Abstract 219: Molecular and therapeutic characterization of a large-scale collection of metastatic colorectal cancer patient-derived xenografts and matched organoids for translational oncology
Authors: Leto Simonetta M. , Grassi Elena , Avolio Marco , Vurchio Valentina , Cottino Francesca , Ferri Martina , Zanella Eugenia R. , Blasio Laura Di , Puliafito Alberto , Primo Luca , Bertotti Andrea , Trusolino Livio 
Published: March 2024

Strong evidence supports the use of patient-derived xenografts (PDXs) as faithful models reflecting patient outcomes. Since not all research can support the use of animals, exploiting patient-derived in vitro models such as organoids (also know as tumoroids) is essential. However, current biobanks of metastatic colorectal cancer (mCRC) tumoroids have important limitations, such as small sample size and a lack of systematic in vivo validation with paired xenografts, which decreases the translational value of tumoroid-based pipelines. Here we describe XENTURION, a unique open-science resource of XENografts and Tumoroids for Research In ONcology that encompasses 129 sibling pairs of mCRC PDXs and PDX-derived tumoroids (PDXTs) with accompanying molecular and therapeutic characterization.The vast majority of XENTURION models were analyzed for mutations (targeted next-generation sequencing of 116 relevant CRC genes), gene copy number architecture (DNA shallow sequencing) and global transcriptomics (RNAseq) and benchmarked against large patient datasets (TCGA and MSK-IMPACT). Results showed that the PDX-PDXT collection proved to be representative of the genetic heterogeneity of mCRCs and displayed high genetic and transcriptional similarity between matched pairs. A PDXT-based population trial with the clinically approved anti-EGFR antibody cetuximab was performed in 116 PDXTs, revealing variable sensitivities that were consistent with clinical response biomarkers and with tumor growth changes in 79 matched PDXs. Cetuximab response profiles also recapitulated the outcome of EGFR knock-out by CRISPR-Casp9 technology in 13 representative PDXTs. Adaptive signals upregulated by EGFR blockade both in tumoroids and PDXs were computationally and functionally prioritized. Top candidates were screened in PDXTs and 3 surviving compounds were identified as actionable co-extinction targets with cetuximab in 12 PDXT models. Results were finally validated in PDXs.To our knowledge, this is the first large-scale study in which a systematic comparison of molecular and therapeutic profiles between PDXT-PDX pairs was attempted. As a publicly available resource, XENTURION will offer a knowledge base of disseminatable methods, resources and information to streamline preclinical studies and accelerate new treatments for patients with mCRC.

Citation Format: Simonetta M. Leto, Elena Grassi, Marco Avolio, Valentina Vurchio, Francesca Cottino, Martina Ferri, Eugenia R. Zanella, Laura Di Blasio, Alberto Puliafito, Luca Primo, Andrea Bertotti, Livio Trusolino. Molecular and therapeutic characterization of a large-scale collection of metastatic colorectal cancer patient-derived xenografts and matched organoids for translational oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 219.