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Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), an important pro-survival protein in the BCL-2 family, is a promising antitumor target. In this study, we chose to investigate the effects of S63845, a small-molecule inhibitor that targets MCL-1, on the normal hematopoietic system. A mouse model of hematopoietic injury was constructed, and the effects of the inhibitor on the hematopoietic system of mice were evaluated via routine blood tests and flow cytometry. The results showed that S63845 affected the hematopoiesis of various lineages in the early stage of action, causing extramedullary compensatory hematopoiesis in the myeloid and megakaryocytic lineages. The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects.

The binding of epidermal growth factor (EGFR) receptors is a good target for the treatment of lung, colon, pancreatic, head and neck cancers. The adverse events that develop as a result of therapy, in the form of lesions of the skin and mucous membranes, is a serious problem for the doctor to choose a long-term treatment strategy. The developing symptoms of skin toxicity, as skin problems in patients are often called, are worrisome and often affect the quality of life and compliance with the treatment regimen. Thus, it is important for doctors to know the prerequisites and ways to manage skin toxicity associated with the use of tyrosine kinase receptor inhibitors of epidermal growth factor. The mechanism and consequences of EGF receptor activation are described to explain the development of undesirable skin toxicity associated with inhibition of the epidermal growth factor receptor.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktória Paulusová Supervisor: doc. RNDr. Jakub Hofman, Ph.D. Title od diploma thesis: Study on the effect of selected targeted drugs on drug resistance mediated by ABC drug transporters. Multidrug resistance (MDR) is one of the major problems associated with cancer treatment. A key determinant of MDR is increased efflux of drugs through membrane ATP- binding cassette (ABC) transporters, which are a family of transporter proteins. Their overexpression contributes to MDR by decreasing intracellular drug concentration due to the efflux of various drugs from cells. Targeting ABC transporters appears to be a promising approach to suppress drug resistance. Therefore, one strategy to reverse the resistance of ABC transporter-expressing tumor cells is the combined use of chemotherapeutic drugs with ABC transporter modulators to enhance therapeutic efficacy. The aim of this work was to investigate the effect of targeted drugs (capmatinib, pralsetinib and tazemetostat) in combination with cytostatics (etoposide and topotecan) on drug resistance mediated by ABC efflux transporters. Results were obtained using MTT assays and caspase activity assays performed on the parental A431 cell line and its...

There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients’ lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling – selumetinib, trametinib, and SCH772984 – increased AKT phosphorylation, and conversely, inhibitors of AKT – capivasertib, idelalisib, and AKT inhibitor VIII – increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy.

Objective: to evaluate clinical efficacy, safety and tolerability of long-term inhaled iloprost treatment in the daily practice for the management of pulmonary arterial hypertension (PAH). Methods: a total of 115 patients with PAH on inhaled iloprost treatment were included. New York Heart Association (NYHA) functional class, brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and 6-minute walk distance (6MWD) were recorded at baseline and at 3rd to 24th month visits. Safety and tolerability of iloprost treatment were also evaluated during follow-up, as were the survival, clinical worsening, and the related risk factors. Results: the treatment was associated with an increase in the percentage NYHA functional class II (from 0.0% at enrolment to 36.2% at 24th month visit) patients but no significant difference was noted in 6MWD values. Clinical worsening was observed in 63.5% patients, while survival rate was 69.6%. NT-proBNP levels were significantly higher in non-survivors than in survivors (p=0.042). Cox regression analysis revealed the association of female sex [odds ratio (OR)=0.318; 95% confidence interval (CI), 0.128-0.792; p=0.014] and scleroderma-related PAH (OR=0.347; 95% CI, 0.140-0.860; p=0.022) with significantly lower risk (3.14 fold and 2.88 fold, respectively) of mortality. Conclusion: our findings indicate favorable efficacy, safety, and tolerability of long-term iloprost treatment in the management of PAH, whereas improved NYHA functional class was not accompanied with a significant change in 6MWD values. Patient age was a risk factor for clinical worsening, while female sex, scleroderma subtype, and lower NT-proBNP levels were associated with significantly lower mortality risk., Bayer Türk

Patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we describe and analyze the outcome of 366 adult patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between February 2020 and January 2022. Median follow-up was 70.5 days (IQR 0-609). Most used targeted drugs were Bruton-kinase inhibitors (BKIs) (N= 201, 55%), anti-CD20 other than rituximab (N=61, 16%), BCL2 inhibitors (N=33, 9%) and lenalidomide (N=28, 8%).Only 16.2% of the patients were vaccinated with 2 or more doses of vaccine at the onset of COVID-19. Mortality was 24% (89/366) on day 30 and 36%(134/366) on the last day of follow-up. Age >75 years (p, EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Relapse remains the main cause of treatment failure in acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Emerging evidence has demonstrated that AML patients might benefit from maintenance therapy post-transplantation, especially for high-risk AML patients. In this mini-review, we will summarize targeted drugs, such as hypomethylating agents, FLT3 inhibitors and isocitrate dehydrogenase inhibitors, as maintenance therapy post-transplantation in AML patients undergoing allo-HSCT.

