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Feature

VEGF: Same molecular target....new approaches to cancer

Posted on: 15 May 06

Summary

DailyUpdates 15th May, 2006: Amongst the 50 or so papers and press releases featured today two focusing on VEGF jump out as being of especial interest. The first, a paper published by Stanford University, reports on the anti-cancer activity of an oncolytic virus in combination with gene therapy. The virus was engineered to selectively replicate in and kill cancer cells . The gene therapy encoded a soluble version of Flk1, one of the VEGF receptors. The two approaches together produce effective a
DailyUpdates 15th May, 2006: Amongst the 50 or so papers and press releases featured today two focusing on VEGF jump out as being of especial interest. The first, a paper published by Stanford University, reports on the anti-cancer activity of an oncolytic virus in combination with gene therapy. The virus was engineered to selectively replicate in and kill cancer cells . The gene therapy encoded a soluble version of Flk1, one of the VEGF receptors. The two approaches together produce effective anticancer activity and prompt the development of a single treatrment comprised of the virus further engineeered to produce soluble Flk1. The second publication is a press release from PTC Therapeutics who are similarly targeting VEGF, but instead have developed a small molecule orally active candidate able to prevent the prost-transcriptional activation of VEGF. Further details on these two publication plus the rest of today's information can be accessed here.

Oncolytic viruses and soluble VEGF receptor gene therapy combines to produce a highly novel and potentially effective approach to cancer:
VEGF exists in multiple isoforms. The original VEGF, now denoted VEGF-A, is regulated under the hypoxic conditions found within tumors, and binds to VEGFR-1 as well as -2. VEGFR-2 (also know as Flk1) is expressed on endothelial cells and its activation plays a pivotal role in endothelial cell differentiation and the formation of new vessels in adulthood.
Despite the therapeutic success of Avastin as a strategy for limiting tumor neovascularization and growth (see Innovative Cancer Therapies: Targeted therapy, a clinical and commercial revolution), as a class, the clinical efficacy of angiogenesis inhibitors has been rather limited. One of the potential problems of this approach is that VEGF is known to play a role in wound healing and also has a number of effects on cardiovascular homeostasis. The inhibition of such effects is likely to contribute to the gastrointestinal perforation and wound dehiscence (wound rupture) and hemoptysis (blood in the sputum) observed in some patients treated with Avastin and represent a class-related risk. Thus targeting Flk1 blockers to the tumor environment represents a promising approach. Today's featured journal article reports on data from Stanford demonstrating a novel approach to this challenge using oncolytic viruses (see Developments in oncolytic viruses - An emerging approach to cancer therapeutics). The Stanford group has found that an oncolytic virus engineered to selectively replicate in cancer cells lacking the G(1)-S cell cycle checkpoint enhanced the expression of an adenovirus encoding soluble Flk1 in tumors. These most exciting data, which underlies a licensing opportunity (contact Dr Steve Thorne for details), suggest a possible dual approach to the treatment of cancer whereby tumors may be destroyed both directly by the virus and indirectly through the interruption of their blood supply by interrupting VEGF signaling. Of even greater potential would be the development of a variant of the oncolytic virus engineered to encode soluble Flk1. The ability of such a virus to selectively replicate in, express soluble VEGF receptor and kill tumors would represent a truly targeted and hopefully efficacious approach.

PTC Therapeutics advance PTC299, a small molecule inhibitor of VEGF post-transcriptional modification:
While oncology therapies currently in development lean heavily on biologic approaches, the ability to avoid the drug delivery challenges associated with antibodies, antisense, gene therapy, or RNAi offers significant advantages. PTC Therapeutics are one company addressing this issue - the company's pipeline is focused on small orally active molecules that are able to selectively block the expression of target proteins. Continuing today's theme PTC have recently announced that it has commenced a Phase 1a clinical trial of PTC299. This candidate is an orally administered small-molecule compound designed to inhibit the production of VEGF in tumors; specifically the post-transcriptional control processes that regulate VEGF formation.

LeadDiscovery

Last updated on: 27/08/2010 11:40:18

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