前列腺癌驱动突变的同基因小鼠模型

Immunotherapy, such as immune checkpoint blockade, has emerged as a highly successful treatment for cancers including melanoma. While prostate cancer has been termed a “cold malignancy”, generation of models that effectively recapitulate the tumor immune environment offers an avenue by which immunotherapeutic approaches with potential clinical viability can be developed. Syngeneic mouse systems-in which implanted tumor tissue is genetically similar to that of a host animal-represent one such model. At present, syngeneic mouse models of prostate cancer-Myc-CaP, TRAMP-C2, RM1 and PPSM ( Pten -/-; P53 -/-; Smad4 -/-)-do not encompass most driver mutations implicated in tumorigenesis. We therefore sought to broaden the suite of available syngeneic systems, by generating mice harboring tumors with the following mutations: Cdk12 inactivation, ERG overexpression, Myc overexpression, SPOP mutation, FOXA1 mutation, BRAF fusion, Brca2 mutation, and MMR deficiency. In producing these lines, we applied a variety of molecular approaches, subjecting prostate tumor cells from pre-existing genetically modified mouse models (GEMMs e.g. p53 knockout) to in vitro overexpression of fusion oncogenes (e.g. ACPP-FGFR2 ) or CRISPR-based knockout of tumor suppressor genes (e.g. Msh2 ). Growth of the resultant tumor lines in immunocompetent mice provided a platform for novel therapeutic testing. For instance, we generated organoids from Rosa26 ERG ;Pten mice, then subcutaneously implanted them in C57Bl/6 hosts. Upon histological examination, resultant tumors exhibited classical adenocarcinoma histology strongly immunopositive for ERG. While tumors were essentially non-responsive to classical immune checkpoint blockade (anti-PD1), they exhibited reduced growth upon treatment with CBPD-409, a degrader of the key prostate cancer transcriptional coactivator CBP/p300. Strikingly, combination therapy with the aforementioned agents yielded overt tumor regression and marked tumor lymphocytic response encompassing CD4, CD8 and NK cells. This proof of concept experiment highlights the utility of our syngeneic models for in vivo combinatorial pharmacologic testing aimed at generating novel immunotherapy vulnerabilities.