Polymerase epsilon-based mouse and derived organoid models of intestinal cancer

PROJECT SUMMARY/ABSTRACT
Intestinal cancer is the 3rd most common malignancy and cause of cancer-related deaths in both men and
women. Unfortunately, recent advances in our understanding of the underlying intestinal biology and cancer-
related pathways have not translated to significantly improved patient outcomes. While numerous animal
models of intestinal cancer have been developed, mostly based on misregulation of the β-catenin pathway,
some key features of human cancers (particularly tumor mutational burden) now known to be critical for tumor
progression and therapy response, have not been adequately modelled or investigated in animal models of
intestinal cancer.
More recently, genome sequencing efforts led to the discovery of an intestinal cancer mutator phenotype
where single amino acid substitutions within proofreading domains of the housekeeping DNA polymerases
result in the highest mutation rates described in human cancers (ultramutation).
Unlike human cancers, genetically-engineered animal models exhibit very low mutation rates, limiting their
utility for studies of intratumoral heterogeneity and competition, immune responses, and immune checkpoint
therapies, now known to be essential aspects of human tumor biology. We propose to overcome these
limitations in intestinal cancer animal models by building upon 1) a strong track record in the generation of
cancer animal models and novel genetic tools for their development 2) a well-characterized conditional PoleP286R
allele that we previously used to develop a robust model of endometrial cancer and 3) expertise in genomics,
inflammation, intestinal cancer, and mouse models of intestinal disease. These models will be useful not only
to recapitulate POL-driven intestinal cancers, but also to humanize any intestinal cancer mouse model with
respect to mutational burden. This proposal is submitted in response to PAR-20-131 to expand and improve the
development of mammalian models for translational cancer research.

Grant Number: 4R01CA265884-04
NIH Institute/Center: NIH
Principal Investigator: DIEGO CASTRILLON