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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.

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.

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.

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.

Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level., (© 2024 Wiley‐VCH GmbH.)

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. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of B‐cell lymphoma (BCL). These drugs interfere with the mechanisms underlying malignant B‐cell pathophysiology, allowing better drug response as well as low toxicity. However, these multiple mechanisms also lead to drug resistance, which compromised the treatment outcome and needs to be solved urgently. This review focuses on genomic variations (such as BTK and its downstream PCLG2 mutations as well as Del 8p, 2p+, Del 6q/8p, BIRC3, TRAF2, TRAF3, CARD11, MYD88, and CCND1 mutations) and related pathways (such as PI3K/Akt/mTOR, NF‐κB, MAPK signaling pathways, overexpression of B‐cell lymphoma 6, platelet‐derived growth factor, toll‐like receptors, and microenvironment, cancer stem cells, and exosomes) involved in cancer pathophysiology to discuss the mechanisms underlying resistance to BTKi. We have also reviewed the newly reported drug resistance mechanisms and the proposed potential treatment strategies (the next‐generation BTKi, proteolysis‐targeting chimera‐BTK, XMU‐MP‐3, PI3K‐Akt‐mTOR pathway, MYC or LYN kinase inhibitor, and other small‐molecule targeted drugs) to overcome drug resistance. The findings presented in this review lay a strong foundation for further research in this field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In this study, poly (lactic acid-glycolic acid) (PLGA) nanoparticles loaded with anti-inflammatory drug ketoprofen (KET) were prepared and then coated with platelet membrane (PLTM) to form KET@PLTM-PLGA nano-particles (NPs). The particle size of the KET@PLTM-PLGA NPs is 176 nm and the surface protein is the same as that of PLTM. The results of confocal microscopy and flow cytometry showed that the KET@PLTM-PLGA NPs uptake of RAW264.7 induced by LPS was significantly higher than that of KET@PLGA NPs, without PLTM, which was due to the binding of P-selectin to CD44 receptors on the surface of RAW264.7 cells induced by LPS on the surface of PLTM. Compared with other KET preparations, KET@PLTM-PLGA NPs have better anti-inflammatory effect. PLGA nanoparticles loaded with anti-inflammatory drug ketoprofen (KET) were prepared, and then coated with platelet membrane (PLTM) to form KET@PLTM-PLGA NPs. The NPs have great anti-inflammatory effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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.

To explore the clinical effects of targeted drug therapy on elderly patients with gastric cancer. Totally 200 metastatic gastric cancer patients who came to our hospital from January 2017 to January 2020 were selected and randomized into four groups, with 50 patients in each group. Bevacizumab (Group I), apatinib (Group II), and recombinant human endostatin (Group III) adopted respectively. While the control group received no targeted drug. Clinical data and clinical effect was collected and compared. After the therapy, the vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-2 (sVEGFR2) and human epithelial growth factor receptor-2 (HER2) positive detection of Group I, Group II, and Group III were better than the control group (P<0.05). In addition, the therapeutic effects of Group I, Group II, and Group III were higher and the incidence of adverse reactions was lower than the control group (P<0.05). Targeted drugs have obvious clinical effects in gastric cancer. It can effectively inhibit tumor growth and reduce the occurrence of complications, which is worthy of extensive clinical application and promotion. [ABSTRACT FROM AUTHOR]

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Introduction: Axial osteosarcoma and Ewing sarcoma are rare, aggressive neoplasms with a worse prognosis than with tumors involving the extremities because they are more likely to be associated with larger tumor volumes, older age, primary metastases, and a poor histological response to chemotherapy. The 5-year OS rates are reportedly in the range of 18–41% for axial osteosarcoma, and 46–64% for Ewing sarcoma. Area covered: The treatment of axial bone tumors is the same as for extremity bone tumors, and includes chemotherapy, surgery and/or radiotherapy. Expert opinion: Local treatment of axial tumors is particularly difficult due to their proximity to neurological and vascular structures, which often makes extensive and en bloc resections impossible without causing significant morbidity. The incidence of local relapse is consequently high, and this is the main issue in the treatment of these tumors. Radiotherapy is an option in the case of surgical resections with close or positive margins, as well as for inoperable tumors. Delivering high doses of RT to the spinal cord can be dangerous. Given the complexity and rarity of these tumors, it is essential for this subset of patients to be treated at selected reference institutions with specific expertise and multidisciplinary skills. [ABSTRACT FROM AUTHOR]

