Uveal Melanoma

P1/2, N=341, Recruiting, IDEAYA Biosciences | Trial completion date: May 2025 --> Mar 2027 | Trial primary completion date: Oct 2024 --> Dec 2026

In summary, targeted sequencing of a large NGS panel can detect predicted ultraviolet radiation mutational signatures in skin cancer with >99% specificity. This preliminary result warrants a potential application of mutational signature characterization in routine tumor profiling testing. Further investigation with larger data sets will follow up to determine the overall sensitivity and specificity for detection.

P2/3, N=280, Recruiting, Replimune Inc. | Not yet recruiting --> Recruiting

SGSM2 may not only serve as an important indicator for prognostic assessment. Still, it may also be a key target for the development of new therapeutic approaches, providing new perspectives on the treatment of UVM patients.

Structural analyses of decellularised matrices revealed microarchitecture of differing fibre density and expression differences in collagen 4, collagen 6A1 and nidogen 1, between metastatic risk groups. This approach is a powerful tool for the generation of ECM matrices relevant to high metastatic risk UM.

P1, N=18, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

The in vitro cytotoxicity was accompanied by exposure of DAMPs, suggesting Bel-sar is a potential treatment for CJM by a dual mechanism of action. This dual mechanism may provide a targeted and direct killing of tumor cells and induce an immune response which might decrease local recurrences and metastasis.

P1, N=352, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

This could contribute to ineffective antitumor immune responses in UM patients. Our findings suggest avenues for developing novel therapeutic approaches to counteract these immunosuppressive effects in UM.

P=N/A, N=50, Recruiting, Centre Jean Perrin | Not yet recruiting --> Recruiting

We developed a precise and stable 3-gene model to predict the metastatic risk and prognosis of patients. CD8 + T cells exhaustion in the tumor microenvironment play a crucial role in UM metastasis.

The recurrence of a choroidal melanoma is substantiated by the histopathological and molecular analyses, including the finding of a GNA11 mutation. This case exemplifies a remarkably delayed distant recurrence of a choroidal melanoma, which manifested clinically 40 years following enucleation.

P1, N=20, Recruiting, Memorial Sloan Kettering Cancer Center | N=10 --> 20

P=N/A, N=500, Recruiting, Leiden University Medical Center | N=250 --> 500

The ratio of MMP-9 to TIMP-1 proteins related to the extracellular matrix degradation was higher in the tumor. These results may indicate activation of EMT-like process in the uveal melanoma cells and degradation of the extracellular matrix, which can contribute to the development of collective invasion in uveal melanoma.

P2, N=19, Not yet recruiting, Thomas Jefferson University | Trial completion date: Dec 2028 --> Apr 2029 | Initiation date: Sep 2024 --> Jan 2025 | Trial primary completion date: Jun 2025 --> Oct 2025

This data suggests that DNMT inhibitors cause changes in UM cells that are maintained in cfDNA. The results suggest that targeting methylation in UM treatment and monitoring response to treatment using cfDNA methylation could be a valuable tool.

P1, N=70, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting | N=50 --> 70

Furthermore, VGF directly binds to TGFBR2 and regulates TGF-β-SMAD signaling pathway, thereby regulating genes associated with endothelial-mesenchymal transition (EMT) to promote metastasis. Taken together, these findings identify VGF as a pivotal driver in the progression and metastasis of Gαq mutant UM and confers a promising therapeutic target and strategy for UM patients.

RNA sequencing revealed a notable overlap between the genes and pathways affected by HDAC and BET inhibition, including the reversal of gene signatures linked to high metastatic risk and upregulation of genes associated with a neuronal phenotype. Together, we found that UM cells are particularly vulnerable to class I HDAC and BET inhibition, and highlight the BET inhibitor mivebresib as a promising candidate for further clinical evaluation.

Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells...Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.