As the most common mutation in papillary thyroid cancer (PTC), B-type Raf kinase V600E mutation (BRAFV600E ) has become an important target for the clinical treatment of PTC. However, the clinical application still faces the problem of resistance to BRAF inhibitors (BRAFi). Therefore, exploring BRAFV600E-associated prognostic factors to providing potential joint targets is important for combined targeted therapy with BRAFi. In this study, we combined transcript data and clinical information from 199 BRAF wild-type (BRAFWT ) patients and 283 BRAFV600E mutant patients collected from The Cancer Genome Atlas (TCGA), and screened 455 BRAFV600E- associated genes through differential analysis and weighted gene co-expression network analysis. Based on these BRAFV600E -associated genes, we performed functional enrichment analysis and co-expression differential analysis and constructed a core co-expression network. Next, genes in the differential co-expression network were used to predict drugs for therapy in the crowd extracted expression of differential signatures (CREEDS) database, and the key genes were selected based on the hub co-expression network through survival analyses and receiver operating characteristic (ROC) curve analyses. Finally, we obtained eight BRAFV600E -associated biomarkers with both prognostic and diagnostic values as potential BRAFi joint targets, including FN1, MET, SLC34A2, NGEF, TBC1D2, PLCD3, PROS1, and NECTIN4. Among these genes, FN1, MET, PROS1, and TBC1D2 were validated through GEO database. Two novel biomarkers, PROS1 and TBC1D2, were further validated by qRT-PCR experiment. Besides, we obtained four potential targeted drugs that could be used in combination with BRAFi to treat PTC, including MET inhibitor, ERBB3 inhibitor, anti-NaPi2b antibody-drug conjugate, and carboplatin through literature review. The study provided potential drug targets for combination therapy with BRAFi for PTC to overcome the drug resistance for BRAFi.

The purpose of the study was to analyze the existing methodological approaches to the experimental testing of resistance to chemotherapy and assess the prospects for their further application.Material and Methods. We analyzed publications regarding the experimental testing of tumor resistance to chemotherapy available in the databases, such as SciVerse Scopus (748), PubMed (1727), Web of Science (1025), RSCI (125). To obtain fulltext publications, the electronic resources of Research Gate, RSCI, CyberLenink were used. Forty-two modern publications (2012–19) including 18 articles of the founders of the methods analyzed in the review were cited.Results. The review discusses the characteristics of the main methods for assessing the resistance / sensitivity of tumor cells obtained from biopsy / surgical specimens to various chemotherapy drugs in vitro in monolayer and suspension cultures, in the form of spheroids, histo and organocultures, as well as in vivo xenografts of tumors in immunodeficient mice. During testing, the proliferative and metabolic activities as well as the level of cell death were considered as the main evaluated characteristics of tumor cells. The main indicators were the intensity of DNA synthesis, the level of protein or ATP in the cell, the activity of NADH-dehydrogenases, the level of apoptosis, and the integrity of cell structures. The advantages and disadvantages of the described methods, as well as the prospects for their further application were discussed.Conclusion. Over the past half century of using the experimental testing of tumor cell resistance in order to personalize chemotherapeutic treatment, the evolution of methodological approaches was based on the increase in their safety and sensitivity through the use of fluorescent compounds. The general vector for improving experiments on the personalization of tumor chemotherapy is aimed at approximating the experimental conditions to the processes occurring in the human body. Each of these methods has its own range of predictive power and, if used properly, can provide a useful guide for treatment.

The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research.

To increase the effectiveness of treatment for breast cancer, representatives of various oncological schools use various approaches and scientific results obtained using high technologies, as evidenced by the analysis of scientific publications of specialists. The aimof this literature review was to analyze the influence of some scientific achievements using high technologies on modern ideas of oncologists about the pathogenesis of breast cancer and new approaches to increasing the efficiency of its treatment. Material and research methods. Scientific articles in journals specializing in Oncology, materials of scientific conferences, Internet resources Research results and their discussion. Unsatisfactory results of the treatment of breast cancer, frequent relapses of this pathology, high mortality, on the one hand, and the results of scientific studies using high technologies, on the other hand, led oncologists to search for new approaches to solving the problem by improving surgical, medicinal and radiation treatments. Conclusions.The search for new approaches to solving the issue of increasing the effectiveness of breast cancer treatment is carried out in different directions: in the field of improving surgical treatment methods, drug methods, taking into account inhibitors of immune control points, new drugs for targeted therapy and the theory of cancer stem cells. The development of new approaches to the treatment of breast cancer has great prospects in addressing the issue of increasing the effectiveness of its treatment

Biliary tract cancer is a group of epithelial cancers associated with the biliary tract. They are anatomically divided into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subgroups. Up to now, surgical treatment is still the main treatment for malignant biliary tumors, but many patients are in advanced stage when they were diagnosed, the opportunity for surgery was lost, and there is still no effective chemotherapy program. Therefore, it is urgent to find an effective targeted drug. In this paper, we discuss some new ideas and molecular research of malignant biliary tumors in recent years. These molecules may be the promising targets for future treatment of malignant biliary tumors.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Júlia Jurčáková Supervisor: RNDr. Jakub Hofman PhD. Title of diploma thesis: The assessment of inhibitory effects of selected targeted anticancer drugs on the activity of ABC drug eflux trasporters. Lung cancer is the leading cause of death within oncological diseases. Non-small cell lung carcinoma (NSCLC) accounts for about 85% of all lung cancer, and its major subtypes include adenocarcinoma and squamous cell carcinoma. In addition to surgery, radiotherapy and chemotherapy, the use of targeted low-molecular substances, which target tumor cells with higher specificity, has recently been used in treatment. The two main causes of death in cancer patients are the formation of metastases and the development of multidrug resistance (MDR). This may also be caused by overexpression of the efflux transporters. ATP-binding cassette (ABC) transporters are groups of transmembrane pumps that use energy in the form of ATP to transfer a wide range of substrates. In particular, P-glycoprotein (ABCB1), breast cancer-resistance protein (ABCG2) and multidrug resistance-associated protein 1 (ABCC1) are associated with MDR. Inhibition of these transporters increases the amount of cytostatic substrate within the...