• Agents targeting the JAK/STAT pathway are categorized into phytochemicals, synthetic drugs, and biomolecules, each of which plays a pivotal anti-cancer role. • Combining JAK/STAT inhibitors with other therapies provides new insights into cancer treatment and addresses the challenge of drug resistance. • Utilizing nanocarriers enhances the solubility and bioavailability of anticancer drugs and represents a new approach to cancer therapy. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, essential for cellular communication, orchestrates a myriad of physiological and pathological processes. Recently, the intricate association between the pathway's dysregulation and the progression of malignant tumors has garnered increasing attention. Nevertheless, there is no systematic summary detailing the anticancer effects of molecules targeting the JAK/STAT pathway in the context of tumor progression. This review offers a comprehensive overview of pharmaceutical agents targeting the JAK/STAT pathway, encompassing phytochemicals, synthetic drugs, and biomolecules. These agents can manifest their anticancer effects through various mechanisms, including inhibiting proliferation, inducing apoptosis, suppressing tumor metastasis, and angiogenesis. Notably, we emphasize the clinical challenges of drug resistance while spotlighting the potential of integrating JAK/STAT inhibitors with other therapies as a transformative approach in cancer treatment. Moreover, this review delves into the avant-garde strategy of employing nanocarriers to enhance the solubility and bioavailability of anticancer drugs, significantly amplifying their therapeutic prowess. Through this academic exploration of the multifaceted roles of the JAK/STAT pathway in the cancer milieu, we aim to sketch a visionary trajectory for future oncological interventions. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly lethal malignant disease. The epithelial-mesenchymal transition (EMT) is crucial in promoting ESCC development. However, the molecular heterogeneity of ESCC and the potential inhibitory strategies targeting EMT remain poorly understood. In this study, we analyzed high-resolution single-cell transcriptome data encompassing 209,231 ESCC cells from 39 tumor samples and 16 adjacent samples obtained from 44 individuals. We identified distinct cell populations exhibiting heterogeneous EMT characteristics and identified 87 EMT-associated molecules. The expression profiles of these EMT-associated molecules showed heterogeneity across different stages of ESCC progression. Moreover, we observed that EMT primarily occurred in early-stage tumors, before lymph node metastasis, and significantly promoted the rapid deterioration of ESCC. Notably, we identified SERPINH1 as a potential novel marker for ESCC EMT. By classifying ESCC patients based on EMT gene sets, we found that those with high EMT exhibited poorer prognosis. Furthermore, we predicted and experimentally validated drugs targeting ESCC EMT, including dactolisib, docetaxel, and nutlin, which demonstrated efficacy in inhibiting EMT and metastasis in ESCC. Through the integration of scRNA-seq, RNA-seq, and TCGA data with experimental validation, our comprehensive analysis elucidated the landscape of EMT during the entire course of ESCC development and metastasis. These findings provide valuable insights and a reference for refining ESCC clinical treatment strategies. • High-resolution single-cell transcriptome data for 209,231 ESCC cells was analyzed. • 87 EMT characteristic molecules were identified. • The expression of EMT characteristic molecules at different stages was heterogeneous. • SERPINH1, a new potential marker for ESCC EMT was identified. • Dactolisib, docetaxel and nutlin could inhibit EMT in ESCC. [ABSTRACT FROM AUTHOR]

With the development of trastuzumab for metastatic breast cancer a new era began in cancer drug development. The drug-diagnostic codevelopment model with its clinical enrichment trial design has enabled development of target specific drugs for molecular defined subsets of patients. Since the simultaneous approval of trastuzumab and the HercepTest in 1998, the number of FDA-approved drug-companion diagnostic combinations within oncology and hematology have steadily increased. By June 2021, the number of drugs that have a companion diagnostic (CDx) linked to its use has reached 46. For these drugs, the CDx assays play an important role in defining the patient population likely to respond and without the assay they will often lose their value. This short article is based on an analysis of the FDA List of Cleared or Approved Companion Diagnostic Devices and relevant information in the Drugs@FDA, and will focus on the drug-CDx combinations, drug classes, clinical development, and the regulatory path and status.

