|
Targeted Agents The Short Term Future Of Cancer Therapeutics
I think that functional, cell-based tests would be vastly more informative on virtually all drugs than marker-based tests, including multi-gene tests.
Functional profiling assays can include anti-vascular drugs, such as Avastin, Sutent, Nexavar, Tarceva, Iressa, Tykerb, both as single agents and in combination with each other and with traditional cytotoxic agents and hormonal therapies.
It can provide more valuable information today than will be provided with marker and genomic based assays 10 years from now. It can simultaneously test for direct anti-tumor activity and for antivascular activity against the microvascular present within the three dimensional tumor cell clusters.
There has been unique cell culture research a new bio-marker assay for microvascular viability to identify potential responders to Avastin, Nexavar, Sutent, and other anti-angiogenic drugs by targeting not the cells themselves, but rather VEFG secreted by tumor cells, and to assess previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva and Iressa.
Prior to this development, it was thought that the lack of an intact tumor micro-vasculature would prevent in vitro drug studies in disaggregated tissues. However, it was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in this microvascular assay.
It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.
Photomicrographs in the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The assay measures the net effect of everything which goes on (Functional Tumor Cell Profiling). Are the cells ultimately killed, or aren't they?
I too believe that the short term future of cancer therapeutics is combinations of "targeted" agents, not only for breast cancer treatments, but for all solid cancers.
About the AngioRx Assay in breast cancer:
ER and PR tests in breast cancer, which detect only VEGF expression, or even overexpression, are valuable not because they measure expression of estrogen and progesterone but rather because they detect (and supposedly measure) the ER and PR receptors in the nucleus. The presence of positive IHC staining of such receptors in at least 10% of nuclei implies that the tumor is hormonally dependent and that, therefore, depriving the cells of the hormone will kill them or retards their growth.
Unlike a test for the presence of receptors to a specific antigen, which only "implies" dependence upon that antigen, an AngioRx assay is functional in that it actually assesses the direct or indirect effect of the drug upon the cell, whether it is a tumor cell or an endothelial cell. VEGF just happens to be one molecule which has been implicated in the process but there may be more.
If it were the only protein involved, then one would expect that VEGF expression would correlate with Avastin activity 100% of the time but it actually does so only about 20% of the time. The AngioRx assay doesn't just focus on VEGF or any one protein or mechanism. Whether it's VEGF alone (unlikely) or in combination with other proteins and other mechanical factors, the assay works by assessing the net effect of all those factors.
|
Linear Mode
