Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers ...involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 is a glycoprotein involved in the regulation of the tumor microenvironment and cancer progression by several mechanisms-in particular, by the control of glycolysis and also by its well-known ability to induce proteinases leading to matrix degradation, tumor cell invasion, metastasis and angiogenesis. Accumulating evidence has demonstrated the role of CD147 expression in tumor progression and prognosis, suggesting it as a relevant tumor biomarker for cancer diagnosis and prognosis, as well as validating its potential as a promising therapeutic target in cancers.
Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this ...melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (
and neuroblastoma RAS viral oncogene homolog (
mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with
and
mutations. We show that in addition to being less frequent,
and
mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the
and
mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical
and
mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.
Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which ...include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.
Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF ...mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMNs and compared them with small and medium CMNs using Sanger sequencing, pyrosequencing, high-resolution melting analysis, and mutation enrichment by an enhanced version of ice-COLD-PCR. Large–giant CMNs displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be investigated. We therefore performed exome sequencing on five specimens of large–giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small–medium CMNs was significantly different, with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero.
A sensitive liquid chromatography coupled with tandem mass spectrometry (MS/MS) method for the analysis in a small volume of plasma of 14 tyrosine kinase inhibitors currently used (imatinib, ...dasatinib, ibrutinib, ponatinib, trametinib, sunitinib, cobimetinib, dabrafenib, erlotinib, lapatinib, nilotinib, bosutinib, sorafenib, and vemurafenib) has been developed and validated. This multianalyte liquid chromatography coupled with MS/MS assay is of interest for anticancer drug combination therapy.
After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultra performance liquid chromatography system coupled with MS/MS in a positive ionization mode. The mobile phase consisted of a gradient elution of 10 mmol/L formate ammonium buffer containing 0.1% (vol/vol) formic acid (phase A) and acetonitrile with 0.1% (vol/vol) formic acid (phase B) at a flow rate of 300 μL/min.
The analysis time was 5.0 minutes per run, and all analytes and internal standard eluted within 1.45-1.79 minutes. The calibration curves were linear over the range from 1 to 500 ng/mL for bosutinib, cobimetinib, dasatinib, ibrutinib, and trametinib, from 5 to 500 ng/mL for ponatinib and sunitinib; from 50 to 2500 ng/mL for lapatinib; from 750 to 100,000 ng/mL for vemurafenib, and from 10 to 2500 ng/mL for dabrafenib, erlotinib, imatinib, nilotinib, and sorafenib, with coefficients of correlation above 0.99 for all analytes. The intra- and interday imprecisions were below 14.36%.
This method was successfully applied to therapeutic drug monitoring in clinical practice.
More than 70% of human NRAS
melanomas are resistant to MEK inhibitors highlighting the crucial need for efficient therapeutic strategies for these tumors. CD147, a membrane receptor, is overexpressed ...in most cancers including melanoma and is associated with poor prognosis. We show here that CD147i, a specific inhibitor of CD147/VEGFR-2 interaction represents a potential therapeutic strategy for NRAS
melanoma cells. It significantly inhibited the malignant properties of NRAS
melanomas ex vivo and in vivo. Importantly, NRAS
patient's-derived xenografts, which were resistant to MEKi, became sensitive when combined with CD147i leading to decreased proliferation ex vivo and tumor regression in vivo. Mechanistic studies revealed that CD147i effects were mediated through STAT3 pathway. These data bring a proof of concept on the impact of the inhibition of CD147/VEGFR-2 interaction on melanoma progression and represents a new therapeutic opportunity for NRAS
melanoma when combined with MEKi.
Considering the growing interest in matched cancer treatment, our aim was to evaluate the ability of a comprehensive genomic profiling (CGP) assay to propose at least one targeted therapy given an ...identified genomic alteration or signature (actionability), and to collect the treatment modifications based on the CGP test results in clinical practise for solid tumors. This retrospective, multicentre French study was conducted among 25 centres that participated in a free of charge program between 2017 and 2019 for a tissue CGP test. Data were collected on the patient, disease, tumor genomic profile, treatment suggested in the report (related to the genomic profile results) and subsequent therapeutic decisions according to the physician's declaration. Among the 416 patients, most had lung cancer (35.6%), followed by biliary tract cancer (11.5%) or rare cancers (11.1%); 75% had a metastatic disease. The actionability was 75.0% (95% CI 70.6%-78.9%) for all patients, 85.1% and 78.4%, respectively in lung cancer and metastatic patients. After exclusion of clinical trial suggestions, the actionability decreased to 62.3% (95% CI 57.5%-66.8%). Treatment modification based on the test results was observed in 17.3% of the patients and was more frequent in metastatic disease (OR = 2.73, 95% CI 1.31-5.71, p = 0.007). The main reasons for no treatment modification were poor general condition (33.2%) and stable disease or remission (30.2%). The genomic-directed treatment changes were performed mostly during the first six months after the CGP test, and interestingly a substantial part was observed from six to 24 months after the genomic profiling. This French study provides information on the real-life actionability of a CGP test based on tissue samples, and trends to confirm its utility in clinical practice across the course of the disease, in particularly for patients with lung cancer and/or advanced disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Wnt/β-catenin signaling plays crucial roles in melanocyte biology and may be implicated in melanoma progression. In this study, we retrospectively examined a real-life cohort of melanomas mutated for ...β-catenin (
CTNNB1
), in association or not with a
MAPK
mutation (of
BRAF
or
NRAS
), and analyzed their clinical, histopathological, and molecular characteristics. Our results indicate that, regardless of the presence of a concurrent
MAPK
mutation,
CTNNB1
mut
cutaneous primary melanomas display more proliferative hallmarks (increased Breslow thickness, mitotic index, and ulceration) than their
CTNNB1
wild-type counterparts. Accordingly, they often progress to the metastatic stage. Furthermore, concurrent
CTNNB1
and
MAPK
mutations do not necessarily confer a deep penetrating nevi phenotype. Altogether, this study provides evidence that
CTNNB1
mutations in melanomas are associated with specific clinical and pathological features.
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