Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma

Introduction: The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials.

Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC.

Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.     

Emerging growth factor receptor antagonists for ovarian cancer treatment

Introduction: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy. EOC outcomes remain unsatisfactory despite aggressive surgical approach, disease chemo-sensitivity and recent introduction of agents targeting angiogenesis and tumour genome instability. Advances in EOC research have allowed for a tailored treatment approach and accelerated development of novel treatments strategies from bench to bed side, anticipated to improve patient outcomes.

Areas covered: Comprehensive review of growth factor receptor antagonists for EOC treatment currently in different stages of development was performed. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase and major conferences. We focused on agents that antagonize growth factors promoting sustained proliferative signaling, angiogenesis and evasion of immune destruction blocking the receptor or its stimulating factors.

Expert opinion: Receptor signaling has been well characterized for most cancer generating pathways. Growth receptor antagonists are represented by both high receptor affinity monoclonal antibodies as well as tyrosine kinase inhibitors; both are especially effective when a related predictive biomarker of response is identified. Therefore, along with the promising development of novel receptor antagonists or modulators in EOC treatment, targeting essential growth pathways in the tumour and associated microenvironment, is fundamental for biomarker discovery and towards achieving significant improvements in response.     

Calcitonin gene-related peptide receptor antagonists for the treatment of migraine: a patent review

Background: Migraine is a debilitating headache disorder which affects ～ 12% of the general population and is the cause of significant loss of productivity (i.e., lost time from work or school) for those afflicted. The current standard of care, the 5-HT_1B/1D agonists known as triptans, is contraindicated in patients with cardiovascular disease due to their inherent vasoconstrictive activity; thus, there is a need to develop an alternative therapy for the treatment of the disorder. Objective: This article reviews patent publications related to the use of small molecule calcitonin gene-related peptide (CGRP) receptor antagonists for the treatment of migraine that have appeared in the literature within the past decade. The commentary is supplemented by information presented in journal articles and focuses on the activity of several major pharmaceutical companies in the field. Conclusion: Two small molecule CGRP receptor antagonists, olcegepant and telcagepant, have been shown to be clinically efficacious in the treatment of migraine, and thus provide validation of this novel therapeutic mechanism.     

治疗尿路上皮癌新药:成纤维细胞生长因子受体酪氨酸激酶抑制剂erdafitinib

erdafitinib (Erd)为一种口服给药的泛成纤维细胞生长因子受体(FGFR)酪氨酸激酶抑制剂,由杨森制药公司生产,于2019年4月12日获美国食品和药物管理局加速批准用于治疗局部晚期或转移性尿路上皮癌成人患者。临床试验表明,FGFR突变的晚期或转移性尿路上皮癌患者接受Erd治疗可取得较好的疗效。Erd治疗相关的3级及以上不良事件包括口腔炎、手足综合征、角膜炎及高磷酸盐血症等,通过调整剂量,患者一般可耐受。     

Emerging growth factor receptor antagonists for the treatment of advanced melanoma

Introduction: Therapy for metastatic melanoma has undergone a rapid transformation over the past 5–10 years. Advances in immunotherapy with checkpoint inhibitors, including both anti-CTLA-4 and anti-PD-1/PD-L1, have led to durable responses in up to 50% of patients. As our understanding of the processes driving the transformation of melanocytes has improved, progress in targeted therapies has also continued.

Areas covered: Angiogenesis and the tumor’s dependence on an expanded vascular supply has been a target for novel therapies since the 1970’s, as this tissue is derived from endothelial cells that are genetically stable in adults. A phase II trial studying combined therapy with bevacizumab (an inhibitor of angiogenesis) and ipilimumab found promising results. Other agents such as sorafenib have not been as successful, failing to extend progression free or overall survival in clinical trials. In this paper other targeted growth factor inhibitors will also be discussed.

