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Targeted drugs are recommended for treatment of metastatic colorectal cancer. Second and further lines therapy options include anti-EGFR therapy, eligible for patients with wild-type KRAS (cetuximab and panitumumab), and relatively new drug — regorafenib, which could be used for all patients.The aim of this study is to compare costs associated with these options in Russia.Materials and methods. We calculated cost of medication for treating one patient during one month with cetuximab, panitumumab and regorafenib. We also employed cost-effectiveness analysis, but its results should be treated with caution due to non-comparable patients in regorafenib and anti-EGRF drugs studies.Results. We found that monthly per patient medication costs of using regorafenib are 255,000 rubles, which is 104,000 rubles less when using cetuximab or 184,000 rubles less when using panitumumab. Cost-effectiveness ratio for regorafenib was estimated at 111,500 rubles per month and is the lowest among the alternatives: 136,000 rubles per month for cetuximab and 310,000 rubles per month for panitumumab.Conclusions. Regorafenib is cost-saving alternative for treatment of metastatic colorectal cancer in second and further lines therapy compared to cetuximab and panitumumab in Russia.

A prognostic model for constructing hypotheses about the relationship of combinations of cytokines with the proliferative activity of cancer cells is proposed. The model is based on the use of inductive inference methods. The methodology takes into account the synergistic interaction of cytokines and uses sequential construction of logical formulas for selecting groups of cytokines, a statistical analysis of contingency tables and logical integration of the obtained estimates. Implementation of the proposed method in the information system of forecasting the effect of targeted anticancer drugs in immunotherapy will greatly accelerate research in this area.

Introduction: The therapeutic scenario of Oncology is enriching of innovative agents which are determining an increase in public expenditure because of their high cost. In Italy, a web-based government Registry is used to monitor the clinical use of these drugs and, in later phases, to obtain funds reimbursement according to specific economic agreements with companies.Methods: A health policy expert Pharmacist was included in the multidisciplinary team of the Department of Abdominal Oncology of the National Cancer Institute (NCI) of Naples “G. Pascale Foundation” in order to improve the management of the Registry for oncologic drugs monitoring. Pharmacist activities were: basal data registration, prescription appropriateness, drug request, response monitoring, toxicity reporting, follow-up, reimbursement request. These activities were conducted in strict interrelation with clinicians. The source of data were medical records and a web-based national reimbursement platform. The analysis of the economic impact of this strategy was descriptive and it was indicated as resources recovery comparing 2 years: 2015 vs. 2016. The currency reference used was the Euro (€).Results: A total of 932 patients were followed-up and registered, 365 treatments are ongoing at the Department of Abdominal Oncology (NCI of Naples, Italy). The most prescribed biologic drug in advanced gastrointestinal cancers was bevacizumab. Compared to the year 2015, in 2016 we recorded a strong increase of reimbursements: EUR 881.712,42 vs. EUR 214.554,98.Conclusions: We suggest that the reimbursement process can be improved when a health policy reimbursement professional Pharmacist is integrated in the multidisciplinary team along with clinicians.

Over the last decade, the possibility of the drug therapy for patients with metastatic colon cancer (mCC) has increased due to the targeted drugs, because most of those drugs have had antiangiogenic activity (bevacizumab, aflibercept, ramucirumab, regorafenib). The combination of chemotherapy and bevacizumab, especially in the patients with mutations in the EGFR signaling pathway, is one of the standard therapy variant in first-line treatment of such patients. However, sooner or later, most patients will develop progression, and no one can say what kind of drugs will be added in 2nd-line treatment in this case. The subject of this review is the difficulty of choosing the sequence of therapy in patients with mCC using antiangiogenic drugs in first-line therapy.

First-line therapy for metastatic colon cancer is most important for a patient. Its median time to progression constitutes the bulk of the patient’s survival. Clearly, it is necessary to choose the most effective combinations of targeted drugs and chemotherapy regimens. The choice of therapy for patients with colon cancer is governed by both the clinical characteristics of the disease and the molecular changes of a tumor. In recent literature, there has been a great deal of evidence for the use of targeted drugs in different clinical situations; the results of comparative trials of different treatment combinations have been published. This all determines the reconsideration of the choice of a treatment regimen in patients with metastatic colon cancer; it is the topic of the present review.