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. [ABSTRACT FROM AUTHOR]

Background: Various types of tumors are likely to acquire drug resistance over time. Hence, the development of novel therapies to overcome drug resistance is critical. Studies have demonstrated that drug resistance is closely associated with the dynamic regulation of mitochondria in tumor cells. The dynamin-related protein 1 (Drp1) is involved in the regulation of mitochondrial fission and plays an important role in maintaining mitochondrial morphology, function, and distribution. It is a key protein in mitochondrial quality control. Drp1 is a GTPase localized to the cytoplasm and is a potential target in cancer therapy. A variety of drugs targeting Drp1 have shown great promise in reducing the viability and proliferation of cancer cells. The dynamic regulation of Drp1-mediated mitochondria is closely associated with tumor development, and treatment. Aim: In this article, the authors reviewed the occurrence and progression of mitochondrial fission regulated by Drp1, and its influence on cell cycle, autophagy, apoptosis, migration, invasion, the molecular mechanism of tumor stemness, and metabolic reprogramming. Targeted inhibition of Drp1 and mitochondrial fission could reduce or prevent tumor occurrence and progression in a variety of cancers. Drp1 inhibitors could reduce tumor stemness and enhance tumor sensitivity to chemotherapeutic drugs. Conclusion: Research into identifying compounds that could specifically target Drp1 will be valuable for overcoming drug resistance in tumors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The recurrence rate of hepatocellular carcinoma (HCC) after partial hepatectomy is still high. How to choose the most appropriate anti-tumor drug in the early postoperative period is crucial to improve the prognosis of patients. Recently, MiniPDX has been widely used as a new and reliable preclinical research model capable of predicting the sensitivities of anti-tumor drugs.Methods: Twenty-eight patients with HCC were selected to use the MiniPDX model to screen the most sensitive anti-tumor drugs from five groups of drug regimens for preventive treatment after partial hepatectomy, and another 42 patients with HCC were selected to be treated with Sorafenib during the same period as the control group. The tumor-free survival rate and overall survival rate were analyzed and compared between these two groups. The relationship between drug sensitivity and biomarkers related to HCC was also analyzed.Results: Kaplan-Meier survival curve analysis showed that the tumor-free survival (DFS) of patients in the MiniPDX group was significantly longer than that in the control group (median DFS: 25.8 months vs. 18.2 months, P = 0.022, HR 2.19, 95% CI 1.17-4.12). The overall survival (OS) of the patients in the MiniPDX group was also longer than that in the control group (median OS: 29.4 months vs. 23.8 months, P = 0.039, HR 2.37, 95% CI 1.12-5.00). The longest follow-up period was 36 months. The relationship analyzed between the efficacy of the five drugs (Regorafenib, Regorafenib, Lenvatinib, Gemcitabine, 5-FU + Oxaliplatin) and AFP, Ki-67, VEGFR, FGFR, P53, and Nrf2 showed different correlations.Conclusion: The use of the MiniPDX model to select drugs to guide anti-tumor treatment after partial hepatectomy could effectively prolong the survival of patients with HCC. [ABSTRACT FROM AUTHOR]

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors., 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 © 2024 Wang, Qiu, Deng and Wan.)

Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non-immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials., (© 2024 Wiley-VCH GmbH.)

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.

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 515% 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.

