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Oncotarget May 2024GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15%...
GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.
Topics: Melanoma; Uveal Neoplasms; Humans; Animals; Mice; Xenograft Model Antitumor Assays; Cell Line, Tumor; Signal Transduction; Autophagy; Ubiquitin Thiolesterase; Doxorubicin; Antineoplastic Agents; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 38758815
DOI: 10.18632/oncotarget.28586 -
Veterinary Medicine and Science May 2024A 15-month-old, grey, Thoroughbred filly presented for investigation of a 6-week history of corneal oedema and blepharospasm on the right eye (OD). The filly was...
A 15-month-old, grey, Thoroughbred filly presented for investigation of a 6-week history of corneal oedema and blepharospasm on the right eye (OD). The filly was otherwise healthy. Following ophthalmic examination, glaucoma on the OD was diagnosed. A space occupying mass within the anterior chamber was documented on transpalpebral ultrasonographic examination. This mass obliterated most of the anterior intraocular structures on the peripheral nasal side (corneal endothelium and drainage angle), leading to secondary glaucoma. After systemic and topical treatment addressing secondary glaucoma, the corneal oedema reduced. The mass was visualised as an irregularly rounded brown structure associated with the iris on the peripheral nasal side of the anterior chamber. Given the filly's signalment, location and appearance of the mass, a tentative diagnosis of intraocular melanoma was made and enucleation was performed. Histopathological evaluation of the globe revealed solid sheets of heavily pigmented melanocytic cells, disrupting the normal ciliary body architecture and extending into the iris and subretinal. The cells were pleomorphic, polyhedral to round with occasional spindle-shaped cells, and contained moderate to large amounts of granular black-brown pigment (melanin). The iridal component expanded into the anterior chamber, with cells directly opposed to Descemet's membrane, with loss of the endothelium and expanding and occluding the filtration angle in this area. The lesion infiltrated locally into the edge of the sclera, but did not extend through the sclera, though occasional perivascular clusters of melanophages were observed within the scleral stroma adjacent to the optic nerve. Diagnosis of a uveal melanocytic neoplasm was confirmed, with characteristics similar to only one reported case . This is a unique case of a rapidly growing, invasive, uveal melanoma in a young horse. Intraocular melanoma should be considered as a differential diagnoses for glaucoma in grey horses, regardless of the age and absence of melanocytic skin lesions.
Topics: Animals; Horses; Horse Diseases; Glaucoma; Melanoma; Female; Eye Neoplasms
PubMed: 38739097
DOI: 10.1002/vms3.1471 -
Molecular Biomedicine May 2024Uveal cancer (UM) offers a complex molecular landscape characterized by substantial heterogeneity, both on the genetic and epigenetic levels. This heterogeneity plays a... (Review)
Review
Uveal cancer (UM) offers a complex molecular landscape characterized by substantial heterogeneity, both on the genetic and epigenetic levels. This heterogeneity plays a critical position in shaping the behavior and response to therapy for this uncommon ocular malignancy. Targeted treatments with gene-specific therapeutic molecules may prove useful in overcoming radiation resistance, however, the diverse molecular makeups of UM call for a patient-specific approach in therapy procedures. We need to understand the intricate molecular landscape of UM to develop targeted treatments customized to each patient's specific genetic mutations. One of the promising approaches is using liquid biopsies, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), for detecting and monitoring the disease at the early stages. These non-invasive methods can help us identify the most effective treatment strategies for each patient. Single-cellular is a brand-new analysis platform that gives treasured insights into diagnosis, prognosis, and remedy. The incorporation of this data with known clinical and genomics information will give a better understanding of the complicated molecular mechanisms that UM diseases exploit. In this review, we focused on the heterogeneity and molecular panorama of UM, and to achieve this goal, the authors conducted an exhaustive literature evaluation spanning 1998 to 2023, using keywords like "uveal melanoma, "heterogeneity". "Targeted therapies"," "CTCs," and "single-cellular analysis".