Objective: To assess the efficacy and safety of camrelizumab plus different targeted drugs in adjuvant therapy after hepatocellular carcinoma (HCC) surgery., Patients and Methods: This retrospective cohort study included HCC patients who, after undergoing failed postoperative adjuvant lenvatinib therapy, received intravenous camrelizumab 200 mg every 3 weeks (C group, n = 97), camrelizumab plus oral apatinib 250 mg daily (C+A group, n = 125), camrelizumab plus oral lenvatinib 12 mg daily (for bodyweight ≥60 kg)/lenvatinib 8 mg daily (for bodyweight <60 kg) (C+L group, n = 120), or camrelizumab plus oral sorafenib 400 mg bi-daily (C+S group, n = 114) between October 2020 and October 2021. The outcomes including the objective response rate (ORR) and disease control rate (DCR) were evaluated by RECIST 1.1 and iRECIST. The median progression-free survival (mPFS), median overall survival (mOS), 6-month OS rate, 12-month OS rate, and adverse events were evaluated., Results: As of 31 May 2022 with last follow-up time, the ORR was 17.2% for the C group, 44.6% for the C+A group, 47.9% for the C+L group, and 36.3% for the C+S group. The DCR was 72.0% for the C group, 81.8% for the C+A group, 85.5% for the C+L group, and 77.9% for the C+S group. The mPFS was 11.0 months (10.1-12.8) for the C group, 14.0 months (12.7-16.5) for the C+A group, 18.0 months (16.9-20.1) for the C+L group, and 12.0 months (9.7-14.4) for the C+S group. The mOS was 13.0 months (11.6-15.3) for the C group, 17.0 months (15.8-19.4) for the C+A group, 19.0 months (17.7-20.2) for the C+L group, and 15.0 months (14.1-17.3) for the C+S group. Grade 3 or 4 treatment-related adverse events occurred in 14 patients (14.4%) for the C group, 10 patients (8.0%) for the C+A group, 5 patients (4.2%) for the C+L group, and 11 patients (9.6%) for the C+S group. The most common adverse events were fatigue and transaminitis., Conclusion: Camrelizumab combined with lenvatinib as adjuvant therapy showed promising efficacy and manageable safety in HCC patients. It might be a potential adjuvant therapy or second-line treatment for these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Cao, Qiu, Ji, Yuan, Wu, Liu, Feng, Ding, Li and Tao.)

Tumorigenesis and tumor development are closely related to the abnormal regulation of ubiquitination. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin ligase critical to the ubiquitination process, plays key roles in the regulation of cancer stem cells, as well as tumor cell functions, including cell proliferation, apoptosis, cell cycle regulation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor drug resistance, by controlling subsequent protein degradation through ubiquitination. NEDD4L primarily functions as a tumor suppressor in several tumors but also plays an oncogenic role in certain tumors. In this review, we comprehensively summarize the relevant signaling pathways of NEDD4L in tumors, the regulatory mechanisms of its upstream regulatory molecules and downstream substrates, and the resulting functional alterations. Overall, therapeutic strategies targeting NEDD4L to treat cancer may be feasible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Zhang, Tian, Zhang, Wang, Tang and Zhao.)

PARP was an enzyme found in the nucleus of eukaryotic cells that played a crucial role in repairing damaged DNA. Recently, PARP inhibitors have demonstrated great potential in cancer treatment. Thus, the FDA has approved several small-molecule PARP inhibitors for cancer maintenance therapy. The combination of PARP inhibitors and radiotherapy relies on synthetic lethality, taking advantage of the flaws in DNA repair pathways to target cancer cells specifically. Studies conducted prior to clinical trials have suggested that the combination of PARP inhibitors and radiotherapy can enhance the sensitivity of cancer cells to radiation, intensify DNA damage, and trigger cell death. Combining radiotherapy with PARP inhibitors in clinical trials has enhanced the response rate and progression-free survival of diverse cancer patients. The theoretical foundation of PARP inhibitors combined with radiotherapy is explained in detail in this article, and the latest advances in preclinical and clinical research on these inhibitors for tumor radiotherapy are summarized. The problems in the current field are recognized in our research and potential therapeutic applications for tumors are suggested. Nevertheless, certain obstacles need to be tackled when implementing PARP inhibitors and radiotherapies in clinical settings. Factors to consider when using the combination therapy are the most suitable schedule and amount of medication, identifying advantageous candidates, and the probable adverse effects linked with the combination. The combination of radiotherapy and PARP inhibitors can greatly enhance the effectiveness of cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Chu, Song, Liu, Chai, Wang and Liu.)