Purpose: This study investigates the therapeutic efficacy of various targeted drugs in combination with chemotherapy on advanced/ metastatic triple-negative breast cancer (TNBC) by a network meta-analysis. Methods: Literatures from PubMed, Web of Science, Embase, and CNKI databases were searched to retrieve the relevant published data, and many randomized controlled trials (RCTs) on TNBC were selected according to the inclusion and exclusion criteria. The progression-free survival (PFS), overall survival (OS), the adverse effect rate (AEs), and treatment response rate (RR) of TNBC patients for all retrieved literatures were extracted. R software and Hasse diagrams was used to analyze the therapeutic effects of different targeted drugs combined with chemotherapy. Results: A total of 16 RCTs were included in the study. The PFS (Hazard ratio (HR) 0.72, 95% CI 0.66-0.79, p < 0.001) and OS (HR 0.92, 95% CI 0.84-1.0, p = 0.0475) were calculated among the studies. By comparing with combined regimens, we found that Iniparib combined with chemotherapy has a better therapeutic effect on prolonging PFS (HR p-Score = 0.55, AEs p-Score = 0.80, RR p-Score = 0.82). Conclusion: Based on the network meta-analysis of combined regimens for TNBC patients with PFS, OS, AEs and RR for screening the optimal treatment regimen, we propose that the PFS of patients with TNBC could be improved by a combination chemotherapy including iniparib, cetuximab, taxane or ipatasertib. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cell competition is recognized to be instrumental to the dynamics and structure of the tumor-host interface in invasive cancers. In mild competition scenarios, the healthy tissue and cancer cells can coexist. When the competition is aggressive, competitive cells, the so called super-competitors, expand by killing other cells. Novel chemotherapy drugs and molecularly targeted drugs are commonly administered as part of cancer therapy. Both types of drugs are susceptible to various mechanisms of drug resistance, obstructing or preventing a successful outcome. In this paper, we develop a cancer growth model that accounts for the competition between cancer cells and healthy cells. The model incorporates resistance to both chemotherapy and targeted drugs. In both cases, the level of drug resistance is assumed to be a continuous variable ranging from fully-sensitive to fully-resistant. Using our model we demonstrate that when the competition is moderate, therapies using both drugs are more effective compared with single drug therapies. However, when cancer cells are highly competitive, targeted drugs become more effective. The results of the study stress the importance of adjusting the therapy to the pre-treatment resistance levels. We conclude with a study of the spatiotemporal propagation of drug resistance in a competitive setting, verifying that the same conclusions hold in the spatially heterogeneous case. [ABSTRACT FROM AUTHOR]

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. 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]. 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. • 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. [ABSTRACT FROM AUTHOR]

Introduction: Osteosarcoma is the most common malignant bone tumor. It is currently treated with pre-and postoperative chemotherapy, associated with surgical resection of the tumor.Area covered: Relapses occur in about one in three patients presenting with localized disease, and three in four of those with metastases at diagnosis. Relapsing disease carries a very poor prognosis, with 5-year survival rates ranging between 13% and 40%.Expert opinion: Patients with unilateral lung involvement or solitary lung metastases and a recurrence-free interval (RFI) longer than 24 months have a better prognosis, and could be managed with surgical resection and close observation. Complete surgical resection of all sites of disease remains essential to survival: patients unable to achieve complete remission have a catastrophic overall survival rate. The role of second-line chemotherapy is not at all clear, and no controlled studies are available on this topic. It is worth considering for patients unable to achieve complete surgical remission, and those with multiple metastases and/or a RFI <24 months. Given their dismal prognosis, patients with multiple sites of disease not amenable to complete surgical resection should also be considered for innovative therapeutic approaches. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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

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.

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications., Competing Interests: The authors declared that they have no conflicts of interest to this paper. Figures were created with BioRender software (https://app.biorender.com/)., (© 2024 The Authors.)

