Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy.

The clinical efficacy of VSVΔ51 oncolytic virotherapy has been limited by tumor resistance to viral infection, so strategies to transiently repress antiviral defenses are warranted. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor currently being tested in clinical trials for its antitumor potential. In this study, we demonstrate that pevonedistat sensitizes human and murine cancer cells to increase oncolytic VSVΔ51 infection, increase tumor cell death, and improve therapeutic outcomes in resistant syngeneic murine cancer models. Increased VSVΔ51 infectivity was also observed in clinical human tumor samples. We further identify the mechanism of this effect to operate via blockade of the type 1 interferon (IFN-1) response through neddylation-dependent interferon-stimulated growth factor 3 (ISGF3) repression and neddylation-independent inhibition of NF-κB nuclear translocation. Together, our results identify a role for neddylation in regulating the innate immune response and demonstrate that pevonedistat can improve the therapeutic outcomes of strategies using oncolytic virotherapy.

Unlocking the potential of dimethyl fumarate: enhancing oncolytic HSV-1 efficacy for wider cancer applications.

Immunotherapy and specifically oncolytic virotherapy has emerged as a promising option for cancer patients, with oncolytic herpes simplex virus-1 (oHSV-1) expressing granulocyte macrophage colony stimulating factor being the first OV to be approved by the FDA for treatment of melanoma. However, not all cancers are sensitive and responsive to oncolytic viruses (OVs). Our group has demonstrated that fumaric and maleic acid esters (FMAEs) are very effective in sensitizing cancer cells to OV infection. Of note, these FMAEs include dimethyl fumarate (DMF, also known as Tecfidera®), an approved treatment for multiple sclerosis and psoriasis. This study aimed to assess the efficacy of DMF in combination with oncolytic HSV-1 in preclinical cancer models. We demonstrate herewith that pre-treatment with DMF or other FMAEs leads to a significant increase in viral growth of oHSV-1 in several cancer cell lines, including melanoma, while decreasing cell viability. Additionally, DMF was able to enhance ex vivo oHSV-1 infection of mouse-derived tumor cores as well as human patient tumor samples but not normal tissue. We further reveal that the increased viral spread and oncolysis of the combination therapy occurs via inhibition of type I IFN production and response. Finally, we demonstrate that DMF in combination with oHSV-1 can improve therapeutic outcomes in aggressive syngeneic murine cancer models. In sum, this study demonstrates the synergistic potential of two approved therapies for clinical evaluation in cancer patients.

Profiling non-small cell lung cancer reveals that PD-L1 is associated with wild type EGFR and vascular invasion, and immunohistochemistry quantification of PD-L1 correlates weakly with RT-qPCR.

Most lung cancer patients are diagnosed at an advanced stage, limiting their treatment options with very low response rate. Lung cancer is the most common cause of cancer death worldwide. Therapies that target driver gene mutations (e.g. EGFR, ALK, ROS1) and checkpoint inhibitors such anti-PD-1 and PD-L1 immunotherapies are being used to treat lung cancer patients. Identification of correlations between driver mutations and PD-L1 expression will allow for the best management of patient treatment. 851 cases of non-small cell lung cancer cases were profiled for the presence of biomarkers EGFR, KRAS, BRAF, and PIK3CA mutations by SNaPshot/sizing genotyping. Immunohistochemistry was used to identify the protein expression of ALK and PD-L1. Total PD-L1 mRNA expression (from unsorted tumor samples) was quantified by RT-qPCR in a sub-group of the cohort to assess its correlation with PD-L1 protein level in tumor cells. Statistical analysis revealed correlations between the presence of the mutations, PD-L1 expression, and the pathological data. Specifically, increased PD-L1 expression was associated with wildtype EGFR and vascular invasion, and total PD-L1 mRNA levels correlated weakly with protein expression on tumor cells. These data provide insights into driver gene mutations and immune checkpoint status in relation to lung cancer subtypes and suggest that RT-qPCR is useful for assessing PD-L1 levels.

Nanomaterials for Antiangiogenic Therapies for Cancer: A Promising Tool for Personalized Medicine.

Angiogenesis is one of the hallmarks of cancer. Several studies have shown that vascular endothelium growth factor (VEGF) plays a leading role in angiogenesis progression. Antiangiogenic medication has gained substantial recognition and is commonly administered in many forms of human cancer, leading to a rising interest in cancer therapy. However, this treatment method can lead to a deteriorating outcome of resistance, invasion, distant metastasis, and overall survival relative to its cytotoxicity. Furthermore, there are significant obstacles in tracking the efficacy of antiangiogenic treatments by incorporating positive biomarkers into clinical settings. These shortcomings underline the essential need to identify additional angiogenic inhibitors that target numerous angiogenic factors or to develop a new method for drug delivery of current inhibitors. The great benefits of nanoparticles are their potential, based on their specific properties, to be effective mechanisms that concentrate on the biological system and control various important functions. Among various therapeutic approaches, nanotechnology has emerged as a new strategy for treating different cancer types. This article attempts to demonstrate the huge potential for targeted nanoparticles and their molecular imaging applications. Notably, several nanoparticles have been developed and engineered to demonstrate antiangiogenic features. This nanomedicine could effectively treat a number of cancers using antiangiogenic therapies as an alternative approach. We also discuss the latest antiangiogenic and nanotherapeutic strategies and highlight tumor vessels and their microenvironments.

Molecular profiling of non-small cell lung cancer.

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.

Systematic Analysis of Spleen Tyrosine Kinase Expression and its Clinical Outcomes in Various Cancers.

BACKGROUND: Spleen tyrosine kinase (SYK) is an important enzyme in the proliferation and differentiation of all hematopoietic tissues. Its role as a cancer driver is well documented in liquid tumors; however, cumulative evidence has suggested an opposite role in other tumor types. OBJECTIVES: To systematically assess the expression of SYK, its prognostic value and epigenetic status in different cancers using bioinformatics tools. METHODS: In this bioinformatics study, Oncomine database and cBioPortal were used to study the SYK gene expression, Kaplan-Meier plotter to study its prognostic value and MethHC to assess the SYK gene methylation in various cancers. RESULTS: From 542 unique analyses of the SYK gene, it was found to be overexpressed in bladder, breast and colon cancers but downregulated in leukemia, lymphoma and myeloma. Compared with normal tissues, breast and brain tumors showed an overexpression of the SYK gene, whereas lymphoma and leukemia had lower expression. The Kaplan-Meier survival analysis revealed that SYK expression in pancreatic, gastric, liver and lung patients were correlated with better overall survival. Using cBioPortal, prostate cancer was found to have the highest SYK gene mutation frequency, and the mean expression was highest in diffuse large B-cell lymphoma, acute myeloid leukemia and thymoma. Using the MethHC database, SYK promoter hypermethylation was found to be significantly higher in breast, renal, liver, lung, pancreatic, prostatic, skin and stomach cancers compared with the normal tissue (P < 0.005). CONCLUSION: The results of this study indicate the potential use of SYK as a diagnostic and therapeutic target for different type of cancers. However, further experimental data are required to validate these results before use of SYK in clinical settings.