Current Drug Targets

Our medical research library holds 8 studies published in Current Drug Targets (2009–2020). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 8 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Bentham Science Publishers
• Published: 2000 to the present, United Arab Emirates
• Language: English
• ISSN: 1389-4501 (print), 1873-5592 (electronic)
• Its record in the NLM Catalog

2020s

• Progress in the Understanding of the Immune Microenvironment and Immunotherapy in Malignant Pleural Mesothelioma. L. Cheng, N. Li, X.L. Xu, et al. 2020;21(15):1606-1612. Review PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) is a remarkably aggressive thoracic malignancy with a limited survival of only 5-12 months. However, MPM still remains unresponsive to conventional standards of treatment, including pleurectomy and decortication, extrapleural pneumonectomy for resectable disease with or without chemotherapy, and/or radiation therapy. The mechanism of carcinogenesis has not been fully elucidated, although approximately 80% of cases can still be linked to asbestos exposure. The tumor immune microenvironment (TME) has been proven to play an important role in MPM pathogenesis and treatment outcomes. Several molecular pathways have been implicated in the MPM tumor microenvironment, such as angiogenesis, apoptosis, cell cycle regulation, and stromal processes. Immunotherapy has already shown promising results in other thoracic solid tumors, such as non-small-cell lung cancer (NSCLC). However, immunotherapy has shown less convincing results in MPM than in melanoma and NSCLC. A multicenter, randomized trial (DETERMINE) proved that immune checkpoint inhibition using tremelimumab, an anti-cytotoxic T lymphocyteassociated protein 4 (CTLA-4) antibody, failed to improve median overall survival. Therefore, it is important to explore the relationship between the characteristics of the tumor microenvironment and immunotherapy. Here, we review the heterogeneity of the TME and the progress in the understanding of the immune microenvironment and immunotherapy in MPM to explore the mechanisms of resistance to immunotherapy.

  Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

2010s

• The Emerging Role of the Hippo Pathway in Lung Cancers: Clinical Implications. S.L. Teoh, S. Das. 2017;18(16):1880-1892. Review PubMed · Publisher

  Abstract

  Background: The incidence of lung cancers has increased globally. Increased exposure to tobacco, passive smoking, less consumption of vegetables and fruits and occupational exposure to asbestos, arsenic and chromium are the main risk factors. The pathophysiology of lung cancer is complex and not well understood. Various microRNAs, genes and pathways are associated with lung cancers. The genes involved in lung cancers produce proteins involved in cell growth, differentiation, different cell cycles, apoptosis, immune modulation, tumor spread and progression. The Hippo pathway (also known as the Salvador-Warts-Hippo pathway) is the latest emerging concept in cancers. The Hippo pathway plays an important role in controlling the size of the tissue and organ by virtue of its action on cell proliferation and apoptosis.

  Objective: In the present review, we highlight the mammalian Hippo pathway, role of its core members, its upstream regulators, downstream effectors and the resistance cases in lung cancers.

  Results: Specific interaction of Mer with cell surface hyaluronan receptor CD44 is vital in cell contact inhibition, thereby activating Hippo pathway. Both transcription co-activators YAP and TAZ (also known as WWTR1, being homologs of Drosophila Yki) are important regulators of proliferation and apoptosis, and serve as major downstream effectors of the Hippo pathway. Mutation of NF2, the upstream regulator of Hippo pathway is linked to the cancers.

  Conclusion: Targeting YAP and TAZ may be important for future drug delivery and treatment.

  Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

• Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies. S. Thellung, R.E. Favoni, R. Würth, et al. 2016;17(7):824-49. Review PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors, highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, did not fulfil the expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors for MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible for the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling that may also be activated by autocrine and paracrine cytokine pathways controlling cell plasticity. Both signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation.

• Dasatinib: an anti-tumour agent via Src inhibition. A. Gnoni, I. Marech, N. Silvestris, et al. 2011;12(4):563-78. Review PubMed · Publisher

  Abstract

  Dasatinib (BMS-354825, Sprycel®) is an oral, multitargeted inhibitor of receptor tyrosine kinases (RTKs), including BCR-ABL fusion protein, stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGFR), and Src family kinases (SFKs). Several early- and late-phase clinical trials for chronic myelogeneous leukaemia (CML) have demonstrated the direct inhibition of BCR-ABL fusion protein and SFKs, which led to dasatinib approval by the Food and Drug Administration (FDA) and the European Union for the treatment of imatinib-resistant or -intolerant CML, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Phase III dose-optimization study was performed to compare different regimens, stating that dasatinib 100 mg once daily is now the recommended schedule for patients with chronic CML, and 140 mg once daily for patients with accelerated phase or myeloid or lymphoid blast phase CML, and for patients with Ph+ ALL until progression. Because of the myriad of critical roles of SFKs in biological processes, SFKs inhibition could induce numerous biological responses. Ongoing clinical trials evaluate dasatinib in the treatment of several solid tumours, including gastrointestinal stromal tumours (GIST), prostate cancer, malignant pleural mesothelioma, sarcomas, NSCLC, colorectal cancer, glioblastoma and other haematologic malignancies as multiple myeloma. Ongoing pre-clinical studies assess the therapeutic potential of dasatinib in other solid tumours, including melanoma, head and neck cancer, breast cancer and ovarian cancer. Dasatinib is generally well tolerated. Myelosuppression is the common adverse event which is, however, reversible by dose reduction, discontinuation, or interruption. Thrombocytopenia is more significant than neutropenia and associated to gastrointestinal bleeding and CNS haemorrhage. The most common non-haematologic adverse events include gastrointestinal symptoms (diarrhoea, nausea, vomiting, abdominal pain and anorexia), headache, peripheral edema, and pleural effusion. In respect of these encouraging studies investigating dasatinib in the treatment of patients with GIST, prostate cancer, multiple myeloma and sarcomas, ongoing phase III clinical trials warrant the drug evaluation as recommended agent for the treatment of these diseases, also in association with chemotherapy or other targeted therapies.