Topics: Humans; Melanoma; Molecular Targeted Therapy; Genetic Heterogeneity; Uveal Neoplasms; Neoplastic Cells, Circulating; Biomarkers, Tumor; Mutation; Circulating Tumor DNA; Liquid Biopsy
PubMed: 38724687
DOI: 10.1186/s43556-024-00182-2 -
Journal For Immunotherapy of Cancer May 2024Tumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array...
BACKGROUND
Tumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. A performant and rational antigen selection pipeline would lay the foundation for immunotherapy trials with the potential to enhance treatment, tremendously benefiting patients suffering from rare, understudied cancers.
METHODS
We present an experimentally validated, data-driven computational pipeline that selects and ranks antigens in a multipronged approach. In addition to minimizing the risk of immune-related adverse events by selecting antigens based on their expression profile in tumor biopsies and healthy tissues, we incorporated a network analysis-derived antigen indispensability index based on computational modeling results, and candidate immunogenicity predictions from a machine learning ensemble model relying on peptide physicochemical characteristics.
RESULTS
In a model study of uveal melanoma, Human Leukocyte Antigen (HLA) docking simulations and experimental quantification of the peptide-major histocompatibility complex binding affinities confirmed that our approach discriminates between high-binding and low-binding affinity peptides with a performance similar to that of established methodologies. Blinded validation experiments with autologous T-cells yielded peptide stimulation-induced interferon-γ secretion and cytotoxic activity despite high interdonor variability. Dissecting the score contribution of the tested antigens revealed that peptides with the potential to induce cytotoxicity but unsuitable due to potential tissue damage or instability of expression were properly discarded by the computational pipeline.
CONCLUSIONS
In this study, we demonstrate the feasibility of the de novo computational selection of antigens with the capacity to induce an anti-tumor immune response and a predicted low risk of tissue damage. On translation to the clinic, our pipeline supports fast turn-around validation, for example, for adoptive T-cell transfer preparations, in both generalized and personalized antigen-directed immunotherapy settings.
Topics: Humans; Antigens, Neoplasm; Immunotherapy; Gene Regulatory Networks
PubMed: 38724462
DOI: 10.1136/jitc-2023-008104 -
Scientific Reports May 2024Inflammatory age (iAge) is a vital concept for understanding the intricate interplay between chronic inflammation and aging in the context of cancer. However, the...
Inflammatory age (iAge) is a vital concept for understanding the intricate interplay between chronic inflammation and aging in the context of cancer. However, the importance of iAge-clock-related genes (iAge-CRGs) across cancers remains unexplored. This study aimed to explore the mechanisms and applications of these genes across diverse cancer types. We analyzed profiling data from over 10,000 individuals, covering 33 cancer types, 750 small molecule drugs, and 24 immune cell types. We focused on DCBLD2's function at the single-cell level and computed an iAge-CRG score using GSVA. This score was correlated with cancer pathways, immune infiltration, and survival. A signature was then derived using univariate Cox and LASSO regression, followed by ROC curve analysis, nomogram construction, decision curve analysis, and immunocytochemistry. Our comprehensive analysis revealed epigenetic, genomic, and immunogenomic alterations in iAge-CRGs, especially DCBLD2, leading to abnormal expression. Aberrant DCBLD2 expression strongly correlated with cancer-associated fibroblast infiltration and prognosis in multiple cancers. Based on GSVA results, we developed a risk model using five iAge-CRGs, which proved to be an independent prognostic index for uveal melanoma (UVM) patients. We also systematically evaluated the correlation between the iAge-related signature risk score and immune cell infiltration. iAge-CRGs, particularly DCBLD2, emerge as potential targets for enhancing immunotherapy outcomes. The strong correlation between abnormal DCBLD2 expression, cancer-associated fibroblast infiltration, and patient survival across various cancers underscores their significance. Our five-gene risk signature offers an independent prognostic tool for UVM patients, highlighting the crucial role of these genes in suppressing the immune response in UVM.Kindly check and confirm whether the corresponding affiliation is correctly identified.I identified the affiliation is correctly.thank you.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.I confirm the abstract is correctly ,thank you.