In pediatric acute myeloid leukemia (AML), fusions involving lysine methyltransferase 2A (KMT2A) are considered hallmarks of aggressive AML, for whom the development of targeted specific therapeutic agents to ameliorate classic chemotherapy and obtain a complete eradication of disease is urgent. In this study, we investigated the antiapoptotic proteins in a cohort of 66 pediatric AML patients, finding that 75% of the KMT2A-r are distributed in Q3 + Q4 quartiles of BCL-2 expression, and KMT2A-r have statistically significant high levels of BCL-2, phospho-BCL-2 S70, and MCL-1, indicating a high anti-apoptotic pathway activation. In an attempt to target it, we tested novel drug combinations of venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, in KMT2A-MLLT3, for being the most recurrent, and KMT2A-AFDN, for mediating the worst prognosis, rearranged AML cell lines. Our screening revealed that both the bromodomain and extra-terminal domain (BET) inhibitor, I-BET151, and kinase inhibitor, sunitinib, decreased the BCL-2 family protein expression and significantly synergized with venetoclax, enhancing KMT2A-r AML cell line death. Blasts t (6; 11) KMT2A-AFDN rearranged, both from cell lines and primary samples, were shown to be significantly highly responsive to the combination of venetoclax and thioridazine, with the synergy being induced by a dramatic increase of mitochondrial depolarization that triggered blast apoptosis. Finally, the efficacy of novel combined drug treatments was confirmed in KMT2A-r AML cell lines or ex vivo primary KMT2A-r AML samples cultured in a three-dimensional system which mimics the bone marrow niche. Overall, this study identified that, by high-throughput screening, the most KMT2A-selective drugs converged in different but all mitochondrial apoptotic network activation, supporting the use of venetoclax in this AML setting. The novel drug combinations here unveiled provide a rationale for evaluating these combinations in preclinical studies to accelerate the introduction of targeted therapies for the life-threatening KMT2A-AML subgroup of pediatric AML.

Chronic stress is an emotional experience that occurs when people encounter something they cannot adapt to. Repeated chronic stress increases the risk of a variety of diseases, such as cardiovascular disease, depression, endocrine disease, inflammation and cancer. A growing body of research has shown that there is a link between chronic stress and tumor occurrence in both animal studies and clinical studies. Chronic stress activates the neuroendocrine system (hypothalamic-pituitary-adrenal axis) and sympathetic nervous system. Stress hormones promote the occurrence and development of tumors through various mechanisms. In addition, chronic stress also affects the immune function of the body, leading to the decline of immune monitoring ability and promote the occurrence of tumors. The mechanisms of chronic stress leading to tumor include inflammation, autophagy and epigenetics. These factors increase the proliferation and invasion capacity of tumor cells and alter the tumor microenvironment. Antagonists targeting adrenergic receptors have played a beneficial role in improving antitumor activity, as well as chemotherapy resistance and radiation resistance. Here, we review how these mechanisms contribute to tumor initiation and progression, and discuss whether these molecular mechanisms might be an ideal target to treat tumor.

Background The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs. Materials and methods Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan–Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis. Results Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million. Conclusion Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma., Highlights • The median survival of patients with metastatic melanoma increased from 11.8 months in 2013 to 21.1 months in 2018. • The gain in survival came along with substantial health care costs; health care costs were on average €100 300 per patient. • Costs were much higher for patients with systemic treatment (€118 905) than for patients without systemic treatment (€8316). • Costs for patients who received systemic treatment remained stable even after the introduction of additional novel drugs. • Insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in metastatic melanoma.

Background: Owing to the high numbers of paediatric cancer-related deaths, advances in therapeutic options for childhood cancer is a heavily studied field, especially over the past decade. Classical chemotherapy offers some therapeutic benefit but has proven long-term complications in survivors, and there is an urgent need to identify novel target-driven therapies. Replication stress is a major cause of genomic instability in cancer, triggering the stalling of the replication fork. Failure of molecular response by DNA damage checkpoints, DNA repair mechanisms and restarting the replication forks can exacerbate replication stress and initiate cell death pathways, thus presenting as a novel therapeutic target. To bridge the gap between preclinical evidence and clinical utility thereof, we apply the literature-driven systematic target actionability review methodology to published proof-of-concept (PoC) data related to the process of replication stress. Methods: A meticulous PubMed literature search was performed to gather replication stress-related articles (published between 2014 and 2021) across 16 different paediatric solid tumour types. Articles that fulfilled inclusion criteria were uploaded into the R2 informatics platform [r2.amc.nl] and assessed by critical appraisal. Key evidence based on nine pre-established PoC modules was summarised, and scores based on the quality and outcome of each study were assigned by two separate reviewers. Articles with discordant modules/scores were re-scored by a third independent reviewer, and a final consensus score was agreed upon by adjudication between all three reviewers. To visualise the final scores, an interactive heatmap summarising the evidence and scores associated with each PoC module across all, including paediatric tumour types, were generated. Results and conclusions:: 145 publications related to targeting replication stress in paediatric tumours were systematically reviewed with an emphasis on DNA repair pathways and cell cycle checkpoint control. Although various targets in these pathways have been studied in these diseases to different extents, the results of this extensive literature search show that ATR, CHK1, PARP or WEE1 are the most promising targets using either single agents or in combination with chemotherapy or radiotherapy in neuroblastoma, osteosarcoma, high-grade glioma or medulloblastoma. Targeting these pathways in other paediatric malignancies may work as well, but here, the evidence was more limited. The evidence for other targets (such as ATM and DNA-PK) was also limited but showed promising results in some malignancies and requires more studies in other tumour types. Overall, we have created an extensive overview of targeting replication stress across 16 paediatric tumour types, which can be explored using the interactive heatmap on the R2 target actionability review platform [https://hgserver1.amc.nl/cgi-bin/r2/main.cgi?option=imi2_targetmap_v1].