Graphical abstract (A). It is known that various proinflammatory cytokines, such as TNF-α, IL-12, IL-23 and IL-17 play a key role in the pathophysiology of spondyloarthritis (SpA). TNF-α is an important mediator of inflammation in patients with various SpA and currently there are 5 commercialized TNF-α inhibitors (infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol). More recently it has been found that IL-17 also plays an important role in the pathophysiology of SpA; IL-17 is produced by Th17 cells. In turn, the development of Th17 cells, together with Th1 cells, is significantly influenced by the IL-12/IL-23 cytokines that have a proinflammatory profile. As against TNF, therapeutic blockade against IL-17 (secukinumab, ixekinumab and brodalumab), the IL-12/IL-23 system (ustekinumab), and the T cell (abatacept) has been developed. Finally, drugs against intracellular mediators of the activation of various cells of the immune system (such as tofacitinib, baricitinib and apremilast) have shown benefit in patients with SpA. (B). Various cytokines and cells of the immune system act in concert from the early stages of pregnancy to delivery. Consequently, therapeutic blocking against these cells and cytokines could have deleterious effects on fetal development (box). Therefore, it is important to know the information available about the use of these drugs during pregnancy in order to maximize the benefit and minimize the risk of side effects on the fetus (References [ 19–21 , 50 , 52 , 66 , 79 , 82 , 96 , 97 ]). This figure was prepared according to previously published recommendations [ 98 ]. Abstract Spondyloarthritis (SpA) are a heterogeneous group of chronic inflammatory joint diseases that includes several clinical subgroups. SpA can affect women in the reproductive stage so pregnancy can influence the course of the disease and SpA can affect the maternal-fetal outcome. The treatment of SpA has changed dramatically in recent years and the use of targeted drugs is part of therapeutic armamentarium. The use of targeted drugs during pregnancy is controversial because the information available on safety during this period is still limited. Several cytokines have an important role in the normal development of pregnancy or other cytokines may play a role in certain maternal-fetal complications. Potentially targeted drugs can affect the function of these cytokines during pregnancy. The aim of this study is to review the interrelationship between SpA during pregnancy and lactation, the role of some cytokines during normal pregnancy and the development of maternal-fetal complications as well as to review recent information on targeted drugs during pregnancy and breastfeeding in these patients in order to maximize their use in these critical periods of life. [ABSTRACT FROM AUTHOR]

Recently, Georgia State University’s Centennial Hall was the premier location for the 2017 International Conference on Triple Negative Breast Cancer (TNBC): Illuminating Actionable Biology, which was held from Sept. 18 to 20, 2017, in Atlanta, USA. The conference featured a stellar line-up of domestic and international speakers and diverse participants including TNBC survivors, luminaries in breast cancer research, medical students and fellows, clinicians, translational researchers, epidemiologists, biostatisticians, bioinformaticians, and representatives from the industry. This report distills the burning questions that spiked the event and summarizes key themes, findings, unique opportunities and future directions that emerged from this confluence of thought leaders. [ABSTRACT FROM AUTHOR]

The mixed treatment comparison study was performed in order to compare the toxicities of Gemcitabine and different targeted drug combinations in the treatment of advanced/metastatic pancreatic cancer (PC). Searches were performed from the inception of PubMed and Cochrane Library databases to February 2017. This study included randomized controlled trials (RCTs) of Gemcitabine and different targeted drug combinations in the treatment of advanced/metastatic PC. Odds ratio (OR) values were calculated by direct and indirect comparisons, and the surface under the cumulative ranking curves (SUCRA) were drawn. A total of six RCTs were finally incorporated into the study. These studies included six therapy regimens: Gemcitabine + Axitinib, Gemcitabine + Trametinib, Gemcitabine + Sorafenib, Gemcitabine + Bevacizumab, Gemcitabine + Erlotinib and Gemcitabine + Tipifarnib. The results showed that Gemcitabine + Axitinib combinations showed lower incidence rates of rashes (all grades) in comparison to Gemcitabine + Trametinib and Gemcitabine + Erlotinib combinations. Compared with Gemcitabine+ Trametinib combinations, Gemcitabine + Axitinib combinations showed lower incidence rates of diarrhea (grade ≥ 3). Moreover, the cluster analyses results revealed that Gemcitabine + Axitinib combinations and Gemcitabine + Sorafenib combinations showed lower incidence rates of hematotoxicity, while Gemcitabine + Axitinib combinations showed lower incidence rates of non-hematotoxicity. Collectively, the data provided strong evidence of Gemcitabine + Axitinib combinations showing lower incidence rates of non-hematotoxicity, and Gemcitabine + Axitinib and Gemcitabine + Sorafenib combinations may have lower incidence rates of hematotoxicity in the treatment of advanced/metastatic PC. [ABSTRACT FROM AUTHOR]

Background: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In nonresectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. Materials and Methods: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. Results: Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. Conclusion: The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0–17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90–100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials. [ABSTRACT FROM AUTHOR]

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[Display omitted] Accumulating evidence has demonstrated that NEDD4 E3 ubiquitin ligase family plays a pivotal oncogenic role in a variety of malignancies via mediating ubiquitin dependent degradation processes. Moreover, aberrant expression of NEDD4 E3 ubiquitin ligases is often indicative of cancer progression and correlated with poor prognosis. In this review, we are going to address association of expression of NEDD4 E3 ubiquitin ligases with cancers, the signaling pathways and the molecular mechanisms by which the NEDD4 E3 ubiquitin ligases regulate oncogenesis and progression, and the therapies targeting the NEDD4 E3 ubiquitin ligases. This review provides the systematic and comprehensive summary of the latest research status of E3 ubiquitin ligases in the NEDD4 subfamily, and proposes that NEDD4 family E3 ubiquitin ligases are promising anti-cancer drug targets, aiming to provide research direction for clinical targeting of NEDD4 E3 ubiquitin ligase therapy. [ABSTRACT FROM AUTHOR]

