Oncogenic signaling in uveal melanoma

Park, John J.; Diefenbach, Russell J.; Joshua, Anthony M.; Kefford, Richard; Carlino, Matteo S.; Rizos, Helen

doi:10.1111/pcmr.12708

Cited by 64 publications

(54 citation statements)

References 123 publications

(143 reference statements)

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“…Regarding the genetic results, different genomic alterations, such as chromosome 3 monosomy and gains of chromosome 8q, are predictive of relapse after primary treatment [ 24 – 28 ]. In this study, we analysed the association between these genomic alterations with PFS.…”

Section: Discussionmentioning

confidence: 99%

Pembrolizumab as first-line treatment for metastatic uveal melanoma

Rossi

Pagliara

Orteschi

et al. 2019

Cancer Immunol Immunother

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Background No standard treatment has been defined for metastatic uveal melanoma (mUM). Although clinical trials testing Nivolumab/Pembrolizumab for cutaneous melanoma did not include mUM, anti PD-1 agents are commonly used for this disease. Patients and methods In this prospective observational cohort single arm study, we investigated efficacy and safety of Pembrolizumab as first-line therapy for mUM. The efficacy was evaluated in terms of progression-free survival (PFS), response rate and overall survival (OS). Toxicity was also assessed. Results Seventeen patients were enrolled. A median of 8 cycles were administered (range 2–28). Two patients achieved partial response (11.7%), 6 a disease stabilization (35.3%), whereas 9 (53%) had a progression. No complete response was observed. PFS of the overall population was 3.8 months. PFS was 9.7 months for patients with an interval higher than 5 years from diagnosis of primary tumor to metastatic disease and 2.6 months for patients with an interval lower than 5 years [ p = 0.039, HR 0.2865 (95% CI 0.0869–0.9443)]. Median OS was not reached. The two responding patients were still on treatment with Pembrolizumab at the time of data analysis. Survival was 12.8 months for patients with clinical benefit, while OS for progressive patients was 3.1 months. PD-L1 expression and genomic abnormalities predictive of relapse after diagnosis of primary tumor were not associated with PFS. Toxicity was mild, without grade 3–4 side effects. Conclusions The efficacy of Pembrolizumab does not seem particularly different when compared to other agents for mUM, but responding patients had a remarkable disease control.

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Section: Discussionmentioning

confidence: 99%

Pembrolizumab as first-line treatment for metastatic uveal melanoma

Rossi

Pagliara

Orteschi

et al. 2019

Cancer Immunol Immunother

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“…GLDC (glycine decarboxylase) was recently described as a critical enzyme of tumor‐initiating cells and thus, as a driver of tumorigenesis in lung nonsmall cell cancer . Furthermore, CYSLTR2 , cysteinyl leukotriene receptor 2, has been related to uveal melanoma progression . The upregulation of SULT1C4 would seem fundamental in maintaining establishment primary renal cell lines ccRCC .…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Mini

Lapucci

Perrone

et al. 2019

Intl Journal of Cancer

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Five‐year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA‐sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease‐free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer‐related genes (n = 14) and cancer‐unrelated genes (n = 16). Three out of four down‐regulated genes were cancer‐related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.

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“…Different studies have found a number of mutational signatures in these tumours, most notably one associated with ageing and explained by spontaneous deamination of 5-methylcytosine, and others related to defects in nucleotide excision and in DNA mismatch repair [4,48]. There are currently no known drugs that target GNAQ/GNA11 and alternative pathway inhibitors have so far not shown clinical benefit in early phase trials, reviewed in [110]. A number of trials are ongoing, targeting a range of UM signalling cascades [111].…”

Section: Um: a Sparsely Mutated Melanoma Subtype With Poor Responses mentioning

confidence: 99%

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

Rabbie

Ferguson

Molina‐Aguilar

et al. 2019

The Journal of Pathology

172

205

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Melanoma is characterised by its ability to metastasise at early stages of tumour development. Current clinico‐pathologic staging based on the American Joint Committee on Cancer criteria is used to guide surveillance and management in early‐stage disease, but its ability to predict clinical outcome has limitations. Herein we review the genomics of melanoma subtypes including cutaneous, acral, uveal and mucosal, with a focus on the prognostic and predictive significance of key molecular aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Oncogenic signaling in uveal melanoma

Cited by 64 publications

References 123 publications

Pembrolizumab as first-line treatment for metastatic uveal melanoma

Pembrolizumab as first-line treatment for metastatic uveal melanoma

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

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