The emergence, in recent decades, of an entirely new area of “Mitochondrial dynamics”, which consists principally of fission and fusion, reflects the recognition that mitochondria play a significant role in human tumorigenesis and response to therapeutics. Proteins that determine mitochondrial dynamics are referred to as “shaping proteins”. Marked heterogeneity has been observed in the response of tumor cells to chemotherapy, which is associated with imbalances in mitochondrial dynamics and function leading to adaptive and acquired resistance to chemotherapeutic agents. Therefore, targeting mitochondria-shaping proteins may prove to be a promising approach to treat chemotherapy resistant cancers. In this review, we summarize the alterations of mitochondrial dynamics in chemotherapeutic processing and the antitumor mechanisms by which chemotherapy drugs synergize with mitochondria-shaping proteins. These might shed light on new biomarkers for better prediction of cancer chemosensitivity and contribute to the exploitation of potent therapeutic strategies for the clinical treatment of cancers.

Simple Summary Alterations in cholesterol level play an important role in cancer development. Lipid transfer proteins (LTPs) are involved in cholesterol distribution between organelles. Among LTPs, some members of steroidogenic acute regulatory-related lipid transfer (START) protein family regulate the cholesterol transportation between organelles and have been revealed as critical for cancer development. This review highlights the recent discoveries of the StAR-related lipid transfer protein domain 3 (STARD3) member of START proteins in cancer development and progression. Blocking cholesterol transportation through the inhibition of STARD3 activity could be an important strategy to treat cancer. Abstract Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.

Cancer is a global health problem responsible for one in six deaths worldwide. Treating cancer has been a highly complex process. Conventional treatment approaches, such as surgery, chemotherapy, and radiotherapy, have been in use, while significant advances are being made in recent times, including stem cell therapy, targeted therapy, ablation therapy, nanoparticles, natural antioxidants, radionics, chemodynamic therapy, sonodynamic therapy, and ferroptosis-based therapy. Current methods in oncology focus on the development of safe and efficient cancer nanomedicines. Stem cell therapy has brought promising efficacy in regenerating and repairing diseased or damaged tissues by targeting both primary and metastatic cancer foci, and nanoparticles brought new diagnostic and therapeutic options. Targeted therapy possessed breakthrough potential inhibiting the growth and spread of specific cancer cells, causing less damage to healthy cells. Ablation therapy has emerged as a minimally invasive procedure that burns or freezes cancers without the need for open surgery. Natural antioxidants demonstrated potential tracking down free radicals and neutralizing their harmful effects thereby treating or preventing cancer. Several new technologies are currently under research in clinical trials, and some of them have already been approved. This review presented an update on recent advances and breakthroughs in cancer therapies.

p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.

Pituitary tumors are a heterogeneous group of lesions (usually benign) and proper understanding of the anatomy, physiology, and pathology of the hypothalamic/pituitary region is essential to make an accurate diagnosis and define the essential treatment options (i.e., surgery, medical therapies, and radiotherapy, alone or in combination). Surgery is the primary treatment for acromegaly, Cushing disease, thyroid-stimulating hormone-secreting adenomas, resistant prolactinomas, and nonfunctioning pituitary adenomas causing mass effect. Medical and radiation therapy are reserved in cases in which surgery is not possible or does not provide a complete cure. In the last decades, tremendous innovations (i.e., targeted drugs and refined surgical tools and techniques) have expanded the treatment strategies for pituitary adenomas. We herein report the current indications for and depiction of the surgical techniques in pituitary surgery, review current medical treatments, and provide a glimpse of future possibilities.

Various physiological processes involve appropriate tissue developmental process and homeostasis - the pathogenesis of several diseases connected with deregulatory apoptosis process. Apoptosis plays a crucial role in maintaining a balance between cell death and division, evasion of apoptosis results in the uncontrolled multiplication of cells leading to different diseases such as cancer. Currently, the development of apoptosis targeting anticancer drugs has gained much interest since cell death induced by apoptosis causes minimal inflammation. The understanding of complexities of apoptosis mechanism and how apoptosis is evolved by tumor cells to oppose cell death has focused research into the new strategies designed to induce apoptosis in cancer cells. This review focused on the underlying mechanism of apoptosis and the dysregulation of apoptosis modulators involved in the extrinsic and intrinsic apoptotic pathway, which include death receptors (DRs) proteins, cellular FLICE inhibitory proteins (c-FLIP), anti-apoptotic Bcl-2 proteins, inhibitors of apoptosis proteins (IAPs), tumor suppressor (p53) in cancer cells along with various current clinical approaches aimed to selectively induce apoptosis in cancer cells.

Due to the strong pathogenicity of Ralstonia solanacearum, a variety of strategies have been used to develop antibacterial agents, however, antibacterial drugs with targeted effects on R. solanacearum remain lacking. Herein, we present a nanoagent targeting R. solanacearum based on our previous research on poly-(lactic-co-glycolic acid) (PLGA) particles (PLGA-NPs) loaded with methyl caffeate and caffeic acid phenethyl ester. Antibodies that have specific effects on R. solanacearum, which were verified using immuno-PCR, were first used to prepare PLGA-targeted nanoparticles (PLGA-TNPs). The antibody coupling process was investigated in terms of antibody binding degree and antibacterial activity. The EC50 value of PLGA-TNPs was 0.021 mg/mL, which was significantly reduced by 92% in comparison to PLGA-NPs. PLGA-TNPs had a perforating effect on the cell membrane of R. solanacearum, but no effects on Escherichia coli according to the SEM results. In addition, a downregulation of the pathogenicity-related genes compared to PLGA-NP treatment was observed, and the expression of egl, phcA, phcB, pilT, polA-238, and pehC decreased by 78, 79, 87, 61, 58, and 41%, respectively. Therefore, PLGA-targeted nanoparticles not only enhance the activity against R. solanacearum, but also provide a new idea for controlling bacterial wilt.