• Drug clonal plasticity and heterogeneity contribute to the development of pharmacological resistances. To minimise treatment failure, research efforts are currently focusing on systematically performing molecular diagnoses at different stages of disease, implementing liquid biopsies as standard practice, including multimodal treatment approaches in clinical trials, introducing targeted drugs earlier in the course of disease, exploiting the use of multitarget kinase inhibitors in certain pathologies, and creating serial tissue sample banking for retrospective analyses. • Future improvements in the way data are managed in Europe depend on the further development of artificial intelligence technologies and data set creation. The European Commission-funded project UNICA4EU seems like a promising platform for such development in paediatric oncology. Another crucial pillar will be the development of an aggregated molecular data set that incorporates data from all current precision medicine trials added to the creation of real-word data sets that integrate information from off-label/compassionate use as well as standard clinical data. • The ITTC-P4 platform has had an enormous impact on the development of preclinical research in Europe to: (i) develop a platform that offers a full set of molecularly characterised preclinical models; (ii) develop a validated method for assessment of the 'actionability' of target genes 'TAR'; and (iii) create a set of guidelines to standardise preclinical data packages and improve translatability of results into the clinic. • The ACCELERATE consortia has created three working groups that tackle essential issues for the creation of efficient drug development plans: (i) The Paediatric Strategic Forums, which are multistakeholder meetings with multitopic discussions on drug development; (ii) The Fit for Filling (FFF) group, which facilitates an industry–academic partnership that ensures the design of academic trials that contribute to marketing authorisation; and (iii) The International Collaborative Group, which coordinates and simultaneously submits investigation plans to US and European Union (EU) regulatory agencies. The development of targeted drugs in paediatric oncology has been notoriously slow, in part due to the peculiarities of this rare and highly heterogeneous population. To provide therapeutic breakthroughs for the highest risk subgroups of childhood cancer, innovative research solutions have been implemented in the last several years by different international collaborative groups and regulators. Here, we discuss and summarise some of these approaches, as well as challenges and unmet needs that are still being addressed. A wide range of topics were covered in this review including molecular diagnosis optimisation, innovative research methodologies, big data approaches, trial enrolment strategies, and improvements in regulation and preclinical research platforms. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the most common retinal vascular disease. Proliferative DR (PDR) is the aggressive stage of DR with angiogenesis as a pathological hallmark, which is the main cause of blindness. There is growing evidence that ferroptosis plays a vital role in diabetics as well as its complications including DR. However, the potential functions and mechanisms of ferroptosis have not been completely elucidated in PDR. The ferroptosis-related differentially expressed genes (FRDEGs) were identified in GSE60436 and GSE94019. Then we constructed a protein-protein interaction (PPI) network and screened ferroptosis-related hub genes (FRHGs). The GO functional annotation and the KEGG pathway enrichment analyses of FRHGs were performed. The miRNet and miRTarbase databases were applied to construct the ferroptosis-related mRNA-miRNA-lncRNA network, and the Drug-Gene Interaction Database (DGIdb) was used for predicting potential therapeutic drugs. Finally, we identified 21 upregulated and 9 downregulated FRDEGs, among which 10 key target genes (P53, TXN, PTEN, SLC2A1, HMOX1, PRKAA1, ATG7, HIF1A, TGFBR1, and IL1B) were recognized with enriched functions, mainly relating to responses to oxidative stress and hypoxia in biological processes of PDR. HIF-1, FoxO and MAPK signalling may be the main pathways that influence ferroptosis in PDR. Moreover, a mRNA-miRNA-lncRNA network was constructed based on the 10 FRHGs and their co-expressed miRNAs. Finally, potential drugs targeting 10 FRHGs for PDR were predicted. Results of the receiver operator characteristic (ROC) curve indicated, with high predictive accuracy in two testing datasets (AUC>0.8), that ATG7, TGFB1, TP53, HMOX1 and ILB1 had the potential to be biomarkers of PDR. • Ferroptosis might involve in the development of diabetic complications and can be a promising therapeutic target of PDR. • LncRNAs is also promising diagnostic biomarkers of proliferative diabetic retinopathy. • LncRNAs may affect the ferroptosis-related gene expression by acting as the competing endogenous RNA. • Bioinformatics analysis can provide primary clues for further researches. [ABSTRACT FROM AUTHOR]

Targeted drugs aimed at driver gene, such as Gefitinib, Erlotinib and Crizotinib, have an irreplaceable position in the therapy of advanced non-small cell lung cancer. These drugs bring benefit to patients, however, higher hepatotoxicity is also presented. Now, drug induced hepatotoxicity and its mechanism are reviewed.

