Uveal Melanoma

P1/2, N=111, Not yet recruiting, VM Discovery, Inc.

Despite advances in our understanding of the pathogenesis of glioblastoma, the mOS median overall survival in our real-world patient cohort did not improve over time. The findings emphasise the need for ongoing research efforts to improve outcomes in this lethal disease.

In human uveal melanoma, expression of the effero-score was correlated with poor survival. Therefore, Effero-seq sheds light on the molecular reprogramming induced by efferocytosis in the TME, opening previously unknown avenues for understanding macrophage function and developing targeted treatments.

P1/2, N=36, Recruiting, Beijing Biotech

These findings suggest that ITGA6 may serve as a potential diagnostic and prognostic biomarker in selected cancers and support a tumor-promoting role for ITGA6 in UVM.

We identified uveal melanoma cell lines expressing elevated levels of the biomarkers, PDE3A and SLFN12, and tested response to velcrin compounds in vitro and in vivo. We show that response correlates mechanistically with decreased levels of tRNA-Leu-TAA and inhibition of nascent protein synthesis and furthermore identify a potential mechanism of resistance.

Despite these barriers, preclinical studies demonstrate that activated NK cells can reduce hepatic metastases. Emerging NK cell-based therapies, such as chimeric antigen receptor-engineered NK cells and NK cell engagers, could provide an effective therapeutic strategy to treat metastatic UM, warranting further clinical investigation.

Low grade nuclear BAP1 immunostaining is a strong, independent predictor of poor prognosis in uveal melanoma, comparable to established histopathological features. Immunohistochemical assessment of BAP1 is a cost-effective tool for risk stratification in routine clinical practice.

We discuss the hypothesis that noncanonical Gαi-associated spindle-orientation machinery may represent a future therapeutic vulnerability in uveal melanoma, while emphasizing that this concept remains to be validated in disease-specific models. This comprehensive analysis underscores the therapeutic promise of modulating heterotrimeric G-protein signaling beyond canonical pathways in uveal melanoma and potentially other cancers.

In multiple models of metastatic UM, silencing of GDF15 inhibited the outgrowth of metastatic lesions, associated with reduced deposition of extracellular matrix and recruitment of endothelial cells. Together, these findings reveal that UM liver metastasis development is dependent upon GDF15-mediated remodeling of the liver microenvironment, which leads to an angiogenic response and matrix deposition that supports tumor growth.

P1, N=30, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2026 --> May 2027 | Trial primary completion date: May 2026 --> May 2027