Topics: Humans; Prognosis; Neoplasms; Biomarkers, Tumor; Inflammation; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Aging; Multiomics
PubMed: 38714870
DOI: 10.1038/s41598-024-61381-z -
The Pan African Medical Journal 2024
Topics: Humans; Melanoma; Choroid Neoplasms; Incidental Findings; Amblyopia; Male; Female; Middle Aged
PubMed: 38708135
DOI: 10.11604/pamj.2024.47.79.42795 -
Biochimica Et Biophysica Acta. Reviews... May 2024Uveal melanoma (UM) is the most common primary ocular tumor in the adult population. Even though these primary tumors are successfully treated in 90% of cases, almost... (Review)
Review
Uveal melanoma (UM) is the most common primary ocular tumor in the adult population. Even though these primary tumors are successfully treated in 90% of cases, almost 50% of patients ultimately develop metastasis, mainly in the liver, via hematological dissemination, with a median survival spanning from 6 to 12 months after diagnosis. In this context, chemotherapy regimens and molecular targeted therapies have demonstrated poor response rates and failed to improve survival. Among the multiple reasons for therapy failure, the presence of cancer stem-like cells (CSCs) represents the main cause of resistance to anticancer therapies. In the last few years, the existence of CSCs in UM has been demonstrated both in preclinical and clinical studies, and new molecular pathways and mechanisms have been described for this subpopulation of UM cells. Here, we will discuss the state of the art of CSC biology and their potential exploitation as therapeutic target in UM.
Topics: Uveal Neoplasms; Humans; Melanoma; Neoplastic Stem Cells; Animals; Drug Resistance, Neoplasm; Molecular Targeted Therapy; Antineoplastic Agents
PubMed: 38701937
DOI: 10.1016/j.bbcan.2024.189104 -
Medicine May 2024Uveal melanoma (UM) is a rare but aggressive malignant ocular tumor with a high metastatic potential and limited therapeutic options, currently lacking accurate...
Uveal melanoma (UM) is a rare but aggressive malignant ocular tumor with a high metastatic potential and limited therapeutic options, currently lacking accurate prognostic predictors and effective individualized treatment strategies. Public databases were utilized to analyze the prognostic relevance of programmed cell death-related genes (PCDRGs) in UM transcriptomes and survival data. Consensus clustering and Lasso Cox regression analysis were performed for molecular subtyping and risk feature construction. The PCDRG-derived index (PCDI) was evaluated for its association with clinicopathological features, gene expression, drug sensitivity, and immune infiltration. A total of 369 prognostic PCDRGs were identified, which could cluster UM into 2 molecular subtypes with significant differences in prognosis and clinicopathological characteristics. Furthermore, a risk feature PCDI composed of 11 PCDRGs was constructed, capable of indicating prognosis in UM patients. Additionally, PCDI exhibited correlations with the sensitivity to 25 drugs and the infiltration of various immune cells. Enrichment analysis revealed that PCDI was associated with immune regulation-related biological processes and pathways. Finally, a nomogram for prognostic assessment of UM patients was developed based on PCDI and gender, demonstrating excellent performance. This study elucidated the potential value of PCDRGs in prognostic assessment for UM and developed a corresponding risk feature. However, further basic and clinical studies are warranted to validate the functions and mechanisms of PCDRGs in UM.
Topics: Humans; Uveal Neoplasms; Melanoma; Prognosis; Male; Female; Nomograms; Biomarkers, Tumor; Transcriptome; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Middle Aged
PubMed: 38701273
DOI: 10.1097/MD.0000000000038021 -
BMC Ophthalmology May 2024Uveal melanoma (UVM) is a malignant intraocular tumor in adults. Targeting genes related to oxidative phosphorylation (OXPHOS) may play a role in anti-tumor therapy....