Background Recent data suggest that Bruton's tyrosine kinase ( BTK) is an emerging therapeutic target in IgE receptor (Ig ER)-cross-linked basophils. Methods We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, and CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1. Results All four BTK blockers were found to inhibit anti-IgE-induced histamine release from basophils in nonallergic subjects and allergen-induced histamine liberation from basophils in allergic donors. Drug effects on allergen-induced histamine release were dose dependent, with IC50 values ranging between 0.001 and 0.5 μmol/L, and the following rank order of potency: ibrutinib> AVL-292>dasatinib> CNX-774. The basophil-targeting effect of ibrutinib was confirmed by demonstrating that IgE-dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti-IgE-induced and allergen-induced upregulation of CD13, CD63, CD164, and CD203c on basophils, whereas AVL-292 and CNX-774 showed no significant effects. Whereas dasatinib and CNX-774 were found to inhibit the growth of HMC-1 cells and KU812 cells, no substantial effects were seen with ibrutinib or AVL-292. Conclusions BTK-targeting drugs are potent inhibitors of IgE-dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined. [ABSTRACT FROM AUTHOR]

Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediatorrelated 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 KITdependent 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 mediatorrelated 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 [ABSTRACT FROM AUTHOR]

Introduction: Several genetic alterations have been identified in different molecular pathways ofanaplastic thyroid cancer (ATC) and associated with tumor aggressiveness and progression (BRAF, p53,RAS, EGFR, VEGFR-1, VEGFR-2, etc). New drugs targeting these molecular pathways have beenrecently evaluated in ATC. Areas covered: We review the new targeted therapies of ATC. Interesting results have been reported with molecules targeting different pathways, as: a-BRAF (dabrafenib/trametinib, vemurafenib); b-angiogenesis (sorafenib, combretastatin, vandetanib, sunitinib, lenvatinib, CLM3, etc); c-EGFR (gefitinib); d- PPARγ agonists (rosiglitazone, pioglitazone, efatutazone). In patients with ATC treated with lenvatinib, a median overall survival of 10.6 (3.8–19.8) months was reported. In order to bypass the resistance to the single drug, the capability of targeted drugs to synergize with radiation, or chemotherapy, or other targeted drugs is explored. Expert commentary: New, affordable and individual genomic analysis combined with the opportunity to test these new treatments in primary cell cultures from every ATC patientin vitro, may permit the personalization of therapy. Increasing the therapeutic effectiveness and avoiding the use of ineffective drugs. The identification of new treatments is necessary, to extend life duration guaranteing a good quality of life. To bypass the resistance to asingle drug, the capability of targeted drugs to synergize with radiation, or chemotherapy, or othertargeted drugs is explored. Moreover, new affordable individual genomic analysis and the opportunity totest these novel treatments in primary cell cultures from every ATC patient in vitro, might permit topersonalize the therapy, increasing the therapeutic effectiveness and avoiding the use of ineffectivedrugs. [ABSTRACT FROM PUBLISHER]

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<0.001) vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001) vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023) vs PDE-5Is, and 3.94 mmHg (95% CI: -6.99, -0.88; P=0.012) vs sGCS. There were no significant differences in all-cause mortality and severe adverse events between prostanoids, ERAs, PDE-5Is, sGCS, combination therapy, and placebo. Conclusion: All targeted drugs for PAH are associated with improved clinical outcomes, especially combination therapy. However, all these drugs seem to show less favorable effects on survival in the short-term follow-up, suggesting further clinical trials are required. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the inhibitory effects of bevacizumab monoclonal antibodies in combination with chemotherapy in different time sequences on a human gastric cancer cell line (MGC-803). Methods: Cultured MGC-803 human gastric cancer cells were treated with bevacizumab in combination with chemotherapy treatment in different time sequences. The effects on cell growth inhibition were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle distribution and the rate of cell apoptosis were determined by propidium iodide staining followed by flow cytometry. Results: Drug administration for different time sequences significantly inhibited the growth of MGC-803 cells. Based on group comparisons ( P < 0.01), the effect of 24 h bevacizumab treatment prior to combination 5-fluorouracil and cisplatin (FP) was the strongest ( F = 241.313, 246.856, all P values <0.001). Treating MGC-803 cells with bevacizumab for 24 h before combination FP induced significant G2/M phase arrest ( F = 231.991, P < 0.001) and significantly increased gastric cancer cell apoptosis. Bevacizumab in combination with chemotherapy significantly inhibits the proliferation of MGC-803 gastric cancer cells. Conclusions: The mechanism may be related to cell cycle arrest at S phase and the induction of apoptosis in MGC-803 gastric cancer cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics. [Display omitted] • Potassium channels play an important role in tumorigenesis. • Potassium channels are involved in tumor proliferation, metastasis, and apoptosis through multiple molecular pathways. • Drugs exert anticancer effects by targeting potassium channels. [ABSTRACT FROM AUTHOR]

