A Novel Separase Inhibitor, Sepin-1, for Neuroblastoma Treatment
Greater than 80% of neuroblastoma (NB) tumors overexpress ESPL1 transcripts, which encode for the Separase protein, an enzyme important for cell division. Separase resolves chromosomal cohesin by proteolytically cleaving chromosomal cohesin protein. Separase is overexpressed in multiple adult (breast, bone, brain and prostate) and pediatric tumors (osteosarcoma, glioblastoma and leukemia). Separase overexpression strongly correlates with high incidence of relapse, metastasis and a lower 5-year overall survival rate. Separase activity is tightly regulated during the cell cycle, and due to its critical role in chromosomal segregation, overexpression of the Separase enzyme leads to aneuploidy (abnormal chromosome number), a hallmark of human tumors. In mouse models, Separase overexpression has been shown to induce aneuploidy, genomic instability, tumorigenesis and intratumor heterogeneity. We have also shown that knock down of ESPL1 transcripts selectively inhibit the proliferation of tumor cells that overexpress Separase.
Based on these mechanistic studies, we propose that modulation of Separase enzymatic activity using a small molecular inhibitors of Separase enzyme constitutes a novel mechanism, never-before tested target and a new therapeutic strategy for targeting Separase-overexpressing neuroblastoma tumors, particularly the refractory tumors that often develop resistance to conventional chemotherapy. Our preliminary data provides strong evidence to support this idea and we show that Sepin-1, a proprietary novel Separase inhibitor developed in my lab can potently inhibit proliferation of Separase overexpressing tumors. Here, we plan to extend these findings into efforts to pursue IND enabling studies for the use of Sepin-1 as a treatment for Separase overexpressing NB tumors.