The most lethal type of prostate cancer is called metastatic castration resistant prostate cancer, with a 5-year survival rate of only 28%. One of the biggest challenges in managing this disease is that many patients will inevitably develop resistance to the current “standard-of-care” Androgen Receptor (AR) targeted therapies within 2 years. Therefore, there is an overwhelming need to understand the biology of resistance, develop new measurable biological markers to predict resistance, and create a new therapeutic approach to fight against resistance.
Using CRISPR and shRNA-based in vivo library screening approach, we have identified several novel genomic alterations which confer resistance to AR targeted therapies in prostate cancer, including CHD1. Using a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), organoid 3D-culturing, and CRISPR library screening, we are dissecting the molecular function of those newly identified tumor suppressors and oncogenes in mediating therapy resistance, in order to develop new therapeutic approaches to overcome resistance.
We identified the chromatin remodeler CHD1 as the guardian suppressing tumor heterogeneity, lineage plasticity and therapy resistance. This work published in Cancer Cell 2020