HIF,hypoxia and the role of angiogenesis in non-small cell lung cancer

Importance of the field: The role of angiogenesis in the initiation and progression of NSCLC and the molecular alterations leading to the growth of tumor vasculature are areas of great interest and recent therapeutic success.

Areas covered in this review: VEGF and its receptors play critical roles in the development of tumor vasculature and can be targeted by agents such as bevacizumab in the treatment of NSCLC. Furthermore, tumor hypoxia and the expression of the hypoxia-inducible factor (HIF) family of proteins are also linked to poorer survival in these patients. Recent studies using genetically engineered mouse models expressing stabilized HIF validate the importance of HIF in the evolution of NSCLC and demonstrate genetically that HIF is involved in NSCLC.

What the reader will gain: An overview of the key pathways and mediators of tumor angiogenesis, their relevance to the pathogenesis of NSCLC, and an update on the current status of angiogenesis inhibitors in NSCLC.

Take home message: Angiogenesis is a key mediator of NSCLC progression. Several antiangiogenic strategies are in clinical use and under development. While candidate predictive biomarkers of response to antiangiogenic therapy exist, they await independent and prospective validation.     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development.

Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib. It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC.

Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

中药促血管新生的研究进展

近年来,缺血性疾病的发病率越来越高,尤其是心肌梗死等血管系统疾病,已成为人类死亡的重要原因之一。治疗性血管新生正逐渐成为该领域的研究热点,大量研究表明,某些中药提取物及其活性成分和中药的成方制剂在诱导血管新生方面具有很好的疗效。为进一步研究中药在血管新生中的促进作用,将近几年国内外的文献进行综述。     

Ligands to the integrin receptor αvβ3

The vitronectin receptor α_vβ₃ is a member of a family of membrane bound adhesion receptors that mediate cell–cell and cell–matrix interactions. This integrin recognises extracellular matrix proteins that express the tripeptide Arg-Gly-Asp (RGD). A number of patents and patent applications have recently appeared describing peptidic and non-peptidic α_vβ₃ antagonists as potential therapeutic agents for the treatment of osteoporosis, cancer, diabetic retinopathy and rheumatoid arthritis. This review covers those issued patents and published patent applications that disclose novel ligands to α_vβ₃ that have appeared since 1999.     

Gene therapy for coronary and peripheral artery disease

Background: Coronary and peripheral artery diseases are highly prevalent diseases, which are characterised by an unmet medical need in the more advanced stages of disease. These comprise the need for vessel regeneration using therapeutic angiogenic gene therapy as well as the prevention of restenosis post-angioplasty using local gene therapy. Both problems have been addressed by extensive research. Objective: Therefore, this article reviews the patents for therapeutic strategies using gene therapy for the prevention of restenosis and induction of therapeutic angiogenesis in the years 1994 – 2008. Methods: Current publications, websites and patents of a number of potentially suitable gene constructs are reviewed. Conclusion: Cardiovascular gene therapy, particularly in therapeutic angiogenesis, has quietly made its way to the first Phase III approval gene therapy trial. There are chances for more gene constructs to reach this stage.     

Patent focus on cancer chemotherapeutics. IV Angiogenesis agents: April 2001 - August 2001

Angiogenesis refers to the formation of capillary blood vessels from existing blood vessels: a process that is believed to be a key driver in cancer growth and metastasis. Angiogenesis inhibition represents an active area of cancer drug discovery, with several agents and approaches now entering late clinical development. This review summarises the key aspects of recent patent applications referring to cancer chemotherapy and cancer drug discovery that involve inhibition or modulation of angiogenesis. The scope includes applications that have been published between April and August 2001. The review covers the main mechanism-based approaches such as MMPIs, inhibitors of the growth factor signalling pathways, integrin antagonists and urokinase inhibitors.     

AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma

The therapy of renal cell carcinoma remains a challenge for medical oncologists and urologists. During the past 10 years, the molecular abnormalities occurring in various subtypes of renal cancer, such as clear cell renal carcinoma, have been well described. The genetic abnormalities found in clear cell tumours involve chromosome 3p and, additionally, hypermethylation of the von Hippel–Lindau (VHL) gene can be detected. The VHL protein is involved in the angiogenic cascade in non-hypoxic conditions, and the possible role of mutant or hypermethylated VHL protein in promoting angiogenesis is, therefore, of interest. The majority of patients with renal cell carcinoma who receive treatment, such as IL-2 and/or IFN, fail and develop progressive disease. Therapy is therefore inadequate and novel approaches, such as those inhibiting angiogenesis, are of interest. The agent AE-941 (Neovostat?; AEterna) was developed based on the observation that shark cartilage may contain biologically active inhibitors of angiogenesis. A variety of in vitro and in vivo activities of this preparation have been identified. At the molecular level, AE-941 appears to exhibit four different potential mechanisms of action: modulation of matrix proteases; inhibition of vascular endothelial growth factor binding to its receptor; induction of endothelial cell apoptosis; and stimulation of angiostatin production. The antitumour effects of AE-941 are seen in multiple murine models and involve not only effects on primary tumour growth but also on development of metastases. AE-941 is administered orally and has an excellent toxicity profile. Of interest are the findings in patients with renal cell carcinoma. Preliminary trials in this setting have suggested that responses to AE-941 occur and that patients receiving higher doses of this agent may have improved survival. Based on these preliminary data, a large, multi-institutional, randomised, Phase III trial of this agent has now been conducted in patients with metastatic clear cell carcinoma of the kidney. Over 300 patients have been entered into this trial, accrual is complete and results still remain preliminary. The clinical studies in a malignancy such as renal cell carcinoma will provide sentinel and potentially important observations on the clinical effectiveness of this agent.     

The role of growth factors in the pathogenesis of diabetic retinopathy

Diabetic retinopathy (DR) is the most severe of several ocular complications of diabetes. The earliest clinical signs of DR are microaneurysms and haemorrhages. Later signs include dilated, tortuous irregular veins and retinal non-profusion, leading to retinal ischaemia that ultimately results in neovascularisation. Diabetic macular oedema, which involves the breakdown of the blood–retinal barrier, also occurs and is responsible for a major part of vision loss, particularly in Type 2 diabetes. The pathogenesis of DR is very complex. Many biochemical mechanisms have been proposed as explanations for the development and progression of DR. Chronic hyperglycaemia leads to oxidative injury, microthrombi formation, cell adhesion molecule activation, leukostasis and cytokine activation. Next, ischaemia-mediated overexpression of growth factors and cytokines occurs. These factors include vascular endothelial growth factor, insulin-like growth factor-1, angiopoetin-1 and -2, stromal-derived factor-1, fibroblast growth factor-2 and tumour necrosis factor. Because of the complex interplay between these factors, targeting a single growth factor will be unlikely to result in therapeutic inhibition of angiogenesis. These growth factors no doubt act in synergy to mediate the steps of angiogenesis, including protease production, endothelial cell proliferation, migration and tube formation. This review attempts to provide an overview of perspectives regarding the pathogenesis of this disease. The focus, however, is on describing the unique features of selected relevant factors and how each growth factor may act in a synergistic manner with other factors.     

Novel targeted therapies in head and neck cancer

Introduction: Molecularly targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC.

Areas covered: Targeted agents for HNSCC expected to improve the effectiveness of current therapy including HER family, Src-family kinase, cell cycle, MET, AKT, HDAC, PARP, COX inhibitors and antiangiogenesis.

Expert opinion: Epidermal growth factor receptor inhibitors are established in HNSCC and the need now is to find biomarkers for sensitivity to better select patients. Moreover, other pathway inhibitors hold significant promise and are being tested in clinical trials. Angiogenesis inhibition is likely to yield only modest efficacy alone but may augment existing standards. Lastly, one clinical arena where targeted therapies may find secure purchase is in the adjuvant or prevention setting where minimal or preneoplastic disease can be affected by inhibition of a single or few targets.     

Prinomastat,a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases

Prinomastat (formerly AG3340, Agouron Pharmaceuticals, Inc.) is a potent, selective oral inhibitor of matrix metalloproteinase-2, -9, -13 and -14. This peculiar selectivity should represent an advantage for prinomastat in terms of efficacy/tolerability. The drug has been shown to inhibit tumour growth and angiogenesis in a variety of preclinical models, including cancer of colon, breast, lung and intriguingly in melanoma and glioma models. Moreover, the combination of prinomastat and several chemotherapeutic agents was shown to induce additive effects. The drug is currently in Phase III clinical trials for patients with non-small cell lung cancer in combination with paclitaxel and carboplatin, as well as in advanced hormone refractory prostate cancer in combination with mitoxantrone. The most common side effects are musculoskeletal pain and stiffness. These side effects generally cease with treatment interruption. Finally, considering the pathophysiology of MMPs, Agouron is exploring the utility of prinomastat in ophthalmology and dermatology.