Background: Lumbar disc degeneration (LDD) is an important pathological basis for the development of degenerative diseases of the lumbar spine. Most clinical patients have low back pain as their main symptom. The deterioration of the biomechanical environment is an important cause of LDD. Although there is a large amount of basic research on LDD, there are fewer reports that correlate biomechanical mechanisms with basic research. Our research aims to identify 304 key genes involved in LDD due to biomechanical deterioration, using a bioinformatics approach. We focus on SMAD3, CAV1, SMAD7, TGFB1 as hub genes, and screen for 30 potential target drugs, offering novel insights into LDD pathology and treatment options., Methods: The Gene Cards, GenCLip3, OMIM and Drugbank databases were explored to obtain genes associated with biomechanics and LDD, followed by making veen plots to obtain both co-expressed genes. GO enrichment analysis and KEGG pathway analysis of the co-expressed genes were obtained using the DAVID online platform and visualised via a free online website. Protein interaction networks (PPI) were obtained through the STRING platform and visualised through Cytoscape 3.9.0. These genes were predicted for downstream interaction networks using the STITCH platform. Then, the GSE56081 dataset was used to validate the key genes. RT-PCR was used to detect mRNA expression of core genes in the degenerated nucleus pulposus (NP) samples and western bolt was used for protein expression. Lastly, the obtained hub genes were searched in the drug database (DGIdb) to find relevant drug candidates., Results: From the perspective of biomechanics-induced LDD, we obtained a total of 304 genes, the GO functional enrichment and KEGG pathway enrichment analysis showed that the functions of these genes are mostly related to inflammation and apoptosis. The PPI network was constructed and four Hub genes were obtained through the plug-in of Cytoscape software, namely SMAD3, CAV1, SMAD7 and TGFB1. The analysis of key genes revealed that biomechanical involvement in LDD may be related to the TGF-β signaling pathway. Validation of the GSE56081 dataset revealed that SMAD3 and TGFB1 were highly expressed in degenerating NP samples. RT-PCR results showed that the mRNA expression of SMAD3 and TGFB1 was significantly increased in the severe degeneration group; Western blot results also showed that the protein expression of TGFB1 and P-SMAD3 was significantly increased. In addition, we identified 30 potential drugs., Conclusion: This study presented a new approach to investigate the correlation between biomechanical mechanisms and LDD. The deterioration of the biomechanical environment may cause LDD through the TGF-β signaling pathway. TGFB1 and SMAD3 are important core targets. The important genes, pathways and drugs obtained in this study provided a new basis and direction for the study, diagnosis and treatment of LDD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: To explore the clinical characteristics, molecular characteristics, treatment and prognosis of pediatric Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) with a therapeutic target., Methods: A total of 27 patients of Ph-like ALL with targeted drug target were initially diagnosed in Children's Hospital of Soochow University from December 2017 to June 2021. The data of age, gender, white blood cell (WBC) count at initial diagnosis, genetic characteristics, molecular biological changes, chemotherapy regimen, different targeted drugs were given, and minimal residual disease (MRD) on day 19, MRD on day 46, whether hematopoietic stem cell transplantation (HSCT) were retrospective analyed, and the clinical characteristics and treatment effect were summarized. Survival analysis was performed by Kaplan-Meier method., Results: The intensity of chemotherapy was adjusted according to the MRD level during induced remission therapy in 27 patients, 10 patients were treated with targeted drugs during treatment, and 3 patients were bridged with HSCT, 1 patient died and 2 patients survived. Among the 24 patients who did not receive HSCT, 1 patient developed relapse, and achieved complete remission (CR) after treatment with chimeric antigen receptors T cells (CAR-T). The 3-year overall survival, 3-year relapse-free survival and 3-year event-free survival rate of 27 patients were (95.5±4.4)%, (95.0±4.9)% and (90.7±6.3)% respectively., Conclusion: Risk stratification chemotherapy based on MRD monitoring can improve the prognosis of Ph-like ALL in children, combined with targeted drugs can achieve complete remission as soon as possible in children whose chemotherapy response is poor, and sequential CAR-T and HSCT can significantly improve the therapeutic effect of Ph-like ALL in children whose MRD is continuously positive during induced remission therapy.

Background: PTEN and mTOR signaling have many roles, including antiinflammatory, immunosuppressant and cancer., Objective: US patents were retrieved to show the current landscape of the mTOR and PTEN targets., Methods: PTEN and mTOR targets were analyzed by patent analysis. The U.S. granted patents from January 2003 to July 2022 were performed and analyzed., Results: The results showed that the mTOR target was more attractive in drug discovery than the PTEN target. Our findings indicated that most large global pharmaceutical companies focused the drug discovery related to the mTOR target. The present study demonstrated that mTOR and PTEN targets showed more applications in biological approaches compared to BRAF and KRAS targets. The chemical structures of the inhibitors of the mTOR target demonstrated some similar features to those of the inhibitors of KRAS targets., Conclusion: At this stage, the PTEN target may not be an ideal target subjected to new drug discovery. The present study was the first one which demonstrated that the group of O=S=O may play a critical role in the chemical structures of mTOR inhibitors. It was the first time to show that a PTEN target may be suitably subjected to new therapeutic discovery efforts related to biological applications. Our findings provide a recent insight into therapeutic development for mTOR and PTEN targets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

