Kinase Inhibitors in the Treatment of Ovarian Cancer: Current State and Future Promises.

Ovarian cancer is the deadliest gynecological cancer, the high-grade serous ovarian carcinoma (HGSC) being its most common and most aggressive form. Despite the latest therapeutical advancements following the introduction of vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors and poly-ADP-ribose-polymerase (PARP) inhibitors to supplement the standard platinum- and taxane-based chemotherapy, the expected overall survival of HGSC patients has not improved significantly from the five-year rate of 42%. This calls for the development and testing of more efficient treatment options. Many oncogenic kinase-signaling pathways are dysregulated in HGSC. Since small-molecule kinase inhibitors have revolutionized the treatment of many solid cancers due to the generality of the increased activation of protein kinases in carcinomas, it is reasonable to evaluate their potential against HGSC. Here, we present the latest concluded and on-going clinical trials on kinase inhibitors in HGSC, as well as the recent work concerning ovarian cancer patient organoids and xenograft models. We discuss the potential of kinase inhibitors as personalized treatments, which would require comprehensive assessment of the biological mechanisms underlying tumor spread and chemoresistance in individual patients, and their connection to tumor genome and transcriptome to establish identifiable subgroups of patients who are most likely to benefit from a given therapy.

Muscle-Organ Crosstalk: Focus on Immunometabolism.

Skeletal muscle secretes several hundred myokines that facilitate communication from muscle to other organs, such as, adipose tissue, pancreas, liver, gut, and brain. The biological roles of myokines include effects on e.g., memory and learning, as well as glucose and lipid metabolism. The present minireview focuses on recent developments showing that exercise-induced myokines are involved in immunometabolism of importance for the control of e.g., tumor growth and chronic inflammation. In this review, immunometabolism is discussed as the non-immune related pathologies leading to an immune response and some degree of inflammation, which promotes metabolic abnormalities.

Human immune cell mobilization during exercise: effect of IL-6 receptor blockade.

NEW FINDINGS: What is the central question of this study? Does blockade of the IL-6 receptor by tocilizumab inhibit immune cell mobilization to the blood stream in humans during an acute bout of exercise? What is the main finding and its importance? Blockade of IL-6 receptor signalling by tocilizumab attenuates mobilization of NK cells and dendritic cells to the blood stream during exercise. This implies an inhibitory effect of tocilizumab on the innate immune response to physical stress, which could be considered in clinical settings. ABSTRACT: Immune cells are recruited from their storage organs and the endothelial walls to the blood stream in response to physiological stress. This is essential for the recognition and clearing of infected, transformed or damaged cells. One of the most potent stimuli to recruit immune cells to the circulation is exercise. Accordingly, exercise has proven beneficial in disease settings, such as cancer and diabetes. Interleukin-6 (IL-6) is released from contracting skeletal muscle in response to exercise, and rodent studies have established a link between exercise-induced IL-6 and recruitment of natural killer (NK) cells. Whether exercise-induced IL-6 is involved in regulating NK cell mobilization in humans is unclear. This study explored the effect of IL-6 receptor blockade on immune cell mobilization during an acute bout of exercise in humans. In a randomized, placebo-controlled clinical study, abdominally obese humans receiving placebo infusions or tocilizumab infusions performed an acute bout of exercise before and after the intervention. Immune cell recruitment was measured by flow cytometry. IL-6 receptor blockade attenuated the increase of NK cells by 53% (mean difference -0.49 (95% CI: -0.89 to -0.08) × 109 cells L-1 , P < 0.001) and dendritic cells by 66% (mean difference -0.14 (95% CI: -0.28 to 0.010) × 109 cells L-1 , P < 0.001) induced by an acute bout of exercises. No changes were observed for T cells, monocytes and neutrophils. Treatments which interact with the exercise-mediated immune surveillance provide relevant clinical information in pursuing the 'exercise as medicine' concept.

Voluntary wheel running can lead to modulation of immune checkpoint molecule expression.

