Replies to post #8211 on Entremed (ENMD)

[C_Peptide]

There are some concerns about bevacizumab (Avastin) in GBM that go beyond the well-known toxicities. There is a concern that Avastin, given over time, may select for stem-like, non-angiogenic, less-proliferative, but highly invasive GBM cells. Much is being learned from post-Avastin radiological and pathological analysis of these tumors in this regard. Preliminarily, there appear to be multifocal recurrences with increases in neural stem cell markers.

The key to clinical benefit from these narrowly targeted drugs, as always, is rational combination. For example, invasive, neural stem-like GBM cells appear to live off the PI3K-AKT pathway and its downstream players, like NF-kB and mTOR. There are several AKT inhibitors in development, as well as curcumin (against IKK/IkB/NF-kB) and rapamycin (Sirolimus) against the aptly-named mammalian target of rapamycin (mTOR). For those cells that are angiogenic, 2-methoxyestradiol (Panzem) is an obvious natural partner of Avastin against HIF.

I would not criticize the FDA for approving Avastin without clear single-agent benefit. As always, the question is not necessarily whether single-agent Avastin shrinks GBM tumors or lengthens median survival, though those are good things. The question is whether it can be an effective addition to a multi-component regimen. The sooner the FDA learns to get out of the way of innovation in this area, the sooner people will start living longer. The FDA is about to lose one of their champions in the Senate to this disease. They've failed him and us.

One way to assure explosive innovation would be to allow drugs to be marketed after phase 1 or 2 for all cancers that have a prognosis of less than one year, with the requirement that appropriate data be collected - a sort of generalized Abigail Alliance.

Reference:
1) Sakariassen et al, Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16466-71. Epub 2006 Oct 20.
http://www.pnas.org/content/103/44/16466.full.pdf

2) Fischer et al, High-grade glioma before and after treatment with radiation and Avastin: initial observations.Neuro Oncol. 2008 Oct;10(5):647.
http://neuro-oncology.dukejournals.org/cgi/content/full/10/5/700?view=long&pmid=18697955

3) Meng Law Brain Tumors: Post Treatment Imaging Los Angeles Radiological Society, Midwinter Radiology Conference - January 24-25, 2009
http://www.larad.org/meetings/MidWinter/2009/MWR09/Law%20Post%20Treatment%20Brain%20Tumors.pdf

4) Abigail Alliance: http://abigail-alliance.org/

Best Regards,
C-Peptide