Current projects ongoing in the laboratory focus on developing targeted therapy for metastatic uveal melanoma based on:
- Targeting metabolic vulnerability of UM tumors: The factors closely associated with poor prognosis in metastatic UM are monosomy of chromosome 3 (M3) and loss of the BAP1 protein. However, these two prognostic markers are difficult to therapeutically target. M3 is the loss of one copy of chromosome 3 and cannot be reversed therapeutically using currently available gene therapy approaches. The loss of the tumor suppressor BAP1 protein is difficult to target therapeutically as well, as it is a classic tumor suppressor and restoring functionality will require restoration of wild type BAP1 gene. Therefore, our studies aim to address these challenges by identifying novel and sustainable strategies to treat metastatic UM. In our preliminary studies we observed a dependence of metastatic UM on oxidative phosphorylation for survival. In our current studies, we are testing compounds that modulate mitochondrial OXPHOS effectors to block UM growth both in vitro and in vivo using our orthotopic mouse model for UM liver metastasis.
- Targeting liver-borne growth factor signaling in UM: Uveal melanoma metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of insulin-like growth factor -1 and its receptor (IGF-1/IGF-1R) signaling in UM. We found that the insulin receptor substrate -1 (IRS-1) is overexpressed in UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2 in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration, and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell survival, migration in vitro and tumor growth in vivo via inhibiting IGF-1 signaling in UM.