Uveal Melanoma

EFNA3 could be a valuable prognostic factor in CM.

To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

This research experience imparts microscopy and image analysis skills and instills the ability to grapple with large datasets, statistical tests, and data interpretation in alignment with biology education principles. Post-laboratory surveys reveal students attain confidence in the above skills and in handling animals, along with a deeper appreciation for model organism research and its relevance to cancer cell biology.

The results demonstrated, first, that the UM cell lines exhibited a mesenchymal phenotype and responded to TGF-β treatment in vitro and, second, that TGF-β promoted a cytostatic effect on the UM cell lines. Our findings indicate that UM cells are sensitive to the two arms of TGF-β signaling, which suggests that targeting the TGF-β pathway could be challenging in UM and would require a precise selection of patients in which only the prometastatic arm of TGF-β is activated.

On the contrary, some patients with mucosal, acral or KIT-mutant melanoma may benefit from TKI-based therapies. Further studies focused on biomarker discovery and randomized trials are necessary to better understand the role of VEGFR1-3 as a therapeutic target in melanoma.

Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).

TCRseq and tumor-Ag tetramer staining characterized the recirculation pattern of the antitumor responses in M3 and D3 tumors. Thus, tumor-Ag responses occur in localized UMs, raising the question of the priming mechanisms in the absence of known lymphatic drainage.

TALL-104 and NK-92MI-mediated cell killing assays were used to examine the immune resistance of UM cells...Notably, lactate secreted by IL-6-treated UM cells was crucial in influencing PD-L1 and HLA-E stability via the GPR81-cAMP-PKA signaling pathway. Our data reveal a novel mechanism by which UM cells acquire an immune-escape phenotype by metabolic reprogramming and reinforce the importance of the link between inflammation and immune escape.

The evolving landscape includes promising systemic treatments, such as tebentafusp, a novel immune-modulating bispecific fusion protein, and targeted therapies...Although recent progress has improved outcomes, ongoing research aims to address the unique challenges of UM and develop effective therapies, particularly for HLA-A*02:01-negative patients who represent a significant unmet medical need. This review comprehensively discusses the molecular characteristics of UM, risk stratification methods, and the current and future spectrum of regional and systemic therapeutic modalities.

Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.

P2, N=14, Active, not recruiting, Sidney Kimmel Cancer Center at Thomas Jefferson University | Trial completion date: Dec 2023 --> Dec 2024

P=N/A, N=20, Recruiting, Medical University of Vienna | Initiation date: Feb 2024 --> Nov 2023

P2, N=44, Not yet recruiting, Diwakar Davar | Trial completion date: Nov 2028 --> Jun 2029 | Initiation date: Nov 2023 --> Jun 2024 | Trial primary completion date: Nov 2026 --> Jun 2026

UM in this study was divided into three CNV subtypes, and a model based on eight aneuploidy score-related genes was established to evaluate the prognosis and drug treatment efficacy of UM patients. The current results may have the potential to help the clinical decision-making process for UM management.

Furthermore, we noted that ADGRE5 exhibited a positive association with targeted drug sensitivity and conversely, a negative association with traditional chemotherapeutic drug sensitivity. Thus, ADGRE5 is expected to be a guiding marker gene for clinical prognosis and personalized tumor immunotherapy.

Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth, suggesting the driver role of these two key molecules. In summary, our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.

Our analysis preliminarily describes the complex function of CMPK2 in cancer progression and immune microenvironment highlighting its potential as a diagnostic and therapeutic target for immunotherapy.

P2, N=210, Active, not recruiting, Sidney Kimmel Cancer Center at Thomas Jefferson University | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

Our study first investigated the role of centrosome-related genes in UVM overall survival (OS). We then constructed a centrosome-related gene signature for UVM, which provides new insights into the role of CA in UVM and identifies novel centrosome-related biomarkers.

P1, N=16, Recruiting, Modulation Therapeutics, Inc. | Trial primary completion date: Dec 2023 --> Apr 2025

P2, N=16, Active, not recruiting, Grupo Español Multidisciplinar de Melanoma | Recruiting --> Active, not recruiting | N=34 --> 16 | Trial completion date: Aug 2024 --> May 2024

The molecular subtyping-based risk assessment system not only aids in predicting patient prognosis but also guides the identification of populations suitable for combined treatment. Molecules represented by HTR2B in the model may serve as effective therapeutic targets for UVM.Communicated by Ramaswamy H. Sarma.

Thus, PGAM1 may promote UVM pathogenesis via modulating immune checkpoint signaling, EMT and apoptosis. Collectively, this study reveals PGAM1 as a valuable prognostic biomarker and potential therapeutic target in aggressive cancers including UVM.

S100A4 silencing can inhibit the proliferation, migration, and invasion and synchronously induces apoptosis in UM cells.

P=N/A, N=50, Recruiting, Medical University of Vienna

We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196...We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

P=N/A, N=20, Recruiting, Medical University of Vienna

Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.

In vitro and in vivo experiments confirm the remarkable anti-tumor efficacy of AMPT. Notably, the study introduces an orthotopic tumor model for UM, demonstrating the feasibility of precise and effective targeted treatment within the ocular system.

However, further analyses are needed to confirm these findings in a larger cohort. The epigenetic characterization of a panel of UM cell lines suggested which cellular models are more suitable for epigenetic investigations.

P=N/A, N=100, Recruiting, Oregon Health and Science University | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=25, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Jan 2024 --> Aug 2024

P2, N=37, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2027 --> Dec 2025

P1/2, N=224, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=57, Completed, Aura Biosciences | Phase classification: P1b/2 --> P1/2

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

Emerging immunotherapies, including T-cell-based therapies and vaccines targeting PRAME, are being investigated to exploit its cancer-specific expression. Ongoing research into the molecular role and mechanism of action of PRAME in skin cancer continues to open new avenues in both diagnostics and therapeutics, with the potential to transform the management of melanoma and related skin cancers.

The histopathology and molecular genetics designated the lesion as having a uveal melanoma-like profile, suggesting that it may behave as a choroidal melanoma. This case underscores the importance of the association between ocular melanocytosis and orbital melanoma and provides additional evidence for primary orbital melanoma etiopathogenesis.

FOXM1 silencing may hinder UVM cell progression, providing a novel theoretical basis and new insights for UVM treatment.

P1, N=300, Active, not recruiting, Xencor, Inc. | Recruiting --> Active, not recruiting

Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.

Progesterone and AdipoQ Receptor 3 (PAQR3) is a member of the AdipoQ receptor...Finally, we investigated the role of PAQR3 in tumor resistance and found that the expression of PAQR3 affects the efficacy of multiple chemotherapy drugs. Based on these studies, we found that PAQR3 plays an important role in cancer and has potential in tumor diagnosis and prognosis.