Of mice and men: what we can learn about human cancer by studying mouse models

Wednesday, December 19, 2018 | 3:00 to 4:00 p.m. ET

Cory Abate-Shen, Ph.D.

Michael and Stella Chernow Professor of Urological Oncology

Professor, Departments of Urology, Medicine, Pathology and Systems Biology

Interim Director, Herbert Irving Comprehensive Cancer Center

Columbia University Irving Medical Center

Website

Summary

The research in Cory Abate-Shen’s laboratory is focused on understanding basic mechanisms of transcriptional regulation and differentiation, and how these become dysregulated in cancer. The laboratory takes a multi-disciplinary approach to investigate genitourinary malignancies, which includes using mechanism-based studies, analyses of genetically-engineered mouse models (GEMMs), and state-of-the-art systems biology approaches. This research focus has its origins in their discovery of Nkx3.1 as a prostate-specific homeobox gene, which is essential for prostate differentiation and whose loss of function predisposes to prostate cancer. Analysis of Nkx3.1 mutant mice provided the foundation for their extensive series of GEMMs based on genomic alterations that occur in human prostate cancer, which represent the spectrum of prostate cancer phenotypes, ranging from pre-invasive to lethal castration-resistant and metastatic disease. To capitalize on these prostate cancer GEMMs, the Abate-Shen laboratory has generated genome-wide regulatory networks for mouse and human prostate cancer, which have enabled cross-species analyses to identify FOXM1 and CENPF as synergistic drivers and robust biomarkers of lethal disease. They have expanded these computational approaches to integrate preclinical data from GEMMs with human clinical data to predict drug response and optimize drug combinations for human prostate cancer. Recent investigations of the mechanisms of failed response to anti-androgens in castration-resistant prostate cancer has identified transdifferentiation as a mechanism of resistance in p53-dependent contexts. These studies have also enabled modeling of de novo bone metastasis in a GEMM of advanced prostate cancer. In addition to these studies focused on prostate cancer, the Abate-Shen laboratory has expanded its interests in GU malignancies to bladder cancer. They have developed novel approaches to target gene recombination specifically to bladder urothelium, and have used these approaches to generate unique GEMMs of muscle invasive bladder cancer. These GEMMs have enabled co-clinical investigations that have advanced to new clinical trials for treatment of high-risk bladder cancer.