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This is theoretical but I love the thought process.. this researcher thinks he knows why Avastin sometimes fails - and thinks he may have a way to block the failure. He did not try it yet - just thinking about it. We (the Musella Foundation) have funded 2 similiar projects - looking at drugs to add to Avastin to make it work better. The first one failed to show a benefit, but the second one is still ongoing. I think this concept is the way to a big breakthrough. We just need to find the right combination.
Future Oncol. 2012 Nov;8(11):1397-1400.
RTK inhibition: looking for the right pathways toward a miracle.
Xie Q, Vande Woude GF, Berens ME.
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49546, USA.
Abstract
Evaluation of: Lu KV, Chang JP, Parachoniak CA et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22(1), 21-35 (2012). In glioblastoma, a well-characterized angiogenic target is VEGF. Bevacizumab is a humanized monoclonal antibody that binds to VEGF and was developed to inhibit the VEGF signaling pathway. Based on promising results from clinical trials that bevacizumab can prolong progression-free survival in recurrent glioblastoma patients, the US FDA granted this drug accelerated approval for the treatment of recurrent or progressive glioblastoma; however, there has been no evidence that the overall median survival of patients is prolonged. More recently, Phase II clinical trials tested bevacizumab in combination with traditional radiation and/or temozolamide in newly diagnosed glioblastoma patients and again showed prolonged progression-free survival in these patients, but overall survival was not significantly changed. More importantly, there was evidence that tumors resistant to or recurring after bevacizumab treatment often showed a more aggressive phenotype. Due to the lack of effective post-bevacizumab therapies, it has been suggested that treatment with bevacizumab not be used until patients have developed late-stage recurrent tumors. Under these circumstances, there is a timely need to uncover the mechanisms of resistance to bevacizumab. In this article, Lu et al. reported a novel mechanism whereby VEGF negatively regulates tumor cell invasion by blocking MET phosphorylation in the MET/VEGFR2 complex. They showed that inhibiting the VEGF pathway results in MET activation in VEGF-knockout mouse models and in patients after bevacuzimub treatment, and that MET knockdown blocked the invasiveness of VEGF knockout tumors, suggesting that blocking the MET pathway can prevent post-bevacizumab treatment tumor recurrence, providing a strong rationale for using a combination of MET and VEGF receptor inhibitors to treat glioblastoma patients.
PMID: 23148613 [PubMed - as supplied by publisher]