Next-generation sequencing has enabled the large-scale profiling of aberrant genetic events associated with prostate and bladder cancer. However, functional annotation of this rich information in relevant model systems is limited. To address this, we use a forward genetic approach with mouse and human prostate and bladder epithelial transformation systems. Benign epithelial cells are modified to stably express specific oncogenic factors, cultured briefly in the permissive environment of Matrigel, and transplanted into immune-deficient mice. The resultant tumors are characterized to gain insight into the mechanisms by which the interaction of specific oncogenic events generate certain phenotypes of prostate and bladder cancer.
We have established a platform integrating RNA-seq and proteomics to nominate tumor-associated antigens enriched in subtypes of advanced prostate cancer with limited systemic expression in normal tissues. Candidate cell surface and intracellular antigens undergo multi-level validation including immunohistochemistry of microarrays of metastatic prostate cancers and benign human tissues. From the validated targets, we engineer and test both humoral and cellular immunotherapies in cell line- and patient-derived xenograft models of advanced prostate cancer.
Myc and AR are transcription factors with essential roles in the pathogenesis and maintenance of typical prostate cancer. We have developed Myc and AR reporter assays that facilitate the dynamic assessment of both subcellular protein localization and protein abundance. We are interrogating these assays with genome-wide CRISPR loss-of-function and gain-of-function screens to uncover the genetic/biologic pathways that modulate Myc and AR localization and stability. These reporters have also been used to complete high-throughput, high-content imaging screens with diverse chemical libraries to identify small molecule inhibitors of Myc and AR. Lead identification is ongoing in collaboration with prominent medicinal chemistry and prostate cancer biology colleagues.