Background: The optimal local treatment for HCC with tumor diameter ≥ 5 cm is not well established. This research evaluated the effectiveness of external beam radiation therapy (EBRT) versus transcatheter arterial chemoembolization (TACE) for HCC with tumor diameter ≥ 5 cm., Methods: A total of 1210 HCC patients were enrolled in this study, including 302 and 908 patients that received EBRT and TACE, respectively. Propensity score matching (PSM) was used to identify patient pairs with similar baseline characteristics. Overall survival (OS) was the primary study endpoint., Results: We identified 428 patients using 1:1 PSM for survival comparison. Compared with the TACE group, the EBRT group had a significantly longer median OS (mOS) before (14.9 vs. 12.3 months, p = 0.0085) and after (16.8 vs. 11.4 months, p = 0.0026) matching. In the subgroup analysis, compared with the TACE group, the EBRT group had a significantly longer mOS for HCC with tumor diameters of 5-7 cm (34.1 vs. 14.3 months, p = 0.04) and 7-10 cm (34.4 vs. 10 months, p = 0.00065), whereas for HCC with tumor diameters ≥ 10 cm, no significant difference in mOS was observed (11.2 vs. 11.2 months, p = 0.83). In addition, the multivariable Cox analysis showed that Child-A, alkaline phosphatase < 125 U/L, and EBRT were independent prognostic indicators for longer survival., Conclusion: EBRT is more effective than TACE as the primary local treatment for HCC with tumor diameter ≥ 5 cm, especially for HCC with tumor diameter of 5-10 cm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Wang, Li, Chi, Zhang, He, Wang, Wen, Song, Chen, Wu, Jiang, Li, Gu, Wang, Li, Liu, Guo, Xu, Guo and Han.)

Pituitary adenoma (PA) is the third most common central nervous system tumor originating from the anterior pituitary, but its pathogenesis remains unclear. The Wnt signaling pathway is a conserved pathway involved in cell proliferation, Self-renewal of stem cells, and cell differentiation. It is related to the occurrence of various tumors, including PA. This article reviews the latest developments in Wnt pathway inhibitors and pathway-targeted drugs. It discusses the possibility of combining Wnt pathway inhibitors with immunotherapy to provide a theoretical basis for the combined treatment of PA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Ma, Zhao, Liu, Ye and Li.)

Introduction: Tumor immunotherapy targeting PD-L1 has emerged as one of the powerful tools for tumor therapy. Numerous studies indicate that tumor-targeted drugs critically have an influence on the interaction between the immune system and tumors by changing the expression of PD-L1, which is beneficial for immunotherapy. Our study provided novel evidence for improving the drug regimen in tumor targeted therapy and immunotherapy., Methods: The expression of PD-L1 on SKBR3, MDA-MB-231, MCF7, 4T1, MC38 and B16 cells was evaluated by flow cytometry after treatment with six preclinical targeted drugs (ARN-509, AZD3514, Galeterone, Neratinib, MLN8237 and LGK974). AURKA was knockdowned by using the specific siRNA or CRISPR-Cas9 technology. In the 4T1-breast tumor and colorectal cancer xenograft tumor models, we determined the number of infiltrated CD3+ and CD8+ T cells in tumor tissues by IHC., Results: We found that AURKA inhibitor MLN8237 promoted the expression of PD-L1 in a time- and concentration-dependent manner while exerted its antitumor effect. Knockdown of AURKA could induce the upregulation of PD-L1 on SKBR3 cells. MLN8237-induced PD-L1 upregulation was mainly associated with the phosphorylation of STAT3. In the 4T1-breast tumor xenograft model, the infiltrated CD3+ and CD8+ T cells decreased after treatment with MLN8237. When treated with MLN8237 in combination with anti-PD-L1 antibody, the volumes of tumor were significantly reduced and accompanied by increasing the infiltration of CD3+ and CD8+ T cells in colorectal cancer xenograft tumor model., Discussion: Our data demonstrated that MLN8237 improved the effect of immunology-related therapy on tumor cells by interacting with anti-PD-L1 antibody, which contributed to producing creative sparks for exploring the possible solutions to overcoming drug resistance to tumor targeted therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Meng, Zhao, Jiang, Xu, Li, Wang, Ma, Li, Liu, Zheng, Peng and Shi.)

The majority of lower-risk myelodysplastic syndromes/neoplasms patients present with anemia. Historically, these patients were treated with erythropoiesis-stimulating agents (ESA), with modest responses. A subset of these patients with del(5q) may do better with lenalidomide. Recently, in randomized trials, luspatercept has shown better responses compared with ESAs in treatment-naive patients and imetelstat in patients refractory to ESAs. Other evaluated novel compounds (fostamatinib, H3B-880, roxadustat, pyruvate kinase receptor activator) have not yet shown meaningful efficacy. More needs to be done to improve outcomes; in pursuance of this, participation in clinical trials evaluating novel therapies should be encouraged. While lower-risk myelodysplastic syndromes/neoplasms tend to have an indolent course, a subset of them has a dismal prognosis. Improving prognostication and serial monitoring will help in identifying high-risk patients for appropriate management.