EZH2 and 8q gain could be taken into consideration when calculating poor prognosis in Chinese patients with uveal melanoma. Monosomy 3 showed no significance in distant metastasis, but this may be due to a small sample size.

Imipridones are a promising strategy for further testing and development in mUM.

We provide evidence that CYSLTR1 is expressed in human UM and plays a significant role in UM progression behavior. Our data highlight the potential beneficial effects of targeting CYSLTR1 in the control of UM progression.

All patients with stage III tumors and a somatic BAP1 mutation (n = 7) developed metastasis, however four of 28 stage I-II tumors without metastasis had somatic BAP1 mutations, with observation time >5 years. The tumor from one germline BAP1 carrier (stage IIIC) with a somatic EIF1AX splice variant, has not developed metastasis within a 22-year observation time.

Moreover, E7107 had the greatest effect on intron retention. This study indicates/suggests that mutated SF3B1 UM cells are more sensitive to the splicing inhibitor E7107 than wild-type SF3B1 UM cells.

In assessing if a CM gene expression panel could aid in the risk stratification of patients with CJM, we found that the uveal melanoma-relevant gene, BAP1, may be important. Additional studies with larger sample sizes are needed to determine the relevance of this and other differentially expressed genes in CJM prognostication.

P1/2, N=109, Not yet recruiting, Thomas Jefferson University

P2, N=30, Not yet recruiting, University of Miami

New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

Although apparently exceedingly rare, epithelioid myxosarcoma should be included as a differential diagnosis for intraocular tumors in cats and they represent a clinical, histologic, and immunohistochemical diagnostic challenge. Early surgical intervention should be considered to prevent local invasion and ascension to the brain.

Finally, molecular docking indicated that STAT6 is a target of Zoledronic Acid, which can delay UM tumorigenicity by inhibiting STAT6 expression. Taken together, our results indicate that the STAT6/LINC01637 axis promotes UM progression via autophagy and may serve as a potential therapeutic target for UM.

DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies.

Tebentafusp, a bispecific T cell engager (TCE) approved for metastatic UM, showed potential in clinical trials, but the objective response rate remains modest...Quantification of predictive power suggested a limited predictive power for single pre-treatment biomarkers, which was improved by early on-treatment biomarkers and combination of predictive biomarkers. Ultimately, this QSP model could facilitate biomarker-guided patient selection, improving clinical trial efficiency and UM treatment outcomes.

None of the carriers of identified variants had familial UM. We identified BRCA1 and MET as genes with pathogenic germline variants in Finnish UM patients, each with a frequency of 0.4% (95% confidence interval, 0-2).

This phenotypical characterization of DNCs in UM demonstrates that CD8+ T-cells and macrophages are capable of DNC formation, and they are important for better understanding metastatic dissemination, thus paving the path towards novel therapeutic avenues.

Checking tumor markers in the aqueous humor can aid in diagnosis, and aggressive treatment of metastatic iris tumors must help maintain patients' Quality of Life.

These findings underscore the potential utility of cytokines/chemokines expression levels, immune cell subsets, and mutation status as critical biomarkers for the selection of patients who are most likely to benefit from immunotherapeutic interventions. Our research provides valuable insights that could guide the development of more targeted and effective treatment strategies for UM patients.

Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis.

This study showed that the local anesthetic TTC effectively induces pyroptosis in uveal melanoma through the caspase-3/GSDME pathway, highlighting its potential application in immunotherapy. Notably, the use of TTC has potential as an agent for inducing pyroptosis and as an adjuvant anticancer therapy in uveal melanoma.

Three (4%) patients carried pathogenic variants in genes previously linked with other cancer syndromes (ATR, BRIP1 and MSH6) and another three cases carried monoallelic pathogenic variants in recessive cancer genes (xeroderma pigmentosum and Fanconi anaemia), indicating that reduced penetrance of phenotype in these individuals may contribute to the development of both UM and CM. These findings highlight the need for further studies characterising the role of these genes in melanoma susceptibility.

Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy amplification and marker selection.