resource for biomedical studies. Mol Cancer. 2017;16(1):116. Smeby J et al. Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity. EBioMedicine. 2020;59:102923.

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