Metastatic Colorectal Cancer (mCRC) Patient Derived Organoids (PDOs) as a preclinical tool to understand mechanisms of resistance to anti-angiogenic drugs


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Somaieh Hedayat1,George Vlachogiannis1,Yann Jamin1,Khurum Khan2,Javier Fernandez-mateos1,Jens C Hahne1,Michaela Rata2,Dow-Ku Koh2,Nina Tunariu2,David Collins3,Monia Bali3,Ian Chau3,Sheela Rao3,David Watkins3,Naureen Sterling3,Nicos Fotoadis3,Ian Huntingford1,Ruwaida Gegum3,Isma Rana3,Massimo Rugge4,Chiara Braconi1,Matteo Fassan4,Suzanne Eccles1,Simon P Robinson1,David Cunningham3,Nicola Valeri1
1Institute of Cancer Research,2Institute of Cancer Research and Royal Marsden Hospital,3Royal Marsden Hospital,4Padua University

Abstract

Background

Regorafenib demonstrated efficacy in pre-treated mCRC patients by inhibiting tumour vasculature. Limited clinical benefit in unselected patient populations highlights the unmet need for better patient selection and identification of mechanisms of action.

Method

mCRC patients with biopsiable metastases were enrolled in a phase II trial (NCT03010722). Biopsies were obtained at baseline, at best response and at disease progression from multiple sites. Functional imaging was acquired in patients pre and post-treatment. PDOs were developed from imaging-guided biopsies of liver, lung and peritoneal metastases and implanted orthotopically in the livers of NSG mice and treated with regorafenib. Changes in tumour and fractional blood volume (fBV) were monitored in vivo by susceptibility-contrast MRI.

Results

PDOs were successfully developed from 35 sequential biopsies and retained genomic and transcriptomic features of parental biopsies over serial passages. PDOs from responder and non-responder patients implanted and metastasized within the liver: vascular density showed significant drop in CD-31 after regorafenib treatment in mice from responder patients (p=0.03, n=6) and no significant changes in those from non-responders (n=10). Morphological analysis revealed a desmoplastic pattern of growth for PDOs established from responders and a pushing/replacement phenotype in those from non-responder patients. Similar findings were observed comparing response to regorafenib in pre and post treatment PDOs from a second responder patient. Susceptibility-contrast-MRI in mice, in keeping with functional imaging in patients, showed a drop in fBV in regorafenib treated mice (n=10; p=0.04) and correlated with CD-31 changes (r2=0.64, p=0.006). Co-culture of sequential PDOs obtained before and after treatment with endothelial cells, cancer associated and normal fibroblasts recapitulated the micro-architecture and response to regorafenib observed in vivo.

Conclusion

PDOs recapitulate pathological, molecular and radiological features of matching metastases upon regorafenib treatment. In vivo and ex vivo co-culture data suggest vessel co-option as a mechanism of primary and acquired resistance to regorafenib.