BACKGROUND
Uveal melanoma (UVM) is a malignant intraocular tumor in adults. Targeting genes related to oxidative phosphorylation (OXPHOS) may play a role in anti-tumor therapy. However, the clinical significance of oxidative phosphorylation in UVM is unclear.
METHOD
The 134 OXPHOS-related genes were obtained from the KEGG pathway, the TCGA UVM dataset contained 80 samples, served as the training set, while GSE22138 and GSE39717 was used as the validation set. LASSO regression was carried out to identify OXPHOS-related prognostic genes. The coefficients obtained from Cox multivariate regression analysis were used to calculate a risk score, which facilitated the construction of a prognostic model. Kaplan-Meier survival analysis, logrank test and ROC curve using the time "timeROC" package were conducted. The immune cell frequency in low- and high-risk group was analyzed through Cibersort tool. The specific genomic alterations were analyzed by "maftools" R package. The differential expressed genes between low- or high-risk group were analyzed and performed Gene Ontology (GO) and GSEA. Finally, we verified the function of CYC1 in UVM by gene silencing in vitro.
RESULTS
A total of 9 OXPHOS-related prognostic genes were identified, including NDUFB1, NDUFB8, ATP12A, NDUFA3, CYC1, COX6B1, ATP6V1G2, ATP4B and NDUFB4. The UVM prognostic risk model was constructed based on the 9 OXPHOS-related prognostic genes. The prognosis of patients in the high-risk group was poorer than low-risk group. Besides, the ROC curve demonstrated that the area under the curve of the model for predicting the 1 to 5-year survival rate of UVM patients were all more than 0.88. External validation in GSE22138 and GSE39717 dataset revealed that these 9 genes could also be utilized to evaluate and predict the overall survival of patients with UVM. The risk score levels related to immune cell frequency and specific genomic alterations. The DEGs between the low- and high- risk group were enriched in tumor OXPHOS and immune related pathway. In vitro experiments, CYC1 silencing significantly inhibited UVM cell proliferation and invasion, induced cell apoptosis.
CONCLUSION
In sum, a prognostic risk score model based on oxidative phosphorylation-related genes in UVM was developed to enhance understanding of the disease. This prognostic risk score model may help to find potential therapeutic targets for UVM patients. CYC1 acts as an oncogene role in UVM.
Topics: Humans; Uveal Neoplasms; Melanoma; Oxidative Phosphorylation; Prognosis; Biomarkers, Tumor; Male; Female; Gene Expression Regulation, Neoplastic; ROC Curve; Risk Assessment; Middle Aged; Risk Factors; Gene Expression Profiling
PubMed: 38698303
DOI: 10.1186/s12886-024-03441-6 -
Oncology Research 2024Numerous studies have characterized the critical role of circular RNAs (circRNAs) as regulatory factors in the progression of multiple cancers. However, the biological...
Numerous studies have characterized the critical role of circular RNAs (circRNAs) as regulatory factors in the progression of multiple cancers. However, the biological functions of circRNAs and their underlying molecular mechanisms in the progression of uveal melanoma (UM) remain enigmatic. In this study, we identified a novel circRNA, , through re-analysis of UM microarray data and quantitative RT-PCR. was found to be upregulated in UM and to promote the proliferation and metastatic ability of UM cells in both and settings. Mechanistically, was observed to bind to the KH1 and KH2 domains of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), thereby enhancing the function of IGF2BP3 by stabilizing its target mRNA. RNA sequencing assays identified () as a target gene of and IGF2BP3 at the transcriptional level. Rescue assays demonstrated that exerts its biological function by stabilizing mRNA and regulating the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway. Collectively, may promote UM progression by stabilizing mRNA and activating the MAPK/ERK signaling pathway through the formation of a /IGF2BP3/ RNA-protein ternary complex, thus providing a potential biomarker and therapeutic target for UM.
Topics: Humans; RNA, Circular; Uveal Neoplasms; ErbB Receptors; RNA-Binding Proteins; Melanoma; Adenosine; Disease Progression; Mice; Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 38686044
DOI: 10.32604/or.2024.045972