Amina Zoubeidi

Dr. Zoubeidi’s research program centers on uncovering how contemporary prostate cancer therapy targeting the androgen receptor induces treatment resistance and controls phenotypic plasticity, a phenomenon associated with clinical recurrence and poor overall survival. Her research program addresses the importance of various factors and signaling pathways that facilitate plasticity in this inherently heterogeneous disease.

Her laboratory discovered that the lineage plasticity switch is assumed by dynamic and reversible epigenetic regulation, which guide alternative cell phenotypes. Comparative analysis by assay for transposase-accessible chromatin followed by sequencing (ATAC-seq) revealed distinct chromatin accessibilities of NEPC compared to adenocarcinoma, indicating that large-scale chromatin remodeling had occurred during the emergence of the NEPC phenotype. Hyper-accessible regions exclusive to NEPC were enriched in binding motifs for various neuronal associated transcription factors, notably the neural “pioneer” transcription factor ASCL1 that possesses the unique capacity to bind to and open closed chromatin regions. ASCL1 motifs were found in proximity to EZH2 binding sites suggestive of a potential interplay between these two factors. This work has nominated ASCL1 as a molecular “conduit” to NE differentiation after hormone therapy that warrants further focus and study (funded by CIHR).

Moreover, she found that the epigenetic dysregulation inherent to NEPC alters chromatin architecture allowing an opportune environment for certain transcription factors to be “reprogrammed” to facilitate tumour lineage plasticity and therapy resistance. In-depth analysis revealed that changes in chromatin accessibility allow the AR to flow between different binding profiles (cistromes) to impart a plastic state of “lineage infidelity”. In particular, her laboratory delineated that an alternative AR transcriptional program is operative during epithelial-to-neuroendocrine lineage conversion to activate stem cell and neuronal programs – granting privileges associated with both fates. Interestingly, we found that the chromatin modifier EZH2, when phosphorylated at T350, functions non-canonically at reprogrammed AR binding sites in NEPC to activate lineage plastic genes, highlighting a largely unknown role for post-translational EZH2 modifications in managing lineage reprogramming. This inherent epigenetic plasticity allowed us to therapeutically re-direct cell fate using epigenetic inhibitors highlighting the clinical potential of reversing resistance phenotypes (funded by TFRI).

Finally, she made the initial discovery that the neuronal lineage-guiding transcription factor BRN2 is sufficient to drive neuroendocrine differentiation when expressed in prostate adenocarcinoma. BRN2 is highly expressed in human NEPC and can be induced by hormone therapy. Expression of BRN2 facilitates global epigenetic reprogramming by increasing H3K27 acetylation (H3K27ac; a mark of a permissive chromatin state) at the expense of H3K27 tri-methylation (H3K27me3; a mark of “non-permissive” chromatin state). These data convey that BRN2 plays a principal role in controlling the chromatin landscape to facilitate lineage plasticity (funded by CIHR). Since first linking BRN2 to the NEPC phenotype, my laboratory has successfully solved the crystal structure and developed first in-field drug targeting BRN2 (patented by UBC), which showed anti-cancer activity in multiple organoids and xenografts (Funded by PCC). We are expanding the testing of this inhibitor into other neuroendocrine cancer and developing a companion biomarker to assess the pharmacodynamics of BRN2 inhibitor in the clinic (Funded by US DOD). We are optimizing BRN2 inhibitor for drug-like proprieties with the goal of initiating a clinical trial in 2021 (Funded by PCF-USA).