The biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they could be used as potential predictors of response and immune-related adverse events (irAEs) for ICIs therapy. The levels of TGF-β, IFN-γ, IL-6, IL-8, IL-10 were measured in sera and plasma by ELISA method of 30 healthy controls (HC) and 32 BRAF wild type (wt) MM patients before and after every 12 weeks of Pembrolizumab, PD-1 inhibitor, until one year or disease progression (DP). Higher pretherapy levels of circulating TGF-β, IFN-γ, IL-6, and IL-10 were shown in MM patients compared to HC. In patients with disease control, TGF-β and IL-6 first decreased during the therapy, while then they started to successively increase reaching the initial values by the end of the follow up. Furthermore, in this group of patients IFN-γ increased, while IL-8 and IL-10 decreased at final points of the follow up. In patients with DP IL-6 increased at the time of progression, while IL-8 decreased when the best response was achieved. In patients with pseudoprogression IL-6 and IL-10 significantly increased compared to the pretreatment values. Melanoma patients with irAEs had increased baseline values of TGF-β, IFN-γ, IL-6, and IL-10 compared to HC. However, no significant changes in cytokines levels were found in these patients during therapy. Inflammatory cytokines monitoring in circulation of BRAFwt MM patients could help in the selection of patients who will have the benefit from Pembrolizumab therapy.

Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy.

Triple-negative breast cancer (TNBC) is the most aggressive and malignant type of breast cancer with limited treatment options and poor prognosis. One of the most significant impediments in TNBC treatment is the high heterogeneity of this disease, as highlighted by the detection of several molecular subtypes of TNBC. Each subtype is driven by distinct mutations and pathway aberrations, giving rise to specific molecular characteristics closely connected to clinical behavior, outcomes, and drug sensitivity. This review summarizes the knowledge regarding TNBC molecular subtypes and how it can be harnessed to devise tailored treatment strategies instead of blindly using targeted drugs. We provide an overview of novel targeted agents and key insights about new treatment modalities with an emphasis on the androgen receptor signaling pathway, cancer stem cell-associated pathways, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, growth factor signaling, and immunotherapy.

Aims Despite efficacy of anti-PD-1 blockade in treatment of metastatic melanoma (MM), many patients achieve rapid disease progression (DP). Therefore, the aim of this study is to better define biomarkers for DP by analysing levels of circulating cytokines TGF-β, IFN-γ, IL-6, IL-8 and IL-10 in MM patients prior to anti-PD-1 therapy. Methods Cytokine levels were evaluated before therapy with pembrolizumab in peripheral blood of BRAF wild-type (wt) MM patients by ELISA method. Results In this study, we give pretherapy levels for circulating TGF-β, IFN-γ, IL-6, IL-8 and IL-10 in BRAFwt MM patients and analyse them according to metastasis stage (M1a+M1 b, M1c, M1d groups), lactate dehydrogenase (LDH) level and occurrence of DP. Increased IL-6 level was found in M1d group (central nervous system metastasis), while LDH+patients (LDH ≥460 IU/L) have increased IL-6 and IL-8 values that correlate with LDH level. Also, IL-6 correlates with C reactive protein values. Furthermore, patients with DP have significantly higher IL-6 level compared with non-DP patients. Conversely, the other analysed cytokines are similar in investigated groups of MM patients. By receiver operating characteristics curve analysis, pretherapy IL-6 level was found to be a biomarker for the occurrence of DP with cut-off value of 3.02 pg/mL. Patients in M1d stage are prevalent in the group with IL-6 ≥3.02 pg/mL that is characterised with reduced progression-free survival and higher pretherapy IL-8 and LDH. Conclusion The evidence in this study implies that baseline IL-6 could be a biomarker of DP and poor prognosis in BRAFwt MM patients treated with pembrolizumab.

Histone deacetylases (HDACs) and Rho-associated coiled-coil containing protein kinases (ROCKs) are critical regulators of tumor development, progression and immunomodulation, particularly in aggressive cancers such as triple negative breast cancer (TNBC). Previous in silico and in vitro studies have demonstrated the therapeutic potential of multitarget HDAC/ROCK inhibition, leading to the identification of C-9 as the first-in-class multitarget HDAC/ROCK inhibitor. In the present study, C-9 served as a lead compound for the rational design of a new series of multitarget inhibitors. Structure-based drug design (SBDD) was used to develop a series of novel HDAC/ROCK multitarget inhibitors. Molecular docking and MM-GBSA binding free energy analysis confirmed strong and specific interactions with the catalytic sites of both targets. Based on these computational insights, ten compounds were synthesized and biologically evaluated using enzyme inhibition and cancer cell assays. Among the synthesized compounds, C-35 and C-40 showed remarkable cytotoxic activity against TNBC cell lines, with IC50 values of 17 µM and 27 µM against MDA-MB-231 cells and about 35 µM against MDA-MB-468 cells, respectively, outperforming known selective HDAC6 and ROCK inhibitors such as tubastatin A and fasudil. Further mechanistic studies revealed that these compounds induce early apoptosis, arrest cell cycle progression and downregulate PD-L1 expression. Remarkably, C-35 also increased the expression of MICA in MDA-MB-231 and MDA-MB-468 cells, possibly promoting the recognition and elimination of tumor cells by immune cells. To further support rational drug optimization, we used synthesized compounds and their IC50 values for the enzymes to form an external blind validation set that enabled the development of machine learning-based quantitative structure-activity relationships (QSAR) models for HDAC6 and ROCK2. These models, developed for the first time for both targets, showed strong predictive performance and were integrated into a comprehensive CADD workflow combining structure-based (molecular docking and MM-GBSA) and ligand-based (QSAR) methods for drug development. Overall, this study highlights the anti-cancer, anti-invasive, anti-migratory and immunomodulatory potential of multitarget HDAC/ROCK inhibition for the treatment of TNBC. Finally, it creates a robust computational-experimental pipeline for future development and optimization of multitarget HDAC/ROCK inhibitors.

Histone deacetylase 6 (HDAC6) regulates many physiological processes that are involved in cancer development and progression such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, by deacetylation of multiple substrates and association with interacting proteins. Due to its the ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cells survival. HDAC6 is often overexpressed in tumors, including colorectal cancer (CRC) and is correlated with poor disease prognosis. However, it has been shown in animal models that HDAC6 is not essential for normal mammalian development. Therefore, it represents a good target for the development of novel cancer therapeutics. Selective inhibition of HDAC6 impairs growth and progression of many tumors without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown potential to reduce tumor progression and to enhance the therapeutic effect of other drugs. As HDAC6 is involved in regulation of immune responses, HDAC6 inhibitors have shown potential to improve antitumor immunity by increasing immunogenicity of tumor cells, augmenting immune cell activity and alleviating immunosuppression in tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect and to overcome resistance to immunotherapy.