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Latest research data strengthens the evidence for AstraZeneca's new anti-vascular approaches to beat cancer New research data for two of AstraZeneca's new anti-vascular cancer therapies are presented at this week's prestigious annual scientific meeting of the American Association for Cancer Research (AACR) held in Washington DC, USA. Pre-clinical studies in a wide variety of tumour types using either the anti-angiogenic compound ZD6474 or the vascular targeting agent ZD6126, alone, or in combination with other treatments, support the potential of anti-vascular therapies as future treatments for cancer. Cancers need to establish their own blood supply to obtain the nutrients and oxygen needed to be able to grow beyond 1-2mm in diameter. This process is called angiogenesis and is stimulated by factors such as Vascular Endothelial Growth Factor (VEGF), produced by the tumour cells themselves. VEGF acts on nearby existing blood vessels, binding to specific receptors on the vessel wall-lining cells (endothelial cells), stimulating the growth of new blood capillaries from the existing vascular system towards the tumour. Once linked to the body's blood stream, tumour growth can continue. Cancer cells may also break away from the main tumour and travel through the circulation to establish metastases in other parts of the body. ZD6474 blocks VEGF signalling through VEGF receptors, thus inhibiting a critical step in the process of new tumour blood vessel formation. In a preclinical study presented at AACR this week1, the effect of combining ZD6474 with radiotherapy was shown to be significantly greater than either agent alone in inhibiting the growth of non-small cell lung cancer xenografts (p < 0.02 and p < 0.0001). Furthermore, data suggested that when administered sequentially (following) to radiotherapy, ZD6474 was significantly more effective in inhibiting tumour growth than if administered concurrently. In another preclinical study2, ZD6474 inhibited angiogenesis stimulated by EGFR inhibitor-resistant NSCLC xenografts. ZD6474 also significantly inhibited the growth of a number of human CNS tumour xenografts (gliomas, medulloblastoma and ependymoma) including chemotherapy-resistant D245 glioma cells3. However, in another CNS tumour model4, although ZD6474 inhibited angiogenesis and the growth of Mel57-VEGF melanoma cells introduced into the blood supply to the brain (as a model of metastasis), overall survival was not affected because this cell line could use existing blood vessels to support its growth. In a pre-clinical model of advanced, metastatic pancreatic cancer5, ZD6474 inhibited primary tumour growth and reduced the number of metastases compared with control or gemcitabine. In addition, combining ZD6474 with gemcitabine provided increased anti-tumour activity than either drug alone. The results presented at AACR confirm previous findings that, in preclinical models, ZD6474 has significant activity against a diverse range of tumours6. Tumour blood vessels differ significantly from normal blood vessels. The endothelial cells which line the vessel walls retain the characteristics of immature, newly formed dividing cells and appear to depend heavily on a tubulin cytoskeleton to maintain their shape. ZD6126 disrupts this cytoskeleton causing the endothelial cells to change their shape from flat to round, resulting in damage to the blood vessel lining. This causes vessel congestion and consequent cessation of blood flow. The tumour is thus starved of oxygen and nutrients, and as a result, much of the tumour dies. ZD6126 has a distinct mode of action with the potential to augment established therapies and is being developed in a variety of solid tumours. ZD6126 was shown to significantly inhibit tumour growth and metastasis in a study presented today7 using a pre-clinical model of human gastric cancer. Following treatment with ZD6126, tumour growth was significantly inhibited (82% decrease) compared with control (p < 0.001). Furthermore, ZD6126 treatment led to a significant decrease in the incidence of peritoneal metastases compared with control (1/12 vs 10/12 cases, p < 0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group as well as a dramatic increase in tumour cell death (7.4-fold increase - p < 0.001), consistent with the vascular targeting activity of ZD6126. Other novel approaches AstraZeneca has a broad portfolio of novel cancer agents in early development for the potential treatment of a wide range of tumours. New pre-clinical data on several novel agents will be presented at the AACR meeting this week including: * AZD3409 - an oral treatment which prevents the activation of a number of growth promoting proteins and thus prevents cancer cells from dividing (proliferating). * An orally active compound known as a Src kinase inhibitor, which reduces the ability of cancer cells to invade normal tissues, preventing tumours from spreading. * CDK (cyclin dependent kinase) and Aurora kinase inhibitors, which interfere with crucial steps in cell division and inhibit the proliferation of cancer cells. AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over $17.8 billion and leading positions in sales of oncology, gastrointestinal, anaesthesia (including pain management), cardiovascular, central nervous system (CNS) and respiratory products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global and European) as well as the FTSE4Good Index. * ends * ZD6126 has been in-licensed by AstraZeneca from Angiogene References
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