Uveal Melanoma

P2, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Therapies targeting specific genetic alterations and immunotherapy agents have been recently developed and introduced in clinical practice for the management of advanced-stage UMs. This review aims to present the latest advances in the clinical molecular pathology of UM, along with the resulting targeted, immunological, and other therapies that have been introduced or are currently under investigation.

Canonical NF-κB signaling is mechanistically related to UM cell survival, proliferation, and migration, as shown by pharmacologic inhibition like BAY11-7082, and niclosamide and genetic modulation like microRNA-9. NF-κB signaling, particularly the canonical branch, is required for UM malignancy, while noncanonical signaling is linked with high-risk features. Branch-specific genetic manipulations and clinically relevant models should be employed in future research to maximize therapeutic strategies.

Plasma analysis identified a pathogenic SPEN variant and human leukocyte antigen (HLA) genotype (HLA-A*02:17 and HLA-A*02:01 alleles), conferring therapeutic eligibility for tebentafusp, and molecular evidence supportive of metastatic uveal melanoma, enabling initiation of appropriate systemic therapy before additional tissue sampling...While the liquid biopsy and ablation of one of the lesions confirmed the diagnosis, the liquid biopsy was a key first step that provided a comprehensive diagnostic and prognostic picture without the need for an invasive procedure. This case highlights how integrating liquid biopsy into the diagnostic pathway for uveal melanoma can lead to earlier, more informed treatment decisions.

P3, N=200, Completed, University Hospital Erlangen | Active, not recruiting --> Completed

Three early-phase OV studies, totaling twenty-nine patients, yielded no radiographic responses but showed tumor-specific T-cell expansion and transient disease stabilization. Safety profiles reflected the mechanism of action: tebentafusp most often caused rash, pyrexia, and usually manageable cytokine-release syndrome with grade-3+ events in 40-70% yet discontinuation in roughly 2%; TIL therapy toxicity was driven by lymphodepleting chemotherapy and high-dose interleukin-2 with one treatment-related death; and OVs were generally well tolerated with no more than 20% grade-3 events.

BAP1 loss in liver metastases independently predicts poorer post-metastatic survival. Patterns of dissemination are set early in primary tumors, enabling molecular profiling to forecast metastatic spread.

Moreover, real-time quantitative PCR (qPCR) and western blot (WB) analyses corroborated the modulation of target expression levels. Therefore, celastrol exerts potent anti-tumor effects in UM by inhibiting the CTNNB1 and STAT3 signaling pathways, thereby suppressing tumor cell proliferation and metastasis, as well as promoting cell cycle arrest and apoptosis.

P=N/A, N=10, Not yet recruiting, Massachusetts General Hospital

We conclude that CD63-mediated transfer of hypoxic exosomal lactate establishes a critically immunosuppressive microenvironment in UM. Targeting the hypoxia/CD63/exosomal lactate axis may represent a promising novel therapeutic strategy to restore anti-tumor immunity in UM.

These findings, grounded in single-cell insights and confirmed by rigorous experimental validation, reveal the tumor's intrinsic "chaperone dependency" and highlight HSP90AA1 as a highly promising therapeutic target. Targeting HSP90AA1 may offer a new strategy for modulating the UVM tumor immune microenvironment and overcoming tumor progression.

ASPHD1 overexpression also upregulated neuronal differentiation-related genes, produced more negative resting membrane potentials on whole-cell patch-clamp recordings, enhanced depolarization-evoked Ca2+ transients on calcium imaging, and increased NeuN protein expression. Together, these findings identify ASPHD1 as a favorable prognostic biomarker in glioma and suggest that high ASPHD1 expression restrains glioma progression while promoting neuron-like differentiation of glioma cells.