BACKGROUND: Exercise and physical activity (PA) are associated with reduced tumor growth and enhanced intra-tumoral immune cell infiltration in mice. We aimed to investigate the role of PA achieved by voluntary wheel running in promoting the immunogenic profile across several murine tumor models, and to explore the potential of checkpoint blockade and PA in the form of voluntary wheel running as combination therapy. MATERIAL AND METHODS: The experiments were performed with C57BL/6 mice bearing subcutaneous tumors while having access to running wheels in their cages, where key immunoregulatory molecules expressed in the tumor tissue were measured by qPCR. Furthermore, we tested the hypothesis that wheel running combined with PD-L1 -or PD-1 inhibitor treatment could lead to an additive effect on tumor growth in mice bearing B16 melanoma tumors. RESULTS: Wheel running increased immune checkpoint expression (PD-1, PD-L1, PD-L2, CD28, B7.1 and B7.2) in B16 tumor-bearing mice, while induction of only PD-L2 was found in E0771 breast cancer and Lewis Lung Cancer. In studies combining voluntary wheel running with PD-1 -and PD-L1 inhibitors we found significant effects of wheel running on attenuating B16 melanoma tumor growth, in line with previous studies. We did, however, not find an additive effect of combining either of the two immunotherapeutic treatments with access to running wheels. CONCLUSION: B16 tumors displayed upregulated expression of immune regulatory molecules and decreased tumor growth in response to PA. However, combining PA with PD-1 or PD-L1 blockade did not lead to a further augmented inhibition of tumor growth.

Calcium electroporation induces tumor eradication, long-lasting immunity and cytokine responses in the CT26 colon cancer mouse model.

Electroporation is used in cancer treatment because of its ability to increase local cytotoxicity of e.g. bleomycin (electrochemotherapy) and calcium (calcium electroporation). Calcium electroporation is a novel anticancer treatment that selectively kills cancer cells by necrosis, a cell death pathway that stimulates the immune system due to high release of antigens and "danger signals." In this exploratory study, we aimed to investigate whether calcium electroporation could initiate an anticancer immune response similar to electrochemotherapy. To this end, we treated immunocompetent balb/c mice with CT26 colon tumors with calcium electroporation, electrochemotherapy, or ultrasound-based delivery of calcium or bleomycin. High treatment efficiency was observed with 100% complete remission in all four groups (12/12 with complete remission in each treatment group). In addition, none of the surviving mice from these groups formed new tumors when re-challenged with CT26 cancer cells 100-d post treatment, whereas mice challenged with different cancer cells (4T1 breast cancer) all developed tumors. Treatment of immunodeficient mice with calcium electroporation and electrochemotherapy showed no long-lasting tumor response. Calcium electroporation and electrochemotherapy was associated with a release of High Mobility Group Box 1 protein (HMGB1) in vitro (p = 0.029) and a significant increase of the overall systemic level of pro-inflammatory cytokines in serum from the treated mice (p < 0.003). These findings indicate that calcium electroporation as well as electrochemotherapy could have a role as immune stimulators in future treatments.

Flexibility and mutagenic resiliency of glycosyltransferases.

The human blood group A and B antigens are synthesized by two highly homologous enzymes, glycosyltransferase A (GTA) and glycosyltransferase B (GTB), respectively. These enzymes catalyze the transfer of either GalNAc or Gal from their corresponding UDP-donors to αFuc1-2ßGal-R terminating acceptors. GTA and GTB differ at only four of 354 amino acids (R176G, G235S, L266M, G268A), which alter the donor specificity from UDP-GalNAc to UDP-Gal. Blood type O individuals synthesize truncated or non-functional enzymes. The cloning, crystallization and X-ray structure elucidations for GTA and GTB have revealed key residues responsible for donor discrimination and acceptor binding. Structural studies suggest that numerous conformational changes occur during the catalytic cycle. Over 300 ABO alleles are tabulated in the blood group antigen mutation database (BGMUT) that provides a framework for structure-function studies. Natural mutations are found in all regions of GTA and GTB from the active site, flexible loops, stem region and surfaces remote from the active site. Our characterizations of natural mutants near a flexible loop (V175M), on a remote surface site (P156L), in the metal binding motif (M212V) and near the acceptor binding site (L232P) demonstrate the resiliency of GTA and GTB to mutagenesis.