[gdpawel]

Uncovering the genetic differences that determine how a person responds to a drug, and developing tests, or biomarkers, for those differences, is proving more challenging than initially hoped. As a result, cancer patients are still being prescribed medicines on a trial-and-error basis, and adverse drug reactions remain a major cause of injury and hospitalizations.

In the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies, the pressure is so great that the companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

If you find one or more implicated genes in a patient’s tumor cells, how do you know if they are functional? Is the encoded protein actually produced? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single gene that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell?

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.