NMI-900

Uveal melanoma (UM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic diseases and have a poor clinical outcome. Immunotherapies are quickly becoming a need, and recent research has produced some amazing achievements in this area. In the current investigation, an attempt was made to evaluate the prognostic usefulness of KDELR3 in UM, particularly its connection with tumor-infiltrating lymphocytes (TILs). The expression patterns of mRNAs and related clinical data of 80 UM patients were obtained from The Cancer Genome Atlas (TCGA). By using RT-PCR, we were able to investigate whether or not UM cells and D78 cells expressed KDELR3. The Kaplan-Meier approach, as well as univariate and multivariate tests, was utilized in order to investigate the potential predictive significance of KDELR3 expression. The associations between KDELR3 and TILs and immunological checkpoints were analyzed in order to evaluate the effect that KDELR3 may have on UM immunotherapy. On the basis of the differential expression of KDELR3, a distribution of the half-maximal inhibitory concentration (IC50) of various targeted medicines was observed. In this study, we found that the expression of KDELR3 was distinctly increased in most types of tumors. In addition, KDELR3 was highly expressed in UM cells. Moreover, patients with high KDELR3 expression exhibited a shorter overall survival and disease-free survival than those with low KDELR3 expression. Multivariate analyses confirmed that KDELR3 expression was an independent prognostic factor for overall survival and disease-free survival in patients with UM. Furthermore, KDELR3 expression was demonstrated to be positively correlated with macrophage M1, T cell CD8, T cell follicular helper, dendritic cell resting, and T cell CD4 memory activated. Meanwhile, the expression of KDELR3 was related to several immune checkpoints. The IC50 of AP-24534, BHG712, bleomycin, camptothecin, cisplatin, cytarabine, GSK1070916, and tipifarnib was higher in the KDELR3 high-expression group. In conclusion, KDELR3 may be applied as a potential diagnostic and prognostic biomarker for UM patients.

Is it possible to eliminate metastasised chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cells from ovarian cortex fragments by inhibition of Aurora B/C kinases (AURKB/C) without compromising ovarian tissue or follicles?

Human ovarian cortex tissue with experimentally induced tumour foci of CML, AML and primary cells of AML patients were exposed to a 24h treatment with 1 μM GSK1070916, an AURKB/C inhibitor, to eliminate malignant cells by invoking mitotic catastrophe. After treatment, the inhibitor was removed, followed by an additional culture period of 6 days to allow any remaining tumour cells to form new foci. Ovarian tissue integrity after treatment was analysed by four different assays. Appropriate controls were included in all experiments.

Foci of metastasised CML and AML cells in ovarian cortex tissue were severely affected by a 24h ex vivo treatment with an AURKB/C inhibitor, leading to the formation of multi-nuclear syncytia and large-scale apoptosis. Ovarian tissue morphology and viability was not compromised by the treatment, as no significant difference was observed regarding the percentage of morphologically normal follicles, follicular viability, glucose uptake or in vitro growth of small follicles between ovarian cortex treated with 1 μM GSK1070916 and the control.

Purging of CML/AML metastases in ovarian cortex is possible by targeting the Mitotic Catastrophe Signalling Pathway using GSK1070916 without affecting the ovarian tissue. This provides a therapeutic strategy to prevent reintroduction of leukaemia and enhances safety of autotransplantation in leukaemia patients currently considered at high risk for ovarian involvement.