Simple Summary Chemotherapy is a key modality in today’s practice of clinical oncology. The potential for systemic treatment of cancer patients with cytotoxic agents was discovered in the mid 20th century and its major shortcomings namely, off target toxicity and resistance to treatment, were apparent from the very beginning. These limitations pushed the scientific and medical communities to search for improvements, which as a final result, shaping modern research and clinical practice in the field. For minimizing off target toxic effects, drug discovery efforts became more focused on targeted therapies and on combinations of anti-cancer drugs in order to overcome the resistance problem. Here we outline the evolution of chemotherapy from its beginning as a single-agent based therapy to poly-drug treatment that involves targeted drugs, and discuss the concept of drug-conjugation based treatment as a strategy for further optimization of treatment regimes. Abstract It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.

Background Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax). Methods Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real‐life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020. Results Severe infections incidence was 23% during 17‐month median follow‐up; cumulative incidence was higher in the first 3–6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3–1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1–4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05–3.3). Infection‐related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed. Conclusion A high proportion of patients presented severe infections during follow‐up, with non‐negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered., Our data describe the infection risk associated with the use of targeted drugs in the treatment of lymphoproliferative diseases in real‐life setting and suggest some infection risk factors that could identify the need for antimicrobial prophylaxis in a selected group of patients.

KRAS mutations have long been considered undruggable. However, a series of direct KRAS mutation inhibitors have been developed since the switch II pocket was discovered recently. This review will summarize progress in the development of direct KRAS G12C mutation inhibitors, current relevant drugs under study and challenges that need to be considered in future research.

Esophageal cancer (EC) is the eighth most common type of cancer worldwide and ranks sixth among the causes of cancer-related mortality. Due to the high mortality rate and poor treatment efficacy for EC, millions of individuals succumb to this disease; thus, the identification of novel treatment targets is of utmost importance and urgency. In recent years, there have been advances if therapies targeting cell cycle regulators. p21 is a type of cell cycle regulator that plays a dual role in tumor cells, as it can not only regulate the cell cycle, induce apoptosis and inhibit cell proliferation, but can also protect cells from apoptosis. It has been found that p21 often exerts a tumor-suppressive effect on EC, which provides a basis for its use as a treatment target for EC. Therefore, the aim of the present study was to review the function of p21 and its potential value as a therapeutic target for EC.

Background Patent ductus arteriosus (PDA) complicated by Eisenmenger syndrome (ES) remains to be a major cause of morbidity and mortality worldwide. Giving increasing evidences of benefit from targeted therapies, ES patients once thought to be inoperable may have increasing options for management. This study aims to explore whether PDA in patients with ES can be treated with transcatheter closure (TCC). Methods Between August 2014 and July 2016, four of fifteen PDA-ES patients whose Qp/Qs improved significantly and Qp/Qs > 1.5 after acute vasodilator testing with 100% oxygen were selected to receive TCC and pulmonary vasodilator therapy. PAH-targeted drugs were prescribed before and after occlusion for all. Trial occlusion was performed before permanent closure. Results The first TCC failed after initiation of PAH-targeted drugs for 6 months in four patients. After the medication was adjusted and extended to 12 months, TCC was performed for all without hemodynamic intolerances during perioperative period. Pulmonary artery systolic pressure (PASP) was significantly decreased (≥ 40%) immediately after TCC. During a mean follow-up of 48 ± 14.70 months, there were a further decrease of PASPs in two patients, the other two showed improved pulmonary vascular resistance, WHO functional class and six-minute walking distance despite deteriorated PASP. Conclusion Some selected PDA-ES patients might benefit from TCC and combined PAH-targeted drugs play a crucial role.