Expert opinion: Ultimately, melanoma may not be vulnerable solely to chemotherapy or targeted therapy, but may be efficaciously treated with immunotherapy due to its high mutational rate resulting in the expression of numerous neo-antigens. Therapies with combinations of agents including growth factor receptor and either other targeted therapies or immunotherapy may be a promising complimentary approach.     

Growth hormone secretagogue receptor antagonists

The patent claims peptidic/nonpeptidic inhibitors of the ghrelin receptor, the growth hormone secretagogue receptor (GHSR) 1A. Among these compounds, it was disclosed that the addition in some compounds of a GlyMetAla tripeptide at the N-terminus of the ghrelin peptide agonists converts them into ghrelin receptor antagonists. One of these peptides, among the few that have been studied in vivo, was shown to be able to reduce food intake and body weight gain in rats.     

表皮生长因子受体和血管内皮生长因子与环氧化酶2在食管癌组织中的表达及其意义

目的 研究食管癌中表皮生长因子受体(EGFR)、血管内皮生长因子(VEGF)、环氧化酶2(COX-2)的表达及其与肿瘤组织病理特征之间的关系.方法 应用免疫组化的方法分别检测94例食管癌组织和30例邻近正常食管黏膜中EGFR、VEGF蛋白、COX-2蛋白表达水平,并分析三者与肿瘤组织病理特征之间的关系.结果 EGFR、VEGF、COX-2在94例食管癌组织中阳性表达率分别为69.2％(65/94)、73.4％(69/94)、84.0％(79/94);而在30例正常食管黏膜中阳性表达率分别为13.3％(4/30)、13.3％(4/30)、3.3％(1/30),2组间表达差异有统计学意义(P＜0.01);且EGFR、VEGF、COX-2与淋巴结转移和TNM分期有关(P＜0.05).结论 EGFR、VEGF、COX-2在食管癌组织中显著表达,且可能参与肿瘤发生、发展,可作为预测食管癌生物学行为的重要参考指标.     

Novel triazole derivatives with improved receptor activity and bioavailability properties as ghrelin antagonists of growth hormone secretagogue receptors (WO2012035124): a patent evaluation

The patent claims triazole compounds as inhibitors of the ghrelin receptor, the growth-hormone secretagogue receptor (GHS-R1a). These compounds are potent GHS-R1a ligands with an improved in vitro antagonistic activity against ghrelin receptors of at least factor 3 compared with a representative compound disclosed in a previous patent, and are expected to possess, on the basis of the results of in vitro assays, improved safety and human oral bioavailability with respect to the lead.     

Keratinocyte growth factor receptor: a therapeutic target in solid cancer

Introduction: The treatment effects of advanced solid cancer are unsatisfactory, and novel therapeutic approaches are much needed. Keratinocyte growth factor receptor (KGFR) is a receptor tyrosine kinase that is primarily localized on epithelial cells. KGFR may play important roles in epithelial cell proliferation and differentiation, epithelial wound repair, embryonic development, immunity, tumor formation and development.

Areas covered: This review summarizes the expression, function and mechanism of KGFR in solid cancer, and analyzes its value for the cancer therapy. Furthermore, this study discusses the limitations of KGFR-based therapy, and envisages future developments in the clinical applications of KGFR.

Expert opinion: KGFR may function as an ideal therapeutic target for solid cancer. Continued basic investigation of KGFR-mediated pathways will push insight into the novel strategies of target therapy. More in vivo studies and clinical trials should be performed to promote the translational bridging of the latest research into clinical application.     

Andrographolide regulates epidermal growth factor receptor and transferrin receptor trafficking in epidermoid carcinoma (A-431) cells

Background and purpose:

Andrographolide is the active component of Andrographis paniculata, a plant used in both Indian and Chinese traditional medicine, and it has been demonstrated to induce apoptosis in different cancer cell lines. However, not much is known about how it may affect the key receptors implicated in cancer. Knowledge of how andrographolide affects receptor trafficking will allow us to better understand new mechanisms by which andrographolide may cause death in cancer cells.

