Preclinical Models and Therapeutics Core

PATHOLOGY CORE: SUMMARY The Pathology Core (PC) will generate and characterize the reagents critical for this proposal, including primary tumor samples, a wide array of patient derived tumor xenograft (PDTX) models and patient derived organoids (PDO). We will use PDTX models to conduct in vivo preclinical animal studies described in Projects 2 and 3. This will allow for efficient and consistent evaluation of the biological relevance of selected mutations/genomic landscapes and generation of models which allows their validation, in each of the two Projects. We have established a large library of primary samples representing the heterogeneity of DLBCL and T-ALL/PTCL, Genetically Engineered Mouse Models (GEMMs) and ultimately a large cohort of PDX and corresponding derivatives. Translational cancer research has been facilitated by the demonstration that human tumors can be grown as xenografts in immunocompromised mice, and the use of PDTX has significantly increased the public knowledge of cancer biology, and improved the preclinical evaluation and predictability of investigational drugs. More importantly, PDTX were maintain many of the features of the original patient tumors, including expression phenotypes, genomic landscape, tumor heterogeneity and intrinsic properties such as their ability to colonize specific organs, suggesting that these models provide an informative platform to study neoplasms and interrogate the impact of changes occurring after genomic and or pharmacological manipulations. Here we will focus on the generation and characterization of ad hoc PDTX corresponding to neoplasms with defined genomic alterations relevant to the three Projects. Both PDTX and 2D/3D derived in vitro models will be molecularly profiled and validated using functional approaches. PDTX are particularly useful for in vivo mechanistic studies in PDOs, and the information from these studies will be instrumental in understanding the biology, stratification criteria and response(s) to targeted therapies described in the Projects. The Core will closely interact with the Computational and Genomics Cores for genomic and functional analyses. The Specific Aims are: (1) To provide normal and pathological samples to cross validate the data generated in in vitro-mouse models and to determine the frequency and contribution of selected mutations; (2) To generate ad hoc PDTX and PDTX-derivatives carrying defined genomic defects (CTCF mutant, etc.) (3) To provide comprehensive planning, preparation and coordination of in vivo PDTX co-clinical studies. (4) To distribute fully characterized PDTX tumors to Project Leaders for mechanistic studies.