Uveal Melanoma

PLEK2 is upregulated in UVM and correlates with poor patient prognosis, likely influencing the calcium signaling pathway. PLEK2 represents a promising prognostic biomarker and therapeutic target for UVM.

CHEMBL82047 and CHEMBL381163 are ideal compounds for inhibiting MMP9. The findings of this study will contribute to the design and improvement of MMP9-targeting drugs.

Although the bispecific tebentafusp is FDA-approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of UM...In particular, the CPT1 inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage and the release of HMGB1 and IL-1β, indicating that the observed cleavage of gasdermins led to pyroptosis...Together, these data show that metabolic inhibitors can induce pyroptosis in UM cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in metastatic UM patients. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.

P2, N=32, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Sep 2025

P=N/A, N=108, Active, not recruiting, Jonsson Comprehensive Cancer Center | Recruiting --> Active, not recruiting

P2, N=51, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting | Trial completion date: Sep 2028 --> Nov 2026 | Trial primary completion date: Jan 2027 --> May 2025

Both treatment sequences are clinically feasible. A clinical benefit was noted in the sequential combination of ICIs followed by tebentafusp. This observation is limited by the retrospective nature of the study and merits further investigation in prospective clinical trials.

P2, N=27, Active, not recruiting, Jose Lutzky, MD | Trial completion date: Dec 2026 --> Jan 2026 | Trial primary completion date: Dec 2024 --> Jan 2024

P2, N=6, Active, not recruiting, Providence Health & Services | Recruiting --> Active, not recruiting | N=30 --> 6 | Trial primary completion date: Jun 2025 --> Dec 2024

P2, N=85, Not yet recruiting, iOnctura

P1, N=6, Active, not recruiting, Vastra Gotaland Region | Recruiting --> Active, not recruiting

Given UVM's limited options, our study highlights the potential of digitoxin as a promising novel therapeutic agent for this aggressive and rare ocular cancer. Our comprehensive approach is effective in identifying the potent, cancer-specific therapeutic agents from herbal plants.

P3, N=290, Recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Not yet recruiting --> Recruiting

P1/2, N=253, Recruiting, Fusion Pharmaceuticals Inc. | Trial primary completion date: Jun 2024 --> Jun 2025

In conclusion, results from the present study suggest that ELF1 is overexpressed in GC. ELF1 combined with MMP9 can serve as a predictor of malignant biological behavior in GC and therefore a prognostic indicator for patients, due to its association with the tumor microenvironment.

P3, N=40, Recruiting, Vastra Gotaland Region | Not yet recruiting --> Recruiting

We also explore molecular and histological features of secondary resistance. Our case highlights that PD-1-resistant melanomas should be screened for GNAQ/11 mutations, as tebentafusp may be a treatment option in this extremely rare disease.

Furthermore, silencing YAP or treating with its inhibitor, Verteporfin, attenuated PD-L1 expression induced by Gq/G11 mutations, thereby enhancing T cell activation and T cell-mediated cytotoxicity. Collectively, this study reveals a potential role of Gq/G11 mutations on immune evasion of UM, a new mechanism of Gq/11 mutations-induced tumorigenesis, highlighting Gq/G11 and YAP as potential immunotherapeutic targets and suggesting Verteporfin as an adjuvant for immunotherapy of UM patients with GNAQ or GNA11 mutations.

Our results reveal that LTEMGs are closely associated with tumor microenvironment. Patients with high LTEMGs score might be resistant to immunotherapy.

Moreover, we discuss the role of SOX10-positive perivascular cells that may be implicated in the complex pathophysiology of GNAQ/GNA11-related entities. Understanding the common molecular foundation of these conditions opens new ways for research and treatment opportunities, potentially leading to more effective, personalized therapeutic strategies.

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.