Experimental approach:

We utilized the well-characterized epidermal growth factor receptor (EGFR) and transferrin receptor (TfR) expressed in epidermoid carcinoma (A-431) cells as a model to study the effect of andrographolide on receptor trafficking. Receptor distribution, the total number of receptors and surface receptors were analysed by immunofluorescence, Western blot as well as flow-cytometry respectively.

Key results:

Andrographolide treatment inhibited cell growth, down-regulated EGFRs on the cell surface and affected the degradation of EGFRs and TfRs. The EGFR was internalized into the cell at an increased rate, and accumulated in a compartment that co-localizes with the lysosomal-associated membrane protein in the late endosomes.

Conclusion and implications:

This study sheds light on how andrographolide may affect receptor trafficking by inhibiting receptor movement from the late endosomes to lysosomes. The down-regulation of EGFR from the cell surface also indicates a new mechanism by which andrographolide may induce cancer cell death.     

Urokinase receptor antagonists: novel agents for the treatment of cancer

The interaction between the urokinase receptor (uPAR) and its ligand urokinase (uPA) mediates phenomena such as tissue remodelling, chemotaxis, tumour invasion, dissemination, proliferation, and angiogenesis. The broad-spectrum of biological processes that the uPA/uPAR interaction plays a role in has led researchers to speculate that this interaction may be a useful molecular target for therapeutic intervention in several pathological conditions, particularly in the prevention and inhibition of the dissemination of cancer cells. In syngeneic and xenograft murine tumour models, in which metastasis is driven by the uPA/uPAR interaction, inhibition of primary tumour growth, metastasis and angiogenesis has been shown with several proteins acting as uPAR antagonists. Immunohistochemistry, in conjunction with prognostic studies, has implicated the uPA/uPAR interaction in the dissemination of tumours, such as malignant melanoma, colon cancer, non-small cell lung cancer (NSCLC) and stomach cancer, as well as breast and ovarian carcinomas. A potential inhibitor of the uPA/uPAR interaction should result in a significant increase in the disease-free interval and survival time following resection of the primary tumour in a clinical Minimal Residual Disease (MRD) setting. Low molecular weight uPAR antagonists should be orally active, and have few side-effects, excellent bioavailability, favourable pharmacokinetic properties and a long half-life. Furthermore, these compounds should be able to inhibit the dissemination of cancer cells without the need for targeted drug and vector delivery.     

Recent advances in novel atypical antipsychotic agents: potential therapeutic agents for the treatment of schizophrenia

There are now numerous drugs in advanced stages of clinical testing as potential antipsychotics. The major focus of development of antipsychotics is serotonin (5-HT)_2A antagonism, based on the hypothesis that this property is a critical facet of the pharmacology of clozapine and risperidone. These drugs have been found to exhibit relatively potent 5-HT_2A antagonism compared to their dopamine D₂ antagonistic effects. A large number of other antipsychotics with a similar 5-HT_2A/D₂ profile have been identified. In general, these compounds have minimal cataleptic effects at doses that block dopamine receptor agonist-induced behaviour, and have highly selective effects on mesolimbic dopamine neurones. Because they differ in relative potency as antagonists of a variety of other key receptors (e.g., D₁, D₂, D₃, D₄, D₅, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇, M₁ and α₁-adrenoceptors), it is likely that these compounds will have significantly different side effects and efficacy profiles (multi-acting receptor targeted agents [MARTA]). Some may be effective in treating negative symptoms and improving cognitive dysfunction. The potential usefulness of N-methyl-D-aspartate (NMDA) receptor agonists for schizophrenia is limited by possible epileptogenic or neurotoxic side effects. In this respect, ligands at strychnine-insensitive glycine binding sites of the NMDA receptor ion channel complex and metabotropic glutamate receptors (mGluR) are expected to have relatively few side effects. A novel sigma₁ receptor antagonist appears to be of particular interest based upon its ability to block the behavioural effects of phencyclidine (PCP). The close relationship between some neuropeptides, such as cholecystokinin and neurotensin, and dopaminergic systems in the brain is sufficient to sustain interest in these apart from the tantalising possibility of mediation by a neuropeptide system of some of the psychopharmacology of schizophrenia.     

