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Poster Display session 3

5713 - Immune competent somatic mosaic model of colorectal cancer


30 Sep 2019


Poster Display session 3



Tumour Site


Stefania Napolitano


Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253


S. Napolitano1, F. Carbone2, D.G. Menter1, T. Troiani3, G. Genovese2, S. Kopetz1

Author affiliations

  • 1 Department Of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 77030-3722 - Houston/US
  • 2 Department Of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, 77030-3722 - Houston/US
  • 3 Medicina Di Precisione, Università degli studi della Campania "Luigi Vanvitelli", 80131 - Naples/IT


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Abstract 5713


Historically, immunotherapies have been tested in syngeneic mouse models and until now only limited CRC syngeneic cells are available. Animal models with functioning human immune systems are critically needed to more accurately evaluate checkpoint blockers delivery, therapeutic response, and to better define biomarker expression in the presence of a competent immune system.


To better address the efficacy of immune checkpoint therapy specifically in relation to presence of a BRAFmutation, we developed a novel platform for the generation of somatic mosaic models of CRC enabling (i) high-throughput generation of genetically complex syngeneic models of cancer, (ii) tracing studies through fluorescence reporters.


Cdx2Cre/+ mice, expressing the Cre recombinaseunder the control of a human Cdx2 promoter/enhancer sequence have been crossed with the R26LSL-Cas9-Gfp strain to generate models allowing for tissue specific activation of Cas9 and Gfpreporter only in CDX2 positive cells. This strain has been crossed with BRAFFSF-V600E mice to generate the final model. 6-8 weeks old mice have then been transduced with AAV constructs expressing the FLPO recombinasethat can be activated by Cre recombinase and sgRNAs targeting APC, TP53, MLH1, MSH2and ARID1Aalone or combined, in order to model MSI CRC (APC-TP53-MLH1and ARID1A-MLH1conditional mosaic knock-outs) and MSS CRC (APC-TP53 conditional mosaic knock-out). Viral particles have been surgically delivered via subserosal cecal injection and mice monitored for tumor formation by IVIS imaging. 35 mice injected with 3 combinations of tumor suppressors provide a diverse immunology repetoire. Cell lines isolated from genetically modified mice will provide a physiologic relevant and feasible means to study the mechanisms of response and resistance to immunotherapies and to understand biological and molecular differences between BRAFmutated MSI and MSS tumors.


This project focuses on the identification and characterization of the functional drivers of CMS1CRC tumors leveraging in vivomosaic genome editing technologies and functional genetic labeling of malignant sub-populations emerging during disease progression and in response to therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.


MD Anderson Cancer Center.


All authors have declared no conflicts of interest.

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