To increase the effectiveness of treatment for breast cancer, representatives of various oncological schools use various approaches and scientific results obtained using high technologies, as evidenced by the analysis of scientific publications of specialists.The aim of this literature review was to analyze the influence of some scientific achievements using high technologies on modern ideas of oncologists about the pathogenesis of breast cancer and new approaches to increasing the efficiency of its treatment.Material and research methods. Scientific articles in journals specializing in Oncology, materials of scientific conferences, Internet resourcesResearch results and their discussion. Unsatisfactory results of the treatment of breast cancer, frequent relapses of this pathology, high mortality, on the one hand, and the results of scientific studies using high technologies, on the other hand, led oncologists to search for new approaches to solving the problem by improving surgical, medicinal and radiation treatments.Conclusions. The search for new approaches to solving the issue of increasing the effectiveness of breast cancer treatment is carried out in different directions: in the field of improving surgical treatment methods, drug methods, taking into account inhibitors of immune control points, new drugs for targeted therapy and the theory of cancer stem cells. The development of new approaches to the treatment of breast cancer has great prospects in addressing the issue of increasing the effectiveness of its treatment, Для повышения эффективности лечения рака молочной железы представители различных онкологических школ используют различные подходы и научные результаты, полученные с использованием высоких технологий, о чем свидетельствует анализ научных публикаций специалистов.Целью данного литературного обзора был анализ влияния некоторых достижений науки с использованием высоких технологий на современные представления онкологов о патогенезе РМЖ и новые подходы к повышению эффективности его лечении.Материал и методы исследования. Научные статьи в журналах по онкологии, материалы научных конференций, Интернет- ресурсыРезультаты исследований и их обсуждение. Неудовлетворительные результаты лечения рака молочной железы, частые рецидивы этой патологии, высокая смертность, с одной стороны, и результаты научных исследований с использованием высоких технологий, с другой стороны, заставили онкологов искать новые подходы к решению проблемы путем улучшения хирургического, лекарственного и лучевого лечения.Выводы. Поиск новых подходов к решению проблемы повышения эффективности лечения рака молочной железы осуществляется в разных направлениях: в области совершенствования методов хирургического лечения, медикаментозных методов с учетом ингибиторов точек иммунного контроля, новых препаратов для таргетной терапии. и теория раковых стволовых клеток. Разработка новых подходов к лечению рака молочной железы имеет большие перспективы в решении проблемы повышения эффективности ее лечения, Для підвищення ефективності лікування раку молочної залози представники різних онкологічних шкіл використовують різні підходи та наукові результати, отримані за допомогою високих технологій, про що свідчить аналіз наукових публікацій фахівців.Метою цього огляду літератури було проаналізувати вплив деяких наукових досягнень із використанням високих технологій на сучасні уявлення онкологів про патогенез раку молочної залози та нові підходи до підвищення ефективності його лікування.Матеріал та методи дослідження. Наукові статті в журналах, що спеціалізуються на онкології, матеріали наукових конференцій, Інтернет-ресурсиРезультати досліджень та їх обговорення. Незадовільні результати лікування раку молочної залози, часті рецидиви цієї патології, висока смертність, з одного боку, та результати наукових досліджень з використанням високих технологій, з іншого, спонукали онкологів до пошуку нових підходи до вирішення проблеми вдосконалюючи хірургічне, медикаментозне та променеве лікування.Висновки. Пошук нових підходів до вирішення питання підвищення ефективності лікування раку молочної залози ведеться в різних напрямках: у галузі вдосконалення методів хірургічного лікування, медикаментозних методів з урахуванням інгібіторів імунних контрольних пунктів, нових препаратів для цільової терапії і теорії ракових стовбурових клітин. Розробка нових підходів до лікування раку молочної залози має великі перспективи у вирішенні питання підвищення ефективності її лікування

Treatment of high-grade osteosarcoma, the most common malignant tumor of bone, is largely based on administration of cisplatin and other DNA damaging drugs. Altered DNA repair mechanisms may thus significantly impact on either response or resistance to chemotherapy. In this study, by using a panel of human osteosarcoma cell lines, either sensitive or resistant to cisplatin, we assessed the value as candidate therapeutic targets of DNA repair-related factors belonging to the nucleotide excision repair (NER) or base excision repair (BER) pathways, as well as of a group of 18 kinases, which expression was higher in cisplatin-resistant variants compared to their parental cell lines and may be indirectly involved in DNA repair. The causal involvement of these factors in cisplatin resistance of human osteosarcoma cells was validated through gene silencing approaches and in vitro reversal of CDDP resistance. This approach highlighted a subgroup of genes, which value as promising candidate therapeutic targets was further confirmed by protein expression analyses. The in vitro activity of 15 inhibitor drugs against either these genes or their pathways was then analyzed, in order to identify the most active ones in terms of inherent activity and ability to overcome cisplatin resistance. NSC130813 (NERI02; F06) and triptolide, both targeting NER factors, proved to be the two most active agents, without evidence of cross-resistance with cisplatin. Combined in vitro treatments showed that NSC130813 and triptolide, when administered together with cisplatin, were able to improve its efficacy in both drug-sensitive and resistant osteosarcoma cells. This evidence may indicate an interesting therapeutic future option for treatment of osteosarcoma patients who present reduced responsiveness to cisplatin, even if possible effects of additive collateral toxicities must be carefully considered. Moreover, our study also showed that targeting protein kinases belonging to the mitogen-activated protein kinase (MAPK) or fibroblast growth factor receptor (FGFR) pathways might indicate new promising therapeutic perspectives in osteosarcoma, demanding for additional investigation.

Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein–Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.

Background Children with cancer are in urgent need of new therapies, as approximately 25% of patients experience a relapse and 20% succumb to their disease. Moreover, the majority of survivors suffer from clinically relevant health problems. Repurposing of targeted agents developed for adult indications could provide novel therapeutic options for paediatric cancer patients. To prioritise targeted drugs for paediatric clinical development, we applied a systematic review methodology to develop a Target Actionability Review (TAR) strategy. These TARs assess the strength and completeness of published preclinical proof-of-concept (PoC) data by structured critical appraisal of and summarising the available scientific literature for a specific target (pathway) and the associated drugs in paediatric tumours. Methods A sensitive literature search in PubMed was performed and relevant papers were identified. For each paper, the individual experimental findings were extracted, marked for paediatric tumour type and categorised into nine separate PoC data modules. Each experimental finding was scored for experimental outcome and quality independently by two reviewers; discrepancies were assessed by a third reviewer and resolved by adjudication. Scores corresponding to one PoC module were merged for each tumour type and visualised in a heat map matrix in the publicly available R2 data portal [r2.amc.nl]. Results and conclusions To test our TAR methodology, we conducted a pilot study on MDM2 and TP53. The heat map generated from analysis of 161 publications provides a rationale to support drug development in specific paediatric solid and brain tumour types. Furthermore, our review highlights tumour types where preclinical data are incomplete or lacking and for which additional preclinical testing is advisable., Highlights • A new strategy to review literature on targeted compounds in paediatric cancer. • Results help to guide and prioritise clinical development of novel targeted agents. • Outcomes are visualised in a publicly available, interactive heat map. • We applied this unique methodology to MDM2 and TP53 and MDM2 inhibitors.

