Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age‐adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299–2312. © 2016 American Cancer Society.

Hypoxia is not only a prominent contributor to the heterogeneity of solid tumors but also a crucial stressor in the microenvironment to drive adaptations for tumors to evade immunosurveillance. Herein, we discuss the potential role of hypoxia within the microenvironment contributing to immune resistance and immune suppression of tumor cells. We outline recent discoveries of hypoxia-driven adaptive mechanisms that diminish immune cell response via skewing the expression of important immune checkpoint molecules (e.g., cluster of differentiation 47, programmed death ligand 1, and human leukocyte antigen G), altered metabolism and metabolites, and pH regulation. Importantly, inhibition of hypoxic stress-relevant pathways can collectively enhance T-cell-mediated tumor cell killing. Furthermore, we discuss how manipulation of hypoxia stress may pose a promising new strategy for a combinational therapeutic intervention to enhance immunotherapy of solid tumors.

The proximal 5′-flanking region of the human platelet-derived growth factor A ( PDGF-A ) promoter contains one nuclease hypersensitive element (NHE) that is critical for PDGF-A gene transcription. On the basis of circular dichroism (CD) and electrophoretic mobility shift assay (EMSA), we have shown that the guanine-rich (G-rich) strand of the DNA in this region can form stable intramolecular parallel G-quadruplexes under physiological conditions. A Taq polymerase stop assay has shown that the G-rich strand of the NHE can form two major G-quadruplex structures, which are in dynamic equilibrium and differentially stabilized by three G-quadruplex-interactive drugs. One major parallel G-quadruplex structure of the G-rich strand DNA of NHE was identified by CD and dimethyl sulfate (DMS) footprinting. Surprisingly, CD spectroscopy shows a stable parallel G-quadruplex structure formed within the duplex DNA of the NHE at temperatures up to 100 ° C. This structure has been characterized by DMS footprinting in the double-stranded DNA of the NHE. In transfection experiments, 10 μ M TMPyP4 reduced the activity of the basal promoter of PDGF-A ∼ 40%, relative to the control. On the basis of these results, we have established that ligand-mediated stabilization of G-quadruplex structures within the PDGF-A NHE can silence PDGF-A expression.

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer. Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect (https://www.sciencedirect.com/), ACS (https://pubs.acs.org/), Wiley (https://onlinelibrary.wiley.com/), NCBI (https://www.ncbi.nlm.nih.gov/) and World Health Organization (https://www.who.int/). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019. Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.

Interleukin (IL)-1–mediated inflammation is proposed to contribute to the development and progression of some cancers. IL-1 family member proteins are known to be expressed constitutively in many melanoma tumor cells, and we hypothesize that these support molecular pathways of inflammation and facilitate tumor growth. To investigate the expression of IL-1α and IL-1β in melanoma patients, and their association with disease progression, immunohistochemical staining was carried out on tissues from 170 patients including benign nevi, primary melanomas, and metastatic melanomas. IL-1β levels were low (or zero) in benign nevi and higher in primary and metastatic melanomas (P < 0.0001). IL-1α was expressed in about 73% of nevi and 55% of metastatic melanomas, with levels significantly higher in primary tumors (P < 0.0001); most (98%) primary melanoma samples were positive for IL-1α. In vitro studies with seven human melanoma cell lines showed that five cell lines expressed IL-1α and IL-1β proteins and mRNA. We identified for the first time several important downstream signaling pathways affected by endogenous IL-1, including reactive oxygen and nitrogen species, COX-2, and phosphorylated NF-κB inhibitor (IκB) and stress-activated protein kinase/c-jun-NH₂-kinase; all of which were decreased by siRNA to IL-1s. Downregulation of IL-1α, IL-1β, or MyD88 substantially increased p21 and p53 levels. Treatment with IL-1 receptor type I neutralizing antibody or IL-1 pathway–specific siRNAs led to growth arrest in IL-1–positive melanoma cells. Furthermore, blocking the IL-1 pathway increased autophagy in IL-1–positive melanoma cells. These results indicate that the endogenous IL-1 system is functional in most human melanoma and interrupting its signaling inhibits the growth of IL-1–positive melanoma cells. Mol Cancer Res; 9(11); 1537–50. ©2011 AACR.