Epidermal growth factor receptor (EGFR) inhibitors were among the first type of targeted agents discovered in cancer and currently constitute the standard of care for a wide range of lung and colon malignancies. However, the therapeutic progress achieved with these drugs has been accompanied by the identification of an ever-increasing number of acquired resistance mechanisms that inevitably appear in nearly all patients. Increased knowledge on EGFR biochemistry, cellular crosstalk, and resistance pathways provides an opportunity to establish effective combination therapies and discover novel-acting inhibitors that prevent or overcome therapeutic resistance. One such strategy is the selective blockade of circulating growth factors such as EGF. In this review, we address the uses and limitations of approved EGFR inhibitors and explore the potential of drug combinations and new third avenues to block the activation of the EGFR. The initial excitement over the efficacy of EGFR-targeted drugs (TKIs and mAbs) has been offset by a growing number of drug-resistant mutations that invariably appear in patients; thus novel-acting drugs and synergistic combinations are in high demand. The direct inhibition of the main activating ligand (EGF) is considered a promising strategy and has been explored with other kinase receptors, such as VEGF, FGF, and TGF-β. EGF is a small protein with no active sites and/or binding cavities that can be efficiently drugged using traditional small-molecule approaches and has thus remained a challenging target. Peptides, vaccines, and single-chain antibodies against EGF have recently emerged as a new class of biotherapeutics in the fight against EGFR-driven tumours. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Résumé Dans cette revue, nous rapportons les avancées majeures de ces dernières années en ce qui concerne les quatre lymphomes les plus fréquents, en France à savoir le lymphome de Hodgkin, le lymphome B diffus à grandes cellules, le lymphome folliculaire et le lymphome à cellules du manteau. Nous avons recensé les pratiques consensuelles en première ligne et distingué ensuite le ciblage par de nouvelles molécules. Ainsi, nous avons voulu mettre en exergue les problématiques pour chacun de ces quatre lymphomes et comprendre les moyens utilisés pour trouver des solutions. In fine, cette revue permet de comprendre dans quelle mesure les nouvelles molécules (thérapies ciblées, immunothérapie) permettent d'améliorer sans cesse la prise en charge des patients atteints de lymphomes. La dynamique globale semble réduire la place des chimiothérapies classiques au profit de ces nouvelles molécules. Cependant, devant la multiplication des possibilités thérapeutiques, le défi reste de trouver la combinaison associée offrant le meilleur ratio bénéfice/risque, sachant que ces nouvelles thérapies sont assorties d'effets secondaires dont la connaissance reste limitée pour l'instant. Abstract In this review, we report the main advances of the last years in the four most common lymphomas in France, namely Hodgkin lymphoma, large cell diffuse B lymphoma, follicular lymphoma and mantle cell lymphoma. We have identified consensual practices in first line in France and then distinguished the targeting by new molecules. Thus, we wanted to highlight the problems for each of these four lymphomas and understand the tools used to find solutions. Finally, this review makes it possible to understand to what extent the new molecules (targeted therapies, immunotherapy) make it possible to continuously improve the management of patients with lymphomas. The global dynamics seems to reduce the place of conventional chemotherapies in favor of these new molecules. However, because of the increase in therapeutic possibilities, the challenge remains to find the combination associated with the best risk-benefit ratio. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Protein homeostasis, an important aspect of cellular fitness that encompasses the balance of production, folding and degradation of proteins, has been linked to several diseases of the human body. Multiple interconnected pathways coordinate to maintain protein homeostasis within the cell. Recently, the role of the protein homeostasis network in tumorigenesis and tumour progression has gradually come to light. Here, we summarize the involvement of the most prominent components of the protein quality control mechanisms (HSR, UPS, autophagy, UPR and ERAD) in tumour development and cancer immunity. In addition, evidence for protein quality control mechanisms and targeted drugs is outlined, and attempts to combine these drugs with cancer immunotherapy are discussed. Altogether, combination therapy represents a promising direction for future investigations, and this exciting insight will be further illuminated by the development of drugs that can reach a balance between the benefits and hazards associated with protein homeostasis interference. • Protein homeostasis, a process crucial to cellular fitness and human diseases, regulates the balance of cellular production, folding, and degradation of proteins. • Maintenance of protein homeostasis in malignant cells promotes tumorigenesis and tumour progression. • Protein homeostasis has emerged as a key regulator of cancer immunity. • Combing protein homeostasis inhibitors with cancer immunotherapy is a promising field of drug development. [ABSTRACT FROM AUTHOR]