ICA-1S和Selinexor降低非典型畸胎样横纹肌样瘤(ATRT)的存活和增殖

Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive and rapidly growing cancerous brain and spinal cord tumor mainly affecting young children, less than 3 years of age. ATRT consists of less than 5% of all pediatric CNS tumors. Abnormalities in chromosome 22q11, which includes the putative tumor suppressor gene SMARCB1 are frequently seen in ATRT. SMARCB1is a component of an SWI/SNF ATP-dependent chromatin-remodeling complex that controls the expression of certain target genes involved in cell cycle regulation. Approximately, 75% of ATRTs contains the homozygous deletions of SMARCB1, or loss of one allele and mutation of the other copy for the gene. Due to the rare and complex nature of the disease, ATRT is under researched. It is crucial to understand the signaling pathways that operate in the cell proliferation and survival of the ATRT tumors, and to establish a targeted therapy for this disease. One promising area that can be explored is the atypical Protein Kinase Cs (aPKCs). Protein Kinase C-iota (PKC-ι), an aPKCs isozyme, is over-expressed in many types of cancers. PKC-ι plays a major role in tumorigenesis because it is over-expressed and impacted by PI3K, PTEN and other signaling pathways. However, the role of aPKCs is yet to be discovered in the cell proliferation and survival of the ATRT cells. Therefore, in this study we aim to use, a novel PKC-ι inhibitor ICA-1S, alone or in-combination with Selinexor, and observe the subsequent effects on the ATRT cell proliferation and survival. The central hypothesis is that a PKC-ι inhibitor (ICA-1S) alone or in combination with Selinexor can restrain pediatric ATRT cell proliferation and cell survival by intercepting the PKC-ι/Cdk7/Cdk2 and PKC-ι/Bad pathways cascade in-vivo. To validate the hypothesis, we examined the effects of ICA-1S alone or in combination with Selinexor on the proliferation of ATRT cells. The results of a proliferation assay after a four-day treatment period with ICA-1S, Selinexor and combination helped us achieve the inhibitory concentration of the drugs that reduced the cancer cell proliferation to approximately 50%, which was at 20μM with ICA-1S alone for both the ATRT cells. We also tested various concentrations of Selinexor ranging from 400nM to 1.5μM, which showed more than 50% reduction in ATRT cell proliferation at 400nM, which was the lowest concentration used for both the cell lines. For the CHLA-05 cells, ICA-1S and Selinexor combination treatments caused significant reductions at 20μM ICA-1S+800nM Selinexor. For the CHLA06 cells, ICA-1S and Selinexor combination treatments caused significant reductions at 20μM ICA-1S+400nM Selinexor. These cell proliferation data suggest that ICA-1S and Selinexor have a synergistic effect on the ATRT cells. Furthermore, we plan on observing the effect the combination treatment on PKC-ι/Cdk7/Cdk2 and PKC-ι/Bad pathways both in-vitro and in-vivo.