Objective: To summarize the situation of antineoplastic agents-induced interstitial lung diseases (ILD), provide reference for strengthening clinical management of druginduced interstitial lung diseases (DILD). Methods: We retrospectively investigated the medical records of 12 patients with antineoplastic agents-induced ILD in a hospital between January and December 2020. Data collected included patients' characteristic (gender, age, ECOG PS score, smoking history, primary tumor, concurrent diseases or complications.) and treatment conditions (DILD-causing drugs, clinical symptoms, chest CT, DILD treatment drugs, onset cycle, onset time, severity of DILD, DILD course and prognosis.). Results: The median age of 12 DILD cases was 68%, 66.67% of the patients were male, lung cancer accounted for 58.33% (7/12). DILD was induced by cytotoxicity drugs, targeted drugs and immune checkpoint inhibitors (ICIs), of which ICIs accounted for 66.67% (8/12). Scattered patchy, cord-like, grid-like or flocculent shadows were observed on chest CT, mainly under the pleura of lungs. Once DILD occurs, the suspected antineoplastic agents were stopped and glucocorticoid was given, among which 83.33% (10/12) patients were treated with antibiotics. Finally, 16.67% (2/12) were cured, 33.33% (4/12) were improved, 16.67% (2/12) were not cured and 33.33% (4/12) were dead. Conclusion: Antineoplastic agents-induced ILD is mostly found in elderly male lung cancer patients with smoking history. The clinical symptoms of DILD are diverse and lack of specificity. ICIs-ILD has the characteristic of high incidence and poor prognosis compared with other antineoplastic agents. Comprehensive evaluation before medication, regular review, early and adequate glucocorticoid shock therapy after onset can improve the prognosis of DILD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Gu, Liu, Sun and Sun.)

Background: In patients with hepatocellular carcinoma (HCC), the tumor microenvironment (TME) is resistant to immunotherapy because of its specificity. It is meaningful to explore the role of macrophage, which is one of the most abundant immune cells in the TME, in cellular communication and its effect on the prognosis and immunotherapy of HCC. Methods: Dimensionality reduction and clustering of the single-cell RNA-seq data from the GSE149614 dataset were carried out to identify the cellular composition of HCC. CellChat was used to analyze the communication between different cells. The specifically highly expressed genes of macrophages were extracted for univariate Cox regression analysis to obtain prognostic genes for HCC cluster analysis, and the risk system of macrophage-specifically highly expressed genes was developed by random forest analysis and multivariate Cox regression analysis. Prognosis, TME infiltration, potential responses to immunotherapy, and antineoplastic drugs were compared among molecular subtypes and between risk groups. Results: We found that HCC included nine identifiable cell types, of which macrophages had the highest communication intensity with each of the other eight cell types. Of the 179 specifically highly expressed genes of macrophage, 56 were significantly correlated with the prognosis of HCC, which classified HCC into three subtypes, which were reproducible and produced different survival outcomes, TME infiltration, and immunotherapy responses among the subtypes. In the integration of four macrophage-specifically highly expressed genes for the development of a risk system, the risk score was significantly involved in higher immune cell infiltration, poor prognosis, immunotherapy response rate, and sensitivity of six drugs. Conclusion: In this study, through single-cell RNA-seq data, we identified nine cell types, among which macrophage had the highest communication intensity with the rest of the cell types. Based on specifically highly expressed genes of macrophage, we successfully divided HCC patients into three clusters with distinct prognosis, TME, and therapeutic response. Additionally, a risk system was constructed, which provided a potential reference index for the prognostic target and preclinical individualized treatment of HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Lin, Yu, Chen, He and Ye.)

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1 bar ) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1 bar -A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

There has been a recent shift in how cancers are defined, where tumors are no longer simply classified by their tissue origin, but also by their molecular characteristics. Furthermore, personalized medicine has become a popular term and it could start to play an important role in future medical care. However, today, a “one size fits all” approach is still the most common form of cancer treatment. In this mini-review paper, we report on the role of nuclear magnetic resonance (NMR) metabolomics in drug development and in personalized medicine. NMR spectroscopy has successfully been used to evaluate current and potential therapies, both single-agents and combination therapies, to analyze toxicology, optimal dose, resistance, sensitivity, and biological mechanisms. It can also provide biological insight on tumor subtypes and their different responses to drugs, and indicate which patients are most likely to experience off-target effects and predict characteristics for treatment efficacy. Identifying pre-treatment metabolic profiles that correlate to these events could significantly improve how we view and treat tumors. We also briefly discuss several targeted cancer drugs that have been studied by metabolomics. We conclude that NMR technology provides a key platform in metabolomics that is well-positioned to play a crucial role in realizing the ultimate goal of better tailored cancer medicine.

