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Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors ( n  = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUV max of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUV max was associated with longer progression-free survival in our clinical trial ( n  = 26). We saw no such trends with pretreatment FDG PET SUV max . Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid., Competing Interests: Funding for the LCCC1531 trial was provided by Merck & Co., Inc., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Sumoylation is an important post-translational modification that involves the conjugation of the Small Ubiquitin-related Modifier (SUMO) onto target proteins. This modification is reversed through the catalytic activity of SUMO isopeptidases, known as SENPs. One of these SENPs, SENP1, was reported to be overexpressed in human pancreatic cancer cells and patient tissues. Since elevated SENP1 expression levels can be used as a prognostic marker for a subset of cancers, we set out to further explore the overexpression of SENP1 in pancreatic cancer. We found that SENP1 protein levels were not significantly different between pancreatic cancer and normal pancreas-derived cell lines. To evaluate SENP1 expression in patient samples, we analyzed large publicly available datasets and found that SENP1 mRNA levels were significantly lower in pancreatic cancer tissue as compared to normal pancreas tissue samples. Furthermore, we found that the SENP1 gene is amplified in less than 1% of sequenced pancreatic cancer patient samples and that expression levels have no association with patient survival. Based on our analysis, we conclude that SENP1 is not overexpressed in pancreatic cancer and is therefore not likely to be an effective biomarker for this disease. Through this work, we also outline a simple but powerful bioinformatics workflow for the assessment of mRNA expression levels, genomic alterations and survival analysis for putative biomarkers for common human cancers., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples ( n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [ RAC1, FGFR1, CARD11, CIITA ; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2 ) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1 . Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort ( n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up ( n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable ( p = 0.09) and adverse ( p = 0.07), respectively]. Somatic mutations in SPEN , and to a lesser extent RAC1 , were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity ( p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53 ), such as RAC1 and SPEN , may have prognostic significance in MM.