PAR-4 as a possible new target for pancreatic cancer therapy

Importance of the field: Pancreatic cancer (PC) is a deadly disease that is intractable to currently available treatment regimens. Although well described in different tumors types, the importance of apoptosis inducer prostate apoptosis response-4 (Par-4) in PC has not been appreciated. PC is an oncogenic kras driven disease, which is known to downregulate Par-4. Therefore, this review highlights its significance and builds a strong case supporting the role of Par-4 as a possible therapeutic target in PC.

Areas covered in this review: Literature-based evidence spanning the last 15 years on Par-4 and its significance in PC.

What the reader will gain: This review provides comprehensive knowledge of the significance of Par-4 and its association with kras status in PC, along with the crosstalk with crucial resistance and survival molecules NF-κB and Bcl-2 that ultimately are responsible for the overall poor outcome of different therapeutic approaches in this disease.

Take home message: Par-4 holds promise as a potential therapeutic target that can be induced by chemopreventive agents and small-molecule inhibitors either alone or in combination with standard chemotherapeutics leading to selective apoptosis in PC cells. It also acts as a chemosensitizer and therefore warrants further clinical investigations in this disease.     

MicroRNAs as therapeutic targets for lung cancer

Lung cancer is one of the leading causes of mortality in the world, indicating the need for innovative therapies for the disease. In recent years, microRNAs have emerged as one of the key players in regulating gene expression. Numerous studies have documented the implications of microRNAs in nearly every carcinogenesis process of lung cancer, including tumor development, apoptosis, invasion and metastasis, as well as anti-cancer drug resistance. Forced expression or suppression of microRNA can regulate the biological alteration during carcinogenesis, underscoring the therapeutic potential of microRNAs in lung cancer. This editorial summarizes recent reports of some key microRNAs that can modulate the lung cancer carcinogenesis process, expound the mechanisms by which they exert their functions, introduce some approaches for manipulating the action of microRNAs, and discuss the perspectives of microRNAs as therapeutic targets for lung cancer.     

Challenges and future directions in therapeutics for pancreatic ductal adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA. The 5-year survival of < 5% has not changed in decades. In contrast to other major cancers, the incidence of PDAC is increasing.

Areas covered: The aims of this paper are first to analyze why PDAC is so difficult to treat and, second, to suggest future directions for PDAC therapeutics. The authors provide an article that is based on a comprehensive search through MEDLINE and the clinicalTrials.gov website.

Expert opinion: Progress has been made recently. Notably, FOLFIRINOX or nab-paclitaxel plus gemcitabine provide survival benefit over gemcitabine alone, which was previously the mainstay of therapy for PDAC. Most of the current trials are testing combinations of repurposed drugs rather than addressing key targets in the PDAC pathogenesis. It is clear that to really make an impact on this disease, it will be necessary to address three different problems with targeted therapeutics. First, it is important to eradicate PDAC stem cells that result in recurrence. Second, it is important to reduce the peritumoral stroma that provides the tumors with growth support and provides a barrier to access of therapeutic agents. Finally, it is important to address the marked cachexia and metabolic derangement that contribute to morbidity and mortality and further complicate therapeutic intervention.     

TrkB as a therapeutic target for ovarian cancer

Background: In many countries, ovarian cancer is the most lethal gynecological malignancy. Its poor prognosis is mainly due to the late stage of disease with metastasis at presentation. The significant failure rate of chemotherapy in patients with advanced stage disease is also a main concern. As such, developing novel therapeutic targets is essential to improve long-term survival. Overexpression of Tropomyosin-related kinase B (TrkB), a tyrosine kinase receptor, has been documented in ovarian cancer and is found to be correlated with poor prognosis. Objective/methods: We discuss the functional roles and the related downstream signaling pathways of TrkB and its ligand brain-derived neurotrophic factor (BDNF) in ovarian cancer. The possible crosstalk between TrkB/BDNF and other putative molecular targets in ovarian cancer is also discussed. Results/conclusions: All these latest findings shed light on the application of TrkB as a therapeutic target for ovarian cancer.     

Adrenomedullin as a therapeutic target in angiogenesis

Importance of the field: Hypoxia, a frequent characteristic in the microenvironment of solid tumors, leads to adrenomedullin (AM) upregulation through the hypoxia inducible factor-1 pathway, explaining its high expression in a variety of malignant tissues. AM is believed to play an important role in tumor progression and angiogenesis in many cancers. Therefore, it could become a new therapeutic target.

Areas covered in this review: We performed a review of the literature based on published data to highlight AM's critical roles in tumor cell growth and cancer invasiveness, and its involvement in tumor angiogenesis through promotion of recruitment of hematopoietic progenitors, vascular morphogenesis, and blood vessel stabilization and maturation. Inhibition of AM has antitumoral effects linked to antiangiogenic effects but in some cases also to direct antiproliferative activity on cancer cells. Several studies demonstrated that systemic inhibition of AM receptors was well tolerated in murine models.

What the reader will gain: The goal of this review is to inform readers about the role of AM in tumor angiogenesis and cancer progression and, therefore, about its possible place as a new therapeutic target.

