[gdpawel]

I've often wondered if the underlying science of Herceptin is sound? Her2 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 Her2 expression would correlate with Herceptin activity 100% of the time but it actually does so only about 20% of the time.

Monoclonal antibodies, which are usually water soluble and large, target extracellular (outside) components of these pathways. In contrast, small molecule inhibitors can enter cells, thereby blocking receptor signaling and interfering with downstream intracellular molecules.

Many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond. And optimal and reproducible Her2 testing continues to evade the diagnositcs of the disease. Numerous other genes, tumor, and patient factors contribute to the risk of the cancer coming back and the effectiveness of chemotherapy for breast cancer.

It could be vastly more beneficial to measure the net effect of all processes (systems) instead of just individual molecular targets. The cell is a system, an integrated, interacting network of genes, proteins, and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just one or a few targets (pathways/mechanisms).

What would be more beneficial is to test those pharmacodynamic endpoints with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry. Using a systems biology approach where compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.

Unlike a test for the presence of receptors to a specific antigen, which only "implies" dependence upon that antigen, a functional assay actually assesses the direct or indirect effect of the drug upon the whole cell, whether it is a tumor cell or an endothelial cell.

A "functional" assay doesn't just focus on Her2 or any one protein or mechanism. Whether it's Her2 alone (unlikely) or in combination with other proteins and other mechanical factors, the assay works by assessing the net effect of all those factors.

There are many pathways/mechanisms to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the individual trees.