Charles University Faculty of Pharmacy in Hradec Kralove Department of Pharmacology & Toxicology Student: Gabriela Burianova Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Flow-cytometric analysis of inhibitory effect of novel targeted drugs on the activity of ABC drug efflux transporters Cancer is the second leading cause of death. Cancer treatment often combines conventional chemotherapy, radiation therapy and surgery. More recent approach to treatment is the use of targeted cancer therapy with a greater specificity towards cancer cells. Development of resistance is a major obstacle in the success of chemotherapy. Multidrug resistance (MDR) can be acquired through various mechanisms e.g. overexpression of efflux transporters. ATP binding cassette (ABC) transporters represents a large family of transmembrane proteins that use ATP to pump molecules across the membrane. The three main ABC proteins related to MDR are: P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Use of ABC transporter inhibitors increases the amount of chemotherapeutical substrates accumulated within the cells. In this study we evaluated interactions of six synthetic small molecule inhibitors (alisertib, ensartinib, entrectinib, talazoparib,...

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.

This article provides an overview of drugs for metastatic colorectal cancer that are currently being evaluated in clinical trials. We discuss possible drug combinations and outlooks of their use in different lines of therapy. In addition to VEGF and EGFR inhibitors, we describe the molecules with fundamentally new mechanisms of action that can significantly expand the list of anticancer agents and increase the number of possible lines of therapy.

Well differentiated thyroid cancer (WDTC) is referred to non-aggressive tumors with a relatively favorable course. However, in 10% of cases, distant metastases are recorded in this pathology, of them 5–15% of cases develop refractoriness to I131 therapy. Resistance to radioactive iodine therapy in patients with WDTC significantly worsens the overall and disease-free survival. In 2014, the targeted drug Sorafenib was registered in our country, as the first drug of choice for the treatment of patients with metastatic radio-refractory WDTC. The article presents his own experience in the therapy of radiorefractory thyroid cancer with a multikinase inhibitor – Sorafenib. This drug is effective for the treatment of this cohort of patients and also helps to maintain a satisfactory quality of life. Therapy with a multikinase inhibitor statistically significantly increases the time to progression and the median time without progression. In this way, patients have been monitored for a process that would not have been possible to achieve without the use of a targeted drug with multikinase inhibition.

Simple Summary This review analyzes the occurrence, clinical characteristics, and prognostic impact and treatment of autoimmune hemolytic anemia (AIHA) in chronic lymphocytic leukemia (CLL). Autoimmune hemolytic anemia is observed in about 10% of CLL. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity, so the different mechanisms are well described in this review which also focuses on drugs associated to CLL-AIHA and on difficulties to diagnose it. There is a comprehensive revision of the main published casistics and then of the treatments; in particular the paper analyzes the main chemo-immunotherapeutic agents used in this setting. Since the therapy depends on the presence and severity of clinical symptoms, disease status, and comorbidities, treatment is nowadays more individualized in CLL and also in CLL-AIHA. Patients not responding to corticosteroids and rituximab are treated with CLL-specific drugs as per current guidelines according to age and comorbidities and new targeted agents against BCR and BCL-2 which can be given orally and have few side effects, are very effective both in progressive CLL and in situations such as AIHA. Abstract Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged apoptosis, produce less immunoglobulins, and could be responsible for antigen presentation and releasing inflammatory cytokines. CLL B-cells can act similar to antigen-presenting cells activating self-reactive T helper cells and may induce T-cell subsets imbalance, favoring autoreactive B-cells which produce anti-red blood cells autoantibodies. Treatment is individualized and it depends on the presence and severity of clinical symptoms, disease status, and comorbidities. Corticosteroids are the standardized first-line treatment; second-line treatment comprises rituximab. Patients not responding to corticosteroids and rituximab should be treated with CLL-specific drugs as per current guidelines according to age and comorbidities. New targeted drugs (BTK inhibitors and anti BCL2) are recently used after or together with steroids to manage AIHA. In the case of cold agglutinin disease, rituximab is preferred, because steroids are ineffective. Management must combine supportive therapies, including vitamins; antibiotics and heparin prophylaxis are indicated in order to minimize infectious and thrombotic risk.

Background. Colorectal cancer (CRC) is the 4th most frequent cause of death among patients with malignant tumors worldwide. In 2012, approximately 1.3 million people were diagnosed with CRC, nearly 690 000 patients died.Objective: to assess the impact of various chemotherapeutic drugs and monoclonal antibodies penetration on the dynamics of CRC-associated mortality in patients with metastatic CRC in Russia.Materials and methods. We analyzed the mortality data for 2014 obtained from the National Cancer Register and the data from the Register of Chemotherapy Drugs (oxaliplatin, irinotecan, capecitabine) and Monoclonal Antibodies (bevacizumab, cetuximab, panitumumab) Procurement for cancer centers from 82 regions of Russia. We performed correlation and regression analysis to estimate the impact of various chemotherapeutic drugs and monoclonal antibodies penetration on the CRC-associated mortality, as well as the mortality from colon cancer and rectal cancer.Results. We observed a correlation between the mortality reduction in patients with metastatic CRC and penetration of irinotecan (k = –0.324, р = 0.003), capecitabine (k = –0.223, p = 0.04), bevacizumab (k = –0.229, p = 0.04), panitumumab (k = –0.232, p = 0.04), any anti-EGFR monoclonal antibody (k = –0.201, p = 0.07) and all monoclonal antibodies (k = –0.256, p = 0.02). Regression analysis demonstrated a decreased mortality rates in patients receiving irinotecan (β = –0.26, р = 0.02), anti-EGFR monoclonal antibodies (β = –0.19, р = 0.09) and oxaliplatin or irinotecan (β = –0.2, р = 0.06).Conclusion. Our results suggest a correlation between the administration of irinotecan and monoclonal antibodies and mortality reduction in patients with metastatic CRC.