Take home message: Taken together, these data support targeting the AM pathway as a new potential therapy in cancer, complementary to other existing treatments.     

PAK as a therapeutic target in gastric cancer

Importance of the field: Gastric cancer is one of the most common causes of cancer death worldwide. P21-activated kinases (PAKs), regulators of cancer-cell signalling networks, play fundamental roles in a range of cellular processes through their binding partners or kinase substrates.

Areas covered in this review: The complex regulation of PAKs through their upstream or downstream effectors in human cancers, especially in gastric cancer, are described and the identified inhibitors of PAKs are summarized.

What the readers will gain: The structural differences and activation mechanisms between two subgroups of PAK are described. Both groups of PAKs play complicated and important roles in human gastric cancer, which indicated a possible way for us to identify the specific inhibitors targeting PAKs for gastric cancer.

Take home message: PAKs play important roles in progression of many cancer types, the full mechanisms of PAKs in gastric cancer are still unclear. It seems there are different roles for two groups of PAKs in cancers. Group I PAKs play their functions mostly through their specific substrates, however, many binding partners that are independent of phosphorylation by group II PAKs were identified. Finding specific inhibitors of PAKs will help us discover the roles of PAKs and target these kinases in human gastric cancer.     

MUC16 as a novel target for cancer therapy

Introduction: MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy.

Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research.

Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.     

cIAP2 as a therapeutic target in colorectal cancer and other malignancies

Colorectal cancer is one of the most common malignancies worldwide and 70% of tumors are resectable, but patients with metastatic diseases cannot be cured with current treatment modalities. Inhibition of the apoptotic pathway is one of the factors that may be responsible for carcinogenesis and drug resistance, and the inhibitor of apoptosis protein (IAP) family is thought to prevent apoptosis through inhibition of direct caspases and pro-caspases. Recently an increasing amount of evidence has been accumulated regarding cIAP2 and other IAP proteins of the antiapoptotic pathway and NF-κB signal transduction. IAPs are abnormally regulated and expressed in the majority of human malignancies at elevated levels. As a result, they have recently been reported to be therapeutic targets. The downregulation of cIAP2 efficiently enhances apoptosis through the activation of caspase 3/7 and 5-fluorouracil (5-FU) sensitivity in colorectal cancer cells exposed to 5-FU. This report reviews the evidence for cIAP2 and other IAP molecules as a therapeutic target for malignancies including colorectal cancer. So far, the information on colorectal cancer is limited; so this study includes other malignancies as well, in order to summarize the current knowledge of drug development targeting IAP molecules and provide an overview of the future course.     

缓释植入剂局部给药治疗系统的药动学模型

目的:创建缓释植入剂局部给药治疗系统的药动学模型.方法:分析体内过程,建立微分方程并特别关注其中局部靶位的数学表达,进而对药物在血循环中及局部吸收部位的分布作理论比较.结果:缓释植入剂局部给药治疗系统的药动学二室模型为:Cc(t)=A1e -Krt A2e -Kat A3e-at A4e-βt,吸收部位与血循环中药物分布的比值为:ACc/ACa≈(Va/V)·(Ka/Ke).结论:该模型立意严谨,有一定的理论意义和实用价值.     

Neuroinflammation: a potential therapeutic target

The increased appreciation of the importance of glial cell-propagated inflammation (termed ‘neuroinflammation’) in the progression of pathophysiology for diverse neurodegenerative diseases, has heightened interest in the rapid discovery of neuroinflammation-targeted therapeutics. Efforts include searches among existing drugs approved for other uses, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses. The use of existing drugs to target neuroinflammation has largely met with failure due to lack of efficacy or untoward side effects. However, the de novo development of new classes of therapeutics based on targeting selective aspects of glia activation pathways and glia-mediated pathophysiologies, versus targeting pathways of quantitative importance in non-CNS inflammatory responses, is yielding promising results in preclinical animal models. The authors briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to onset or progression of neurodegenerative diseases. The authors conclude with opinions based on recent experimental proofs of concept using preclinical animal models of pathophysiology. The focus is on Alzheimer’s disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component.     

STXBP1 as a therapeutic target for epileptic encephalopathy

Introduction: STXBP1 is an essential protein for presynaptic vesicle release. Mutations in STXBP1 have been associated with a series of (epileptic) neurodevelopmental disorders collectively referred to as STXBP1-encephalopathy (STXBP1-E). In this review we hypothesize about the potential of STXBP1 as a therapeutic target in the field of epileptic encephalopathies.

Areas covered: A state of the art overview on current understanding of the pathophysiologic mechanism underlying STXBP1-E is presented. Possibilities of different treatment modalities are discussed including unbiased compound screening, specific protein-protein interaction inhibition and gene therapy, consisting either of gene suppletion or upregulation of gene expression.