Introduction: Although cancer remains a major health problem all over the world, its treatment is limited by affordability of patients in a developing country like India. Information generated from cost analysis studies will be helpful for both the doctors in choosing the correct medicine for their patients and also for policy makers in successfully utilizing the meager resources that are available. Aim: The aim of the present observational study was to analyse the price variations of anti-cancer drugs available in India. Materials and Methods: The cost of a particular anti-cancer drug being manufactured by different companies, in the same dose and dosage form, was obtained from latest issue of ‘‘Current Index of Medical Specialties’’ (CIMS) January–April, 2016. The difference between the maximum and minimum prices of various brands of the same drug was analysed and percentage variation in the prices was calculated. The results of the study were expressed as absolute numbers and percentages. Results: Overall, the price of a total of 23 drugs belonging to 6 different categories available in 52 different formulations were analysed. Among alkylating agents, oxaliplatin (50mg; injection) showed the maximum price variation of 125.02%. In anti-metabolites, methotrexate (2.5mg; tablet) showed the maximum price variation of 75.30%. The maximum price variation among natural products was seen with paclitaxel (260 mg; injection) of 146.98%, among hormonal drugs, was seen with flutamide (250mg; tablet) of 714.24%, among targeted drugs was seen with imatinib mesylate (100mg; film coated tablet) of 5.56% and among supportive drugs, granisetron (1mg; tablet) showed the maximum price variation of 388.68%. Conclusion: The average percentage variations of different brands of the same anti-cancer drug in same dose and dosage form manufactured in India is very wide. The government and drug manufacturing companies must direct their efforts in reducing the cost of anti-cancer drugs and minimizing the economic burden on the patients.

Predator species of animal can absorb plant microRNA that can regulate target gene expression and physiological function across species. The herb Lycium barbarum , a traditional Chinese medicine, has a wide range of antitumor effects. However, there are no reports on the effects of microRNA derived from it on the cross-border regulation of renal cell carcinoma (RCC). We performed in vitro and in vivo experiments to explore the role and mechanism of the L. barbarum -derived microRNA miR166a (Lb-miR166a) in cross-border regulation of RCC. Our mRNA sequencing analysis showed that Lb-miR166a regulates the expression of various genes in tumor cells, including 1232 upregulated genes and 581 downregulated genes, which were enriched to 1094 Gene Ontology entries and 43 Kyoto Encyclopedia of Genes and Genomes pathways. In vitro cell experiments confirmed that Lb-miR166a can inhibit the proliferation of RCC cells, promote the apoptosis of tumor cells, and inhibit the invasion and metastasis of tumor cells by regulating the expression of related genes. Furthermore, our in vivo tumor-bearing experiment showed that subcutaneous tumor formation volume decreased in Lb-miR166a mice, along with the number of liver metastases. This study elucidates the role and mechanism of Lb-miR166a in RCC treatment (Fig. 1). Our results further mechanistically confirm the antitumor properties of L. barbarum. Our study may contribute to the clinical development of a targeted drug for RCC treatment. [ABSTRACT FROM AUTHOR]

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities., (© 2023. The Author(s).)

With the in-depth study of the human genome and the increasing popularity of gene sequencing, it has been gradually confirmed that genetics can play a crucial role in infertility. To provide references for clinical treatment, we have focused on genes and drug therapy for genetic infertility. This review recommends adjuvant therapy and drug substitution. Examples of these therapies include antioxidants (such as folic acid, vitamin D, vitamin E, inositol, coenzyme Q10 etc.), metformin, anticoagulants, levothyroxine, dehydroepiandrosterone, glucocorticoids, and gonadotropins etc. Based on the pathogenesis, we provide an overview of the current knowledge, including randomized controlled trials and systematic reviews, and predict potential target genes and signaling pathways, proposing possible future strategies for the use of targeted drugs to treat infertility. Non-coding RNAs are anticipated to become a novel target for the treatment of reproductive illnesses since they have a significant role in controlling the occurrence and development of reproductive diseases.

RET and ROS1 are becoming key targets for targeted therapy. To show current landscape of ROS1 and RET targets, a patent analysis was performed. The present results indicated that inhibitor structures of ROS1 target demonstrated unique elements compared with inhibitor structures of RET or BRAF targets. Our study was the first time to uncover that a number of inhibitor structures of ROS1 target contained sulfur and boron elements. The inhibitors of RET target could be developed for treatment of various cancers, including lung cancer, thyroid cancer, and other solid tumor, while the inhibitors of ROS1 target are virtually developed for treatment of lung cancer. Our findings provide a new insight for drug discovery of ROS1 and RET target.

CLDN6 is a member of the CLDNs family that is specifically and highly expressed in cancers such as ovarian, testicular, endocervical, liver and lung adenocarcinoma, but hardly expressed in adult normal tissues. CLDN6 is able to activate multiple signaling pathways, which take part in the development and progression of cancer, including promoting tumor growth, migration and invasion, and promoting chemoresistance in cancer. In recent years, CLDN6 has received much attention as a novel target for cancer therapeutics. Many types of anticancer drugs targeting CLDN6 have been developed, including antibody-conjugated drugs (ADC), monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T). This paper briefly summarizes the structure, expression and function of CLDN6 in tumors, and reviews the current status and ideas of developing targeted CLDN6 anticancer drugs.