Taking real advantage of Europe's excellence in research to improve citizens' lives presents challenges that Europe's policymakers have not yet fully met. The EU has shown some clarity of assessment in recognising the needs, and some laudable determination to improve the situation, and it has intermittently taken some real steps to deliver on its ambitions to turn its research into valuable innovations. But Europe still faces harsh choices about whether it is actually going to do what it has so often discussed. The EU has to make some firm decisions about what research deserves support - and where. It must turn words into deeds to promote effective links between research and innovation. That requires a sharper focus on developing and retaining the right skill sets in Europe, on funding innovation, on creating an encouraging regulatory environment, and on building greater public understanding and engagement. Here, among other issues, the authors discuss where resources should be deployed, how to maximise the potential of personalised medicine, the time it takes for search to be turned into products ready for market, education, and the EU's regulatory role.

// Nico Jacobi 1 , Rita Seeboeck 2 , Elisabeth Hofmann 2 , Helmut Schweiger 1 , Veronika Smolinska 1 , Thomas Mohr 3 , Alexandra Boyer 1 , Wolfgang Sommergruber 4 , Peter Lechner 5 , Corina Pichler-Huebschmann 5 , Kamil Onder 6, 7 , Harald Hundsberger 2 , Christoph Wiesner 2 and Andreas Eger 1, 2 1 IMC University of Applied Sciences Krems, Department Life Sciences, Research Institute for Applied Bioanalytics and Drug Development, A-3500 Krems, Austria 2 IMC University of Applied Sciences Krems, Department Life Sciences, Institute of Medical and Pharmaceutical Biotechnology, A-3500 Krems, Austria 3 Medical University of Vienna, Institute for Cancer Research, A-1090 Vienna, Austria 4 Boehringer Ingelheim, RCV GmbH and Co KG, A-1121 Vienna, Austria 5 University Clinic Tulln, Department Surgery, A-3430 Tulln, Austria 6 Research Program for Rational Drug Design in Dermatology and Rheumatology, Department of Dermatology, Paracelsus Medical University of Salzburg, A-5020 Salzburg, Austria 7 ProComCure Biotech, A-5081 Anif, Austria Correspondence to: Andreas Eger, email: andreas.eger@fh-krems.ac.at Keywords: drug discovery; 3D models; ERBB signaling; targeted drugs; oncogene addiction Received: August 25, 2017 Accepted: October 27, 2017 Published: November 17, 2017 ABSTRACT Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of ErbB family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments.

Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

Xiao-Fei Gao,1 Jun-Jie Zhang,1,2 Xiao-Min Jiang,1 Zhen Ge,1,2 Zhi-Mei Wang,1 Bing Li,1 Wen-Xing Mao,1 Shao-Liang Chen1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 2Department of Cardiology, Nanjing Heart Center, Nanjing, People’s Republic of China Background: Pulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH.Methods: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD).Results: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003) vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008) vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028) vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P

Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid-1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long-term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18- to 65-year-old patients diagnosed during the period 1992-2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high-dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life-prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first- or second-line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long-term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.

Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid-1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long-term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18- to 65-year-old patients diagnosed during the period 1992-2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high-dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life-prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first- or second-line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long-term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.

The emergence of new targeted drugs, affecting B-cell receptor signaling pathway opens a new page in the treatment of chronic lymphocytic leukemia (CLL). It is not simply expanding choice, it will likely to change total strategy of CLL management. Clinical trials have shown improvement of overall survival in CLL patients in both first line and relapsed disease settings. Targeted drugs lack typical complications of chemotherapy, such as myelosupression. However, they have their specific side effects that require particular attention to avoid unjustified dose reduction and treatment cessation. The present review focuses on practical use of ibrutinib, the first inhibitor of Bruton’s tyrosinkinase.

Tumor driver genes are genes where structural or sequence mutations confer a selective advantage for cancer cells. The individualized targeting of tumor driver genes has become a topic of interest for tumor treatment. The prognosis for medulloblastoma (MB), a common type of malignant intracranial tumor found in children, is poor. The tumor driver genes and the corresponding targeted drugs remain to be studied. The present study analyzed tumor driver genes from tumor tissue and peripheral blood from one patient with nodular desmoplastic MB with Sonic Hedgehog activation and screened targeted drugs for the tumor driver genes. Additionally, MB tissue was successfully implanted into the SCID mouse which were then used for subsequent drug screening. The present study explored novel treatments for MB from the perspective of tumor driver genes, and may provide new ideas for choosing individualized targeted therapies for patients with MB.

Introduction: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies (representing 15–40% of fatal TC cases), classified as stage IV by the American Joint Committe...

Background: Bone and soft-tissue sarcomas represent 13% of all paediatric malignancies. International contributions to introduce next-generation sequencing (NGS) approaches into clinical application are currently developing. We present the results from the Precision Medicine program for children with sarcomas at a reference centre. Results: Samples of 70 paediatric sarcomas were processed for histopathological analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS) with a consensus gene panel. Pathogenic alterations were reported and, if existing, targeted recommendations were translated to the clinic. Seventy paediatric patients with sarcomas from 10 centres were studied. Median age was 11.5 years (range 1–18). Twenty-two (31%) had at least one pathogenic alteration by NGS. Thirty pathogenic mutations in 18 different genes were detected amongst the 22 patients. The most frequent alterations were found in TP53, followed by FGFR4 and CTNNB1. Combining all biological studies, 18 actionable variants were detected and six patients received targeted treatment observing a disease control rate of 78%. Extrapolating the results to the whole cohort, 23% of the patients would obtain clinical benefit from this approach. Conclusions: Paediatric sarcomas have a different genomic landscape when compared to adult cohorts. Incorporating NGS targets into paediatric sarcomas’ therapy is feasible and allows personalized treatments with clinical benefit in the relapse setting.