Expert opinion: Current treatment for STXBP1-E is largely limited to seizure control and future therapies will need to target the developmental aspects of the disease as well. Both in vitro- and animal models used to study the pathophysiology of STXBP1-E could be further optimized as a model for compound screening. They should reflect both the hyper excitable state and the psychomotor delay of STXBP1-E. Specific protein-protein interaction and gene therapy are promising future treatment options that need to be investigated further. We suggest a parallel research strategy on basic pathophysiology and compound development with both fields working in close collaboration with the patient/clinical community.     

Progranulin as a therapeutic target for dementia

Introduction: Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms.

Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models.

Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures.     

SOCS3分子——治疗人类多种疾病的潜在靶标

业已发现,多种细胞因子和炎症因子可诱导SOCS3的表达,表明SOCS3在细胞信号转导通路中发挥重要调控作用。经10多年研究,SOCS3分子在人体多种组织的生理功能维持和病理变化进展中的作用已日益明确。本文从近年来研究SOCS3较多的疾病(炎症、病毒感染、肥胖及肿瘤)出发,综述该分子在疾病的发生、发展、诊断和治疗中的作用。在人类多种疾病发生发展中,SOCS3均表现出水平异常或功能发挥异常,提示SOCS3可作为一些疾病诊断及预测预后的生物分子指标,以及特定疾病的治疗靶标。     

Bradykinin receptors as a therapeutic target

Biologically-active kinins, including bradykinin (BK) and Lys⁰-BK (kallidin), are short-lived peptide mediators predominantly generated by the enzymatic action of kallikreins on kininogen precursors. A diverse spectrum of physiological and pathological actions attributed to local kinin production is a consequence of the activation of G-protein-coupled receptors (GPCRs). Currently, two major subtypes of kinin receptor, designated B₁ and B₂, are recognised, although there is much evidence for pharmacological heterogeneity, particularly within the B₂ receptors. Considering these facts and the widespread distribution of kinin receptors in many human tissues, it is no surprise that the therapeutic potential of kinins and kinin receptor antagonists remains the focus of numerous investigations. Studies in animals and animal tissues, instrumental in elucidating the biological roles of kinins, are well-documented in numerous excellent reviews. Unfortunately, and despite the enormous potential illustrated by animal studies, attempts to develop kinin analogues as therapeutic agents to combat human disease have largely proven disappointing. Consequently, this review selectively focuses upon studies that are directly relevant to the targeting of human BK receptors as a therapeutic intervention. In addition to providing a succinct review of well-documented pathological conditions to which kinin receptors contribute, the authors have also included more recent data that illustrate new avenues for the therapeutic application of kinin analogues.     

The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis

Introduction: Fibroblast growth factors (FGFs) are endowed with a potent pro-angiogenic activity. Activation of the FGF/FGF receptor (FGFR) system occurs in a variety of human tumors. This may lead to neovascularization, supporting tumor progression and metastatic dissemination. Thus, a compelling biologic rationale exists for the development of anti-FGF/FGFR agents for the inhibition of tumor angiogenesis in cancer therapy.

Areas covered: A comprehensive search on PubMed was performed to identify studies on the role of the FGF/FGFR system in angiogenesis. Endothelial FGFR signaling, the pro-angiogenic function of canonical FGFs, and their role in human tumors are described. In addition, experimental approaches aimed at the identification and characterization of nonselective and selective FGF/FGFR inhibitors and their evaluation in clinical trials are summarized.

Expert opinion: Different approaches can be envisaged to inhibit the FGF/FGFR system, a target for the development of ‘two-compartment’ anti-angiogenic/anti-tumor agents, including FGFR selective and nonselective small-molecule tyrosine kinase inhibitors, anti-FGFR antibodies, and FGF ligand traps. Further studies are required to define the correlation between tumor vascularization and activation of the FGF/FGFR system and for the identification of cancer patients more likely to benefit from anti-FGF/FGFR treatments. In addition, advantages and disadvantages about the use of selective versus non-selective FGF inhibitors remain to be elucidated.     

FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity

Introduction: Regulatory T cells (Treg) characterized by expression of FOXP3 and strong immunosuppressive activity play a key role in regulating homeostasis in health and disease.

Areas covered: Human Treg are highly diverse phenotypically and functionally. In the tumor microenvironment (TME), Treg are reprogrammed by the tumor, acquiring an activated phenotype and enhanced suppressor functions. No unique phenotypic markers for Treg accumulating in human tumors exist. Treg are heterogeneous and use numerous mechanisms to mediate suppression, which either silences anti-tumor immune surveillance or prevents tissue damage by activated T cells. Treg plasticity in the TME endows them with dual functionality. Treg frequency in tumors associates either with poor or improved survival. Treg responses to immune checkpoint inhibition (ICI) differ from the restorative effects ICIs induce in other immune cells. Therapies used to silence Treg, including ICIs, are only partly successful. Treg persistence and resistance to depletion are critical for maintaining homeostasis.

Expert opinion: Treg emerge as a heterogeneous subset of immunosuppressive T cells, which usually, but not always, favor tumor progression. Treg are also engaged in non-immune activities that benefit the host. Therapeutic silencing of Treg in cancer requires a deeper understanding of Treg activities in human health and disease.     

Identification of human LDHC4 as a potential target for anticancer drug discovery

One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.