枸杞多糖对肝癌细胞中VEGF表达的影响

目的：探讨枸杞多糖在肝癌细胞血管内皮生长因子（VEGF）表达调控中的作用。方法：体外培养高转移性人肝癌细胞株HCCLM3,分为对照组、枸杞多糖浓度5μmol/L,10μmol/L,15μmol/L等4组,处理6小时后,通过MTT法检测枸杞多糖对肝癌细胞株HCCLM3增殖的抑制程度,采用Westernbolt技术观察VEGF蛋白表达的变化,而后用20μmol/L,处理6小时后,采用免疫荧光技术观察VEGF蛋白表达的变化。结果：枸杞多糖可抑制肝癌细胞的增值,使肝癌细胞HCCLM3的VEGF蛋白的表达下降,这种抑制作用随着枸杞多糖浓度增大而增大（P〈0.01）,呈正相关关系,用免疫荧光技术观察VEGF蛋白表达的变化时,发现当LBP浓度为20μmol/L时,VEGF蛋白的表达完全被抑制。结论：枸杞多糖对体外培养的人肝癌细胞（HCCLM3）的生长有明显抑制作用,其作用机制与VEGF有很大的关系。     

Epidermal growth factor receptor (EGFR)-targeted therapies in mesothelioma

Introduction: Malignant mesothelioma (MM) is an aggressive malignancy arising from the mesothelial cells lining the pleura and other serosal membranes. It is associated with an extremely poor prognosis and has limited therapeutic options.

Areas covered: Epidermal growth factor receptor (EGFR) is known to be highly overexpressed in mesothelioma with reported EGFR overexpression between 44 to 97%. Given this, several anti-EGFR agents have been trialed in mesothelioma. In this review, we provide an overview of the current available data on anti-EGFR therapies in MM and future directions of investigation with these targeted agents in MM.

Expert opinion: While many anti-EGFR therapies have failed to show significant efficacy in the management of MM, the pathway is biologically active and its abrogation preclinically points toward it being a valid target. Toward targeting the pathway, many novel EGFR-based therapies are still being investigated. Current ongoing research of interest in MM include EGFR-targeted nanotechnology approach for drug delivery, antibodies targeting the extracellular EGFR and potentially anti-EGFR antibody drug conjugates.     

表皮生长因子受体在胸腺瘤中的表达

目的探讨表皮生长因子受体(EGFR)在胸腺瘤中的表达及其意义。方法免疫组化SP法检测63例患者胸腺瘤(胸腺瘤组)和20例胸腺增生(胸腺增生组)组织中EGFR的表达,分析胸腺瘤EGFR表达与其病理分级及临床分期的相关性。结果胸腺瘤组EGFR表达阳性率高于胸腺增生组(52.4%vs.20.0%)(P<0.05)。直径>6cm的胸腺瘤EGFR表达阳性率高于直径≤6cm的胸腺瘤(P<0.05)。胸腺瘤EGFR表达水平与病理分级及临床分期呈正相关。胸腺瘤的预后和临床分期相关。结论 EGFR可能在胸腺瘤的进展和预后中发挥重要作用。EGFR可能成为胸腺瘤新的治疗靶点和预后的标志物。     

The potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer

Importance of the field: Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents.

Areas covered in this review: Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors.

What the reader will gain: Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC.

Take home message: Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.     

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.     

