Prostate cancer can be lethal, but is more commonly indolent, with PSA screening having led to over-diagnosis and overtreatment. A critical question then is how to distinguish lethal from indolent disease. Our lab was among the first to identify prognostically relevant gene-expression and genomic features of prostate cancer. We also identified and validated AZGP1 as a biomarker of favorable outcomes, since incorporated into a commercial multi-gene assay. Our ongoing studies seek to define intratumor heterogeneity and genome evolution, with respect to distinguishing lethal from indolent cancers.
Benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH) is the enlargement of the prostate gland leading to urinary symptoms in many older men. BPH pathogenesis is poorly understood, and current treatments are only partially effective. By transcriptional profiling of bulk tissue and single cells, we recently identified novel signaling molecules linked to BPH pathogenesis (e.g., BMP5 and CXCL13), and discovered a fundamental “re-landscaping” of cell types in BPH. Current efforts seek to further define the cells and molecules driving BPH, and leverage that knowledge towards new disease-focused therapies.
Genome initiatives have largely ignored rare neoplasms that are of no less biologic interest and clinical importance to those patients affected. We have been carrying out genomic studies of ameloblastoma, an uncommon tumor arising from the ameloblast-lineage, the cells that deposit enamel during tooth development. We have newly identified actionable driver mutations, including mutations in the Hedgehog (SMO) and MAP-kinase (BRAF) pathways. Current efforts focus on further characterizing tumor pathobiology, and conducting preclinical studies with molecularly-directed therapies.
Patient-derived cell culture models
Not all cancer subtypes and genotypes are well represented by existing cell line models. Adopting the “Georgetown” method of conditional reprogramming (ROCK inhibitor plus irradiated fibroblast conditioned media), we have been generating patient-derived cell culture models of varied cancerous and benign diseases, employing both two- and three-dimensional approaches.