Dual check point inhibitor

PURPOSE OF REVIEW: The aim of this review is to outline the current landscape of advanced melanoma treatment options, provide insights on selecting combination therapies within different clinical scenarios, capture clinical relevance of anti-programmed cell death protein 1 (PD-1) monotherapy, and explore the unmet needs with immune check-point inhibitors (ICI) in advanced melanoma. RECENT FINDINGS: ICI based treatment consisted of single agent ICI or dual combination ICI-ICI is the standard of care of front-line treatment of metastatic or unresectable melanoma...

The drug therapy for non-small cell lung cancer (NSCLC) have always been issues of poisonous side effect, acquired drug resistance and narrow applicable population. In this study, we built a novel network analysis method (difference- correlation- enrichment- causality- node), which was based on the difference analysis, Spearman correlation network analysis, biological function analysis and Bayesian causality network analysis to discover new therapeutic target of NSCLC in the sequencing data of BEAS-2B and 7 NSCLC cell lines...

Tumor bone metastasis is still difficult to cure despite the development of various treatment strategies. Drug delivery systems can improve the poor biological distribution of anticancer drugs in tumors. But only a very small number of nanoparticles can cross the physiological barrier to reach the tumor. In addition, the progression of bone metastasis is influenced by tumor cells, osteoclasts and bone matrix. To address these problems, a bone and tumor dual targeted nanocarrier was developed by utilizing NF-κB inhibitor loaded into zeolitic imidazolate framework-8 (ZIF-8) (CZ), which was then coated with hyaluronic acid/alendronate (HA/ALN)...

Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable...

Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption...

Radiation-induced immune effects have been extensively deciphered over the last few years, leading to the concept of the dual immune effect of radiotherapy with both immunostimulatory and immunosuppressive effects. This explains why radiotherapy alone is not able to drive a strong anti-tumor immune response in most cases, hence underlining the rationale for combining both radiotherapy and immunotherapy. This association has generated considerable interest and hundreds of trials are currently ongoing to assess such an association in oncology...

BACKGROUND AND OBJECTIVES: Neuraxial hematoma is a rare complication of the epidural technique which is commonly used for high quality postoperative pain relief. In case of urgent initiation of multiple antithrombotic therapy, the optimal timing of epidural catheter removal and need for treatment modification may be quite challenging. There are no specific guidelines and published reports are scarce. CASE REPORT: We present the uneventful removal of an indwelling epidural catheter in a patient who was put on emergency triple antithrombotic treatment with Low Molecular Weight Heparin (LMWH), aspirin and clopidogrel in the immediate postoperative period, due to acute coronary syndrome...

PURPOSE OF REVIEW: To discuss treatment decisions in the first-line setting of metastatic renal cell carcinoma (mRCC). RECENT FINDINGS: Immune check point inhibitor (ICI) combinations have replaced sunitinib as the standard of care in the first-line treatment of mRCC. Dual ICI treatment with nivolumab and ipilimumab was shown to significantly improve overall survival and objective response rates. Similarly, the ICI-tyrosine kinase inhibitor combinations pembrolizumab and axitinib and nivolumab and cabozantinib have demonstrated superiority in terms of overall survival, objective response rates and progression-free survival versus sunitinib...

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients...

Protein kinases are intracellular signaling enzymes that catalyze the phosphorylation of specific residues in their target substrate proteins. They play important role for regulation of life and death decisions. The complexity of the relationship between death receptors and protein kinases' cell death decision-making mechanisms create many difficulties in the treatment of various diseases. The most of fifteen different cell death pathways, which are reported by Nomenclature Committee on Cell Death (NCCD) are protein kinase signal transduction-mediated negative or positive selections...

Immunotherapy with check-point inhibitors serves as a promising treatment strategy in patients with upper gastrointestinal (GI) tumors. Human epidermal growth factor receptor 2 (HER2) is the only identified therapeutic target in upper GI tumors, whose potential interaction with programmed death-ligand 1 (PD-L1) is unknown. The aim of this study was the investigation of PD-L1 and HER2 in upper GI tumors. We retrospectively identified patients with HER2 positive gastroesophageal cancers and matched them with a HER2 negative group...

We have recently described a novel therapeutic antibody product (IL2-F8-TNFmut ), featuring the simultaneous fusion of murine IL2 and of a TNF mutant with scFv(F8), an antibody specific to the alternatively-spliced extra domain A of fibronectin (EDA). Here, we report on the in vivo characterization of the anti-cancer activity of IL2-F8-TNFmut in four immunocompetent murine models of cancer, CT26, WEHI-164, F9 teratocarcinoma and Lewis lung carcinoma (LLC), using the product alone or in combination with a monoclonal antibody specific to murine PD-L1...

Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs)...

The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation-based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in three-dimensional spheroids and organoids...

Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC₅₀=5...

The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins...

Di-n-butyl-(2,6-difluorobenzohydroxamato)Tin(IV) (DBDFT), a potential antitumor agent against malignancies, exhibited high activities both in vitro and in vivo. Flow cytometric analysis showed that treatment with DBDFT against Human Gastric Carcinoma (SGC-7901) cells induced a concentration and time-dependent cell accumulation in the G2/M phase of the cell cycle with a parallel depletion of the percentage of cells in G0/G1, the cell apoptosis was observed by characteristic morphological changes and AnnexinV/PI dual-immunofluorescence staining...

Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance...

p27Kip1 is a critical regulator of the eukaryotic cell cycle. It acts as a check point protein and regulates cell cycle progression at the G1 and G1/S phase as well as predominantly blocks cell cycle progression in the absence of growth factors. Intracellular turnover of p27 is tightly regulated at the level of translation as well as by posttranslational modification. The mechanism by which p27 protein is rapidly degraded during the G1 and G1/S phase transition is well characterized. However, the process by which p27 remains extremely stable in the absence of growth factors remains unknown...

Expression of the epidermal growth factor (EGF) receptors HER1 and HER2 has been implicated in tumour growth and poor survival, whereas expression of HER3 and HER4 has been associated with improved survival of bladder cancer patients. The balance between the expression of the EGF family members may therefore have a role to play in determining the final outcome in cancer cells. To check this, we examined the effect of HER1 activation and inhibition on the expression of the EGF receptors HER3 and HER4 and ligands - the heregulins (HRGs)...