血管内皮生长因子受体KDR在大肠癌发展中的研究

目的探讨血管内皮细胞生长因子(vascularendothelialgrowthfactor,VEGF)受体KDR和大肠癌间质新生血管与大肠癌预后的关系。方法应用免疫组化方法监测86例大肠癌组织VEGF及KDR蛋白表达和微血管密度(Mi鄄crovesseldensity,MVD),分析VEGF、KDR和MVD及其与大肠癌Dukes分期、淋巴结转移的关系。结果VEGF及KDR阳性者MVD值显著高于阴性者(P<0.01),VEGF、KDR表达和MVD与大肠癌Dukes分期(P<0.01)、淋巴结转移(P<0.01)密切相关。结论KDR及VEGF与大肠癌的血管生成密切相关;对大肠癌的复发和转移有促进作用。KDR、VEGF和MVD可作为反映大肠癌生物学行为的客观指标。     

Inhibitors targeting hepatocyte growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases

Amgen disclosed a series of 4-heteroaryloxy quinoline/quinazoline compounds as multiple kinase inhibitors, including hepatocyte growth factor (HGF) receptor tyrosine kinase c-Met and vascular endothelial growth factor (VEGF) receptor tyrosine kinase. These compounds are stated to have wide therapeutic applications for the treatment of a variety of cancers, hypertension, arteriosclerosis, myocardial infarction and rheumatoid arthritis.     

人大肠癌组织血管内皮生长因子C及血管内皮细胞生长因子受体3和P53蛋白的表达及临床意义

目的研究血管内皮生长因子（VEGF）C及血管内皮生长因子受体（VEGFR）3和P53蛋白在大肠癌组织中的表达及其与临床病理和预后的关系。方法对89例大肠癌患者手术切除标本的癌组织、癌旁组织及正常大肠组织采用免疫组织化学方法检测VEGF—C、VEGFR-3和P53蛋白表达情况,分析其变化规律。结果VEGF—C、VEGFRG和P53在大肠癌组织中的阳性表达高于癌旁组织及正常大肠组织,差异有统计学意义[癌组织：67．4％（60／89）、55．1％（49／89）和66．3％（59／89）,癌旁组织：22．6％（12／53）、20．8％（11／53）、11．3％（6／53）,正常组织：13．2％（7／53）、11．3％（6／53）、0,P〈0．05]。DukesB、C和D期的大肠癌P53阳性率[分别为：61．1％（11／18）、76．2％（16／21）、87．1％（27／31）]均高于DukesA期[26．3％（5／19）],差异均有统计学意义（均P〈0．05）;DukesD期高于DukesB期（P〈0．05）。大肠高分化腺癌P53阳性率低于中分化和低分化腺癌,差异均有统计学意义[45．7％（16／35）比78．3％（18／23）、81．1％（25／31）,P〈0．05],中分化腺癌与低分化腺癌P53阳性率的差异无统计学意义（P〉0．05）。89例大肠癌中60例有淋巴结转移,VEGF—C和VEGFR-3阳性率分别为76．7％（46例）和63．3％（38例）;无淋巴结转移者29例,VEGF-C和VEGFRG阳性率分别为48．3％（14例）和37．9％（11例）;有淋巴结转移患者中VEGF—C和VEGFR-3阳性率明显高于无淋巴结转移者（P〈0．05）。VEGF—C在黏膜下层、肌层和浆膜层的阳性率分别为50．0％（12／24）、67．6％（25／37）和82．1％（23／28）,黏膜下层阳性率与浆膜层的差异有统计学意义（P〈0．05）;VEGFR-3的阳性率分别为29．2％（7／24）、54．1％（20／37）和78．6％（22／28）,浆膜层阳性表达率高于黏膜下层和肌层,差异有统计学意义（P〈0．05）。在大肠低、中、高分化腺癌组织中VEGF—C阳性率分别为83．9％（26／31）、69．6％（16／23）、51．4％（18／35）,VEGFR-3阳性率分别为77．4％（24／31）、56．5％（13／23）、34．3％（12／35）,VEGF-C和VEGFR-3在低分化程度阳性表达率高于高分化程度者,差异有统计学意义（P〈0．05）。结论大癌组织中VEGF—C及VEGFR~、P53的表达可能是肿瘤发生、浸润、转移的重要因素,联合检测对判断肿瘤的恶性程度、转移、预后、评价复发具有重要的临床意义。