Abstract
Prostate cancer remains one of the leading causes of cancer death in men around the world, regardless of intense research and development of novel therapies in the last 10 years. One of the new avenues that has been tested ⿿ inhibition of angiogenesis ⿿ has been disappointing so far in clinical studies in spite of strong evidence that determinants of angiogenesis (e.g. vascular endothelial growth factor) are strongly associated with disease progression. One of the reasons for these outcomes may be our poor understanding of the biology of angiogenesis in prostate cancer (and probably other cancers as well) resulting in inhibition of both detrimental and favourable molecules. We discuss here novel targeted and more specific approaches to inhibit angiogenesis in prostate cancer as well as a completely new therapeutic modality to do this ⿿ modulation of alternative splicing ⿿ that may be applicable to other molecules/biological processes as well.
Highlights
In the last 15 years, there has been an increase in the use of drugs that target angiogenesis in cancers
Despite the above-mentioned evidence for the importance of angiogenesis in Prostate cancer (PCa), trials with different anti-angiogenic inhibitors combined with the main treatment for advanced PCa (Docetaxel and Prednisone) have failed to this date to show an improvement in overall survival [12]
We have reported previously [36] that Serine-arginine protein kinase 1 (SRPK1) is a key regulator of the balance between two splice isoforms − VEGF165a, the canonical one that is proangiogenic and VEGF165b, resulting from an alternative 3 splice site in the terminal exon that has been shown in numerous studies to be anti-angiogenic [37,38]
Summary
In the last 15 years, there has been an increase in the use of drugs that target angiogenesis in cancers. The most well-known anti-angiogenic drug is Bevacizumab (Avastin), a humanized monoclonal antibody against vascular endothelial growth factor—A (VEGF-A) that is approved to be used in various cancers like colon cancer, non-small cell lung cancer or kidney cancer [1,2]. Following the initial excitement regarding the use of anti-angiogenics, they have not proven to induce a robust antitumoural treatment, with many clinical studies showing a modest progression-free survival and overall survival [3]. While there may be several explanations for this situation, it is more and more clear that we do not understand enough the vascular biology of tumours as well as many functional aspects of the molecules involved, missing the chance to design more targeted treatments. This article discusses the current state of using antiangiogenics in prostate cancer and our own work in finding a novel angle from which this problem may be solved
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