Progress of Molecular Targeted Therapies for Advanced Renal Cell Carcinoma (original) (raw)
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npj Precision Oncology
Clear cell renal cell carcinoma (ccRCC) is known for its highly vascular phenotype which is associated with elevated expression of vascular endothelial growth factor A (VEGF), also known as vascular permeability factor (VPF). Accordingly, VEGF has been an attractive target for antiangiogenic therapies in ccRCC. Two major strategies have hitherto been utilized for VEGF-targeted antiangiogenic therapies: targeting VEGF by antibodies, ligand traps or aptamers, and targeting the VEGF receptor signaling via antibodies or small-molecule tyrosine-kinase inhibitors (TKIs). In the present article we utilized two entirely different approaches: targeting mammalian target of rapamycin (mTOR) pathway that is known to be involved in VEGF synthesis, and disruption of VEGF/Neuroplin-1 (NRP1) axis that is known to activate proangiogenic and pro-tumorigenic signaling in endothelial and tumor cells, respectively. Everolimus (E) and a small-molecule inhibitor EG00229 (G) were used for the inhibition of...
Angiogenesis in cancer - general pathways and their therapeutic implications
Journal of B.U.ON. : official journal of the Balkan Union of Oncology
A vast amount of data shows that angiogenesis has a pivotal role in tumor growth, progression, invasiveness and metastasis. This is a complex process involving essential signaling pathways such as vascular endothelial growth factor (VEGF) and Notch in vasculature, as well as additional players such as bone marrow-derived endothelial progenitor cells. Primary tumor cells, stromal cells and cancer stem cells strongly influence vessel growth in tumors. Better understanding of the role of the different pathways and the crosstalk between different cells during tumor angiogenesis are crucial factors for developing more effective anticancer therapies. Targeting angiogenic factors from the VEGF family has become an effective strategy to inhibit tumor growth and so far the most successful results are seen in metastatic colorectal cancer (CRC), renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLL). Despite the initial enthusiasm, the angiogenesis inhibitors showed only moderate su...
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Investigational New Drugs, 2012
Several angiogenic mechanisms are involved in the pathology of renal cell carcinoma (RCC). Increasing knowledge of angiogenesis and the associated signalling pathways has led to the development of targeted antiangiogenic agents for the treatment of metastatic RCC and the introduction of these agents has significantly improved outcomes for these patients. This article provides an overview of the angiogenic mechanisms implicated in RCC, focusing on the main vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and mammalian target of rapamycin (mTOR) signalling pathways. Targeted antiangiogenic agents for the treatment of mRCC include receptor tyrosine kinase inhibitors (such as sunitinib, sorafenib, pazopanib, axitinib, cediranib and tivozanib), monoclonal antibodies (such as bevacizumab) and mTOR inhibitors (such as temsirolimus and everolimus). In this article, we consider the modes of action of these targeted agents and their differing target receptor profiles and we also evaluate how these correlate with their clinical efficacy and tolerability profiles.
Molecular and clinical aspects of targeting the VEGF pathway in tumors
Journal of oncology, 2010
Tumor angiogenesis is a complex process resulting from many signals from the tumor microenvironment. From preclinical animal models to clinical trials and practice, targeting tumors with antiangiogenic therapy remains an exciting area of study. Although many scientific advances have been achieved, leading to the development and clinical use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib, these therapies fall short of their anticipated benefits and leave many questions unanswered. Continued research into the complex signaling cascades that promote tumor angiogenesis may yield new targets or improve upon current therapies. In addition, the development of reliable tools to track tumor responses to antiangiogenic therapy will enable a better understanding of current therapeutic efficacy and may elucidate mechanisms to predict patient response to therapy.
Anti-angiogenesis in cancer therapeutics: the magic bullet
Journal of the Egyptian National Cancer Institute
Background Angiogenesis is the formation of new vascular networks from preexisting ones through the migration and proliferation of differentiated endothelial cells. Available evidence suggests that while antiangiogenic therapy could inhibit tumour growth, the response to these agents is not sustained. The aim of this paper was to review the evidence for anti-angiogenic therapy in cancer therapeutics and the mechanisms and management of tumour resistance to antiangiogenic agents. We also explored the latest advances and challenges in this field. Main body of the abstract MEDLINE and EMBASE databases were searched for publications on antiangiogenic therapy in cancer therapeutics from 1990 to 2020. Vascular endothelial growth factor (VEGF) is the master effector of the angiogenic response in cancers. Anti-angiogenic agents targeting the VEGF and HIF-α pathways include monoclonal antibodies to VEGF (e.g. bevacizumab), small-molecule tyrosine kinase inhibitors (TKIs) e.g. sorafenib, deco...
VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness
Theranostics, 2019
Hypoxic zones are common features of metastatic tumors. Due to inactivation of the von Hippel-Lindau gene (VHL), renal cell carcinomas (RCC) show constitutive stabilization of the alpha subunit of the hypoxia-inducible factor (HIF). Thus, RCC represents a model of chronic hypoxia. Development of the lymphatic network is dependent on vascular endothelial growth factor C (VEGFC) and lies at the front line of metastatic spreading. Here, we addressed the role of VEGFC in RCC aggressiveness and the regulation of its expression in hypoxia. Methods: Transcriptional and post transcriptional regulation of VEGFC expression was evaluated by qPCR and with reporter genes. The involvement of HIF was evaluated using a siRNA approach. Experimental RCC were performed with immuno-competent/deficient mice using human and mouse cells knocked-out for the VEGFC gene by a CRISPR/Cas9 method. The VEGFC axis was analyzed with an online available data base (TCGA) and using an independent cohort of patients. Results: Hypoxia induced VEGFC protein expression but down-regulated VEGFC gene transcription and mRNA stability. Increased proliferation, migration, over-activation of the AKT signaling pathway and enhanced expression of mesenchymal markers characterized VEGFC-/-cells. VEGFC-/-cells did not form tumors in immuno-deficient mice but developed aggressive tumors in immuno-competent mice. These tumors showed down-regulation of markers of activated lymphocytes and M1 macrophages, and up-regulation of M2 macrophages markers and programmed death ligand 1 (PDL1). Over-expression of lymphangiogenic genes including VEGFC was linked to increased disease-free and overall survival in patients with non-metastatic tumors, whereas its over-expression correlated with decreased progression-free and overall survival of metastatic patients. Conclusion: Our study revisited the admitted dogma linking VEGFC to tumor aggressiveness. We conclude that targeting VEGFC for therapy must be considered with caution.