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Exelixis, Inc. Message Board

  • biglabowski99 biglabowski99 Mar 6, 2013 12:31 AM Flag

    Effects of Dual Targeting of Tumor Cells and Stroma

    Abstract

    Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In in vitro cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited in vitro. Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from in vitro experiments, in vivo blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be nee

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    • "Of importance, in contrast to the results from in vitro experiments, in vivo blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity."

      DUDE!! Great find! That really explains a lot concerning the mixed GBM results. What an interesting dynamic. Thanks for posting this great work out of Hungary. Search Dude's title to see and download the full paper.

      Sentiment: Strong Buy

    • So in layman's terms am I correct in saying that XL 184 kicks butt but that eventually the cancer cells escaped via vessel co option (not sure what that is). Wonder how much it increased OS i.e. how long is significantly increased?

      • 1 Reply to commonwealthinc
      • "eventually the cancer cells escaped via vessel co option (not sure what that is). Wonder how much it increased OS i.e. how long is significantly increased?"

        Biology is not a strong point for me, but I'll share my thoughts anyways. Cancer cells primarily obtain their nutrients from host blood supply. They use two processes to do this. They cop-opt existing vessels and propagate along the vasculature in a threadlike pattern or they induce the formation of new vessels (angiogenesis) and grow as a clump. One school of thought is that co-option generally precedes angiogenesis. Without angiogenesis a group of cells reaches a critical mass and growth is limited. With angiogenesis a tumor can grow at a rapid and sustained rate. In the presence of a VEGF inhibitor, angiogenesis is reversed resulting in a hypoxic environment. One observed result of this stimulus is a return to or a reemphasis on vessel co-option as a means of spread and growth resulting in a more diffuse and invasive tumor structure and behavior. Remember though, each cancer is unique and what may be seen as a "normal" or common response does not apply in all cases. Also tumor tissue is genetically unstable and as a result can respond to stimuli rapidly and unpredictably which is why treatment efficacy is mostly temporary as cancer tissue will respond in a Darwinian fashion in an almost lifelike attempt to survive.

 
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