Prostate cancer is among the leading causes of cancer related death in men. An unmet need is the availability of genetically complex preclinical models to study disease development and response to therapy. The Prostate Cancer Preclinical Mouse Modelling Platform (ProMPt) utilizes a biobank of prostate cancer organoids that covers 150 genetically unique combinations as seen in patients. An exploratory characterization of 20 models is presented to showcase this platform and investigate the genetic basis of therapeutic response to androgen deprivation therapy (ADT).

Mice harbouring inducible alterations for PTEN, TP53, MYC, TMPRSS2/ERG, RB1, and APC were bred to achieve 20 genetically unique models. Prostatic organoids were generated from these models and this syngeneic biobank has been characterized through bulk RNA sequencing and mass cytometry by time of flight (CyTOF) for phenotypic alterations in response to androgen deprivation therapy. Permutation of organoid culture media in combination with ADT revealed upregulation of druggable pathways that have been assessed through targeted drug screens in vitro and ProMPt mouse models.

Viability assessment revealed varied response to long term ADT exposure across 20 genetically unique organoid models, with resistant lines harbouring 3 or more genetic alterations. To investigate the influence of culture media on response to therapy, organoids were deprived of EGF, Noggin, R-Spondin1, and A83-01 in combination with ADT prior to CyTOF data collection. A striking response was seen between EGF removal and increased sensitivity to ADT in a genotype dependant manner when focused on alterations in a Pten and P53 deleted background. Overexpression of MYC rescued this sensitivity and CyTOF analysis revealed Pten-P53-MYC organoids maintain upregulation of phosphorylated 4E-BP1 in EGF null and ADT conditions, indicating a cell autonomous mode of survival. These results were translated to a targeted drug screen where ErbB, AKT, MAPK and translation inhibitors were assessed in multiple combinations in conjunction with ADT. Homoharringtonine, an FDA approved translation inhibitor, showed exceptional results in reducing viability when used in combination with ErbB inhibitors. This effect is currently being assessed in vivo against a Pten-MYC and Pten-P53-MYC model of prostate cancer.

ProMPt allows for rapid in vitro and in vivo modelling that can be used to investigate many aspects of prostate cancer biology. To demonstrate the platform, the therapeutic response of 20 unique prostate cancer organoids were assessed at the proteomic level. Vulnerabilities were further highlighted through permutation experiments which have been translated to active preclinical in vivo trials. ProMPt will soon be publicly available, providing a novel catalogue of prostate cancer material.