• Predictive markers for haematological toxicity of pemetrexed. S.C. Kao, V.H. Phan, S.J. Clarke. 2010;11(1):48-57. Review PubMed · Publisher

  Abstract

  Pemetrexed is a multi-targeted anti metabolite that inhibits several key folate-dependent enzymes in the thymidine and purine biosynthetic pathways, including thymidylate synthase. It is currently approved for use in patients with non-small cell lung cancer and malignant mesothelioma. The sporadic and unpredictable occurrence of haematological toxicities of pemetrexed leading to potentially life threatening complications during the early developmental phase, prompted urgent need to identify potential predictive factors for haematological toxicities from pemetrexed. There is a well established association between elevated plasma homocysteine concentration, which is indicative of impaired functional folate status, and increased risk of haematological toxicity from pemetrexed. The decrease in incidence of toxicity after vitamin supplementation confirms the importance of functional folate status as a predictor for haematological toxicity. We review other factors that have a documented impact on haematological toxicity, including pemetrexed schedule, and pharmacokinetic parameters that are indicative of the extent of drug exposure. Further potential factors are explored in this review, such as the genotype of the pemetrexed metabolising enzymes and varying incidences of polymorphism of these genotypes in different ethnic groups that may account for the ethnic differences in neutropenic response to pemetrexed.

• The role of pemetrexed combined with targeted agents for non-small cell lung cancer. K. Konopa, J. Jassem. 2010;11(1):2-11. Review PubMed · Publisher

  Abstract

  Pemetrexed is a novel third-generation multitargeted antifolate agent used in the first- and second-line treatment of unresectable pleural mesothelioma and advanced non-small cell lung cancer (NSCLC). Owing to its mild toxicity, this compound is a preferred partner in the multidrug regimens. In the last few decades, better understanding of molecular oncology and genetics has allowed for the development of an array of molecular targeted agents, many of which have been found active in NSCLC. It has been hoped that these compounds will disrupt tumor signaling pathways complementary to those targeted by chemotherapy. This review outlines the current preclinical and clinical studies using pemetrexed in combination with targeted agents in advanced NSCLC. Clinical experience with the use of these combinations is still limited and mostly includes phase I and II trials. These investigations have mainly focused on compounds previously shown to be active in NSCLC: anti-angiogenic agents (bevacizumab and small molecule tyrosine kinase inhibitors) and inhibitors of epidermal growth factor receptor (cetuximab and erlotinib). Preliminary results have shown the feasibility of these combinations and their promising activity but large phase III studies are warranted to verify the real value of this strategy. Combinations of pemetrexed with other targeted agents, such as mTOR inhibitors and compounds targeting proteasome are still at early stages of development.

• The role of pemetrexed in lung adenocarcinoma, mixed subtype with bronchioloalveolar carcinoma features. M. Duruisseaux, J. Cadranel, M. Pérol, et al. 2010;11(1):74-7. Review PubMed · Publisher

  Abstract

  Bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (ADC-WBF) belong to the same anatomo-clinical entity and show very similar epidemiologic, clinical and biological characteristics. However there is a lack of consensus for the treatment of unresectable forms. Although epidermal growth factor receptor tyrosine kinase inhibitors and paclitaxel do have some efficacy, the aim of this review is to assess the role that pemetrexed, a new generation antifolate, could play in this context. Pemetrexed has proved to be particularly effective in advanced lung adenocarcinomas and unresectable mesotheliomas, and cases of major and sustained responses of ADC-WBF to pemetrexed have been reported. The preclinical rationale explaining this efficacy is that it inhibits the growth of BAC cell lines in vitro. BAC tumors overexpress FR-alpha, a protein involved in pemetrexed intracellular transport, at rates higher than those observed in lung adenocarcinomas and mesotheliomas and it would seem that pemetrexed efficacy is correlated to FR-alpha expression. The role played by thymidylate synthase expression level in sensitivity to pemetrexed also needs to be specifically explored in ADC-WBF. The results of two phase II trials, SWOG 0526 and IFCT 05-04, will hopefully provide decisive information on the relevance of pemetrexed in ADC-WBF management and the molecular predictors of response.

2000s

• Molecular targets in malignant pleural mesothelioma treatment. G. Pasello, A. Favaretto. 2009;10(12):1235-44. Review PubMed · Publisher

  Abstract

  Malignant mesothelioma is an aggressive tumour of the serosal surfaces with poor prognosis and increasing incidence due to widespread previous asbestos exposure. Relative chemotherapeutic and radiotherapeutic resistance makes malignant pleural mesothelioma (MPM) difficult to manage, even though encouraging results were achieved with multimodality treatment. Better knowledge of angiogenesis and molecular pathways involved in MPM seems to be the right way to define new targets for systemic treatment. Neoangiogenesis may be considered as a critical step in the development of mesothelioma. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are autocrine growth factors in MPM and epidermal growth factor receptor (EGFR) appears highly expressed in this tumour. Tyrosine kinase inhibitors (TKIs) targeting growth factors like vandetanib, dasatinib, and angiogenesis inhibitors like bevacizumab, are among the most promising agents under evaluation in clinical trials. Mesothelioma is a malignancy which owes its chemoresistance to an apoptotic defect. Thus the introduction of new biologic drugs like vorinostat, bortezomib, everolimus and temsirolimus, in the treatment of MPM finds a strong rationale. This review focuses on the current target therapies and evaluates future biologic approaches for the systemic management of MPM.

Browse every journal in the library or the library by type of article, or return to medical research.