|Lyons iii, John|
Submitted to: Journal of Gastrointestinal Cancer
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/30/2011
Publication Date: 6/1/2012
Citation: Anthony, C.T., Bastidas, J.G., Thomson, J.L., Lyons III, J., Lewis, J.M., Schwimer, J.E., Casey, P., Abadi, J., Frey, D.J., Woltering, E.A. 2012. A study of pipeline drugs in neuroendocrine tumors. Journal of Gastrointestinal Cancer. 43(2):296-304. Interpretive Summary: Growth of new blood vessels (angiogenesis) is seen in diseases such as cancer, psoriasis, diabetic retinopathy, and rheumatoid arthritis. Halting this process is essential for slowing or stopping the growth of cancerous tumors, as well as stopping cancer’s spread to other parts of the body. In this study, we tested the use of a human tumor angiogenesis model (HTAM) for evaluating the effectiveness of five cancer drugs currently in clinical trials. We found that one drug was effective at inhibiting angiogenesis, two were effective at slowing or stopping growth once it had started, one was effective at inhibiting and stopping growth, while one had no effect on either inhibition or growth. To date, there have been no human tissue-based models of angiogenesis that can assess the relative effectiveness of pipeline drugs for pharmaceutical development. Our study shows that the HTAM has clear advantages for the evaluation of anti-angiogenic activity. First and foremost, the model utilizes only human tissue. Second, the assay is a rapid and economical method for screening drugs for antiangiogenic activity in a specific disease population. Third, the model can be used to guide the choice of treatment for individual patients. Lastly, with the exception of one drug, clinical trial outcomes for the drugs evaluated in this study were similar to those projected using the HTAM. Other tissue-specific adaptations of this technology will allow us to evaluate angiogenic responses in human skin, fat, heart muscle, retina, veins, arteries, parathyroids, and a host of other tissues.
Technical Abstract: Inhibition of neovessel development can stabilize tumor growth. A rapid in vitro method that can evaluate the effectiveness of anti-angiogenic drugs would aid in drug development. We tested a series of investigational agents to determine their ability to inhibit angiogenesis in our in vitro human angiogenesis model. A total of 74 neuroendocrine tumors were tested with five therapeutic agents for anti-angiogenic activity. Angiogenic responses were assessed visually, and the percent of tumor explants that developed an angiogenic response was determined. The extent of neovessel growth was rated using a validated semi-quantitative visual scale. Analysis of variance was used to compare treatment outcome results to control values for these angiogenic parameters. Vatalanib (2 x10-5 M) and patupilone (1x10– 8 M) were highly effective inhibitors of human tumor angiogenesis (mean overall angiogenic response for drug versus control 1.3 vs. 5.9 and 0.2 vs. 5.2, respectively), and were statistically significant at p<0.0001. Imatinib (2.5 x 10-6 M) and everolimus (1x 10-8 M) were also effective (mean overall angiogenic response for drug versus control 2.2 vs. 5.9 and 4.5 vs. 5.9, respectively), and these were also statistically significant at p<0.0001. Pasireotide (1x10-8M) had no effect on angiogenesis (mean overall angiogenic response for drug vs. control 5.5 versus 5.2). Significant differences in angiogenic response to test drugs were noted in this neuroendocrine patient population. In vitro screening of a large series of fresh human tumors may be a cost-effective way to select drugs for continued clinical development.