CIS Program Event: Nathaniel Mabe

Leveraging Tumor Lineage for Target Discovery

Nathaniel Mabe, assistant professor in the Medicinal Chemistry and Molecular Pharmacology department at Purdue University, will be a speaker for the PICR Seminar Series.

Pediatric cancers demonstrate a paucity of genetic mutations, and therefore have not realized as many gains in targeted therapies as adult cancers. Pediatric cancers typically arise from dysregulation that occurs during normal development. As such, pediatric tumors retain lineage-encoded transcriptional programs from their tissue of origin. Thus, perturbation of pathways underlying altered lineage state may provide an opportunity to the selective targeting of these diseases. In the first segment of my seminar, we mined the Pediatric Dependency Map to identify that neuroblastomas require activity of the Polycomb Repressive Complex 1.1, also known as the BCOR complex, to maintain a de-differentiated cell state. Using integrated multi-omics analysis, we identified that small molecule inhibition of the deubiquitinase USP7 destabilized the BCOR complex, leading to loss of BCOR complex activity and an induction of neurodifferentiation. Neuroblastomas exhibit the capability of switching their differentiation state from an adrenergic to a mesenchymal lineage, which underlies resistance to FDA-approved, anti-GD2 immunotherapies. In the second segment, we utilized a FACS-based, genome-wide CRISPR/Cas9 screening platform to identify that the simultaneous loss of epigenetic enzymes EZH2 and menin induced a cell state transformation, thereby inducing GD2 expression. Mechanistically, combined Menin and EZH2 inhibition induced cell state transformation by increasing the expression of genes marked by bivalent chromatin domains, defined by the paradoxical presence of permissive H3K4me3 and repressive H3K27me3 histone marks.

The event is hosted by Majid Kazemian.