دانلود رایگان مقاله انگلیسی سیگنالینگ آنژیوژنیک و مقاومت دارویی تومور - الزویر 2018

Abstract

Angiogenesis research in the past two decades has contributed significantly towards understanding the molecular pathophysiology of cancer progression and inspired target-oriented research and pharma industry for the development of novel anti-angiogenic agents. Currently, over eleven drugs targeting angiogenesis have been approved by the FDA for the treatment of various malignancies. Of the registered anti-angiogenic clinical trials until the end of 2017 (ClinicalTrials.gov), over 47% were completed, 10% were terminated, 3% withdrawn, over 0.5% were suspended and only 4 trials have culminated in FDA approval for marketing. On the one hand, the clinical benefits of anti-angiogenic drugs prompted the development of novel anti-angiogenic agents. On the other hand, however, a plethora of recent studies demonstrated the emergence of tumor drug resistance towards currently used anti-angiogenic therapeutics. Series of preclinical and clinical studies have highlighted the enigma of drug resistance with functional bypass pathways, and identified compensatory or alternative angiogenic mechanisms assuring tumor growth in the midst of an antiangiogenic stress environment. In the present review the classical literature of such redundant angiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described. A strategic discourse regarding increasing tumor drug resistance and future modalities for anti-angiogenic therapy is also discussed in view of recent advances.

Conclusions

The clinical benefits of anti-angiogenic therapy have been appreciated both for malignant and nonmalignant human diseases. Initially, this therapy was appreciated on certain limited understandings; however, the previously forecasted straightforward assumptions in relation to its unbeatable efficacy and ‘resistant to drug resistance’ candidature turned out to be an illusion and now this therapeutic regimen is described as “the great discovery and greater complexity” owing to frequently emerging drug resistance phenomena. The impressive repertoire of tailored investigations carried out in the past two decades unraveled the fact that tumors employ multiple mechanisms of vascularization that compensate for the treatment of the currently used antiangiogenic agents. The discouraging performance of anti-angiogenic agents in the clinics fueled the revisitation of research in tumor angiogenesis. Several combinatorial approaches that target the compensatory angiogenic factors or pathways have been tested in series of preclinical and clinical settings and many novel approaches are evolving for circumventing tumor resistance to antiangiogenic agents. In the midst of toxicity and other negative concerns of the anti-angiogenic regimens, judicious and rationale efforts are needed while designing novel combinatorial treatment approaches, else the threat of ‘several cooks spoil the meal’ cannot be ruled out. The combinatorial approach of cancer therapy seems to be indispensable owing to a “Target-rich and lead-poor” imbalance, reflecting an insufficiency of chemists pursuing drug discovery of current anti-cancer drug development. Taking into consideration the emerging, intrinsic and adaptive tumor resistance, the inscrutable acts of compensatory angiogenic factors/pathways and their conspiracy in crosstalks, the dynamics and daunting tumor heterogeneity and the limitations of the currently used anti-angiogenic therapy, one needs to make a paradigm-shift from ‘one drug-one target’ to a ‘one drug-multi-targets’ approach for the development of novel anti-cancer leads. Our current understandings are mostly centered on VEGF per se which seems to be a key player in angiogenesis, while our knowledge of other molecular underpinnings conferring drug resistance is still evolving and is in its infancy. The current situation warrants deeper understandings of the molecular signatures that govern compensatory angiogenesis, which perhaps may lead to the development of novel anti-angiogenic agents that may target all types of tumor vessels and improve the therapeutic index of the anti-angiogenic modality. When we change the approach we may observe novel avenues, and we may hence achieve the target. New approaches of looking at the complex and dynamic nature of cancer may lead to the design of more effective and costcompromised anti-cancer therapies, which might reduce life-threatening malignancies and economic burden of cancer patients and make them realize that cancer is not a capital punishment.