WORKPACKAGE 5

Preclinical in vitro and in vivo models for functional characterization of DCIS and validation of DCIS genes

 

The key aspect of this workpackage entails the functional validation of candidate DCIS genes that enroll from the comprehensive genomic characterization of DCIS samples. It will be important to discriminate between passenger mutations, DCIS genes that induce indolent disease or lesions with a low propensity to progress to invasive carcinoma, and DCIS genes that induce aggressive lesions that rapidly progress to invasive disease.

Hypothesis-driven questions

1. What are the key driver mutations that differentiate aggressive from indolent DCIS?
2. What are the differences in overall transcriptomic, mutational, proteomic and methylomic profiles between aggressive and indolent DCIS?
3. What are the differences in the microenvironment between aggressive and indolent DCIS?
4. What are the druggable vulnerabilities of poor prognosis DCIS?

Workpackage 5 is responsible for the project objective to deliver a set of drugs with demonstrated in vivo activity against specific subtypes of aggressive DCIS

Milestones

5.1 A collection of well-characterised 3D tumoroids of DCIS
5.2 A collection of well-characterised genetically engineered mouse models (GEMMs) of DCIS
5.3 A collection of well-characterised patient-derived xenograft (PDX) models of DCIS
5.4 A compendium of drugs with proven preclinical activity against (specific subtypes of) poor prognosis DCIS

WP lead

Professor Jos Jonkers

Group Leader and Division Head of Division Molecular Pathology

The Netherlands Cancer Institute, Amsterdam, The Netherlands