Combination Targeted Therapy
A targeted drug agent refers to an antibody (chemical structure) that is only supposed to interact with one type of molecule in the body. The idea that a targeted drug can interact with only one pathway and work only on one cellular pathway is unlikely. Molecular pathways inside cells have an incredible amount of cross-talk. So blocking one molecule precisely is like keeping one person from talking and expecting that the rumor won't spread just as fast.
Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR), vascular endothelial growth factor VEGF, or some other pathway. Although these targeted therapies are initially effective in a subset of patients, the drugs eventually stop working, and the tumors begin to grow again.
All the VEGF/EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one targeted drug is better or worse than some other drug which may target a specific pathway. There are differences. The drug has to get inside the cells in order to target anything.
The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few pathways. The cell "function" methodology measures the net effect of all processes within the cancer, acting with and against each other in real time, and it tests living cells actually exposed to drugs and drug combinations of interest.
The ultimate driver of the functional assay is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.
VEGF/EGFR-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the function of live cells. True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases are merely additive, where the whole equals the sum of its parts, and not synergistic.
The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.
Gregory D. Pawelski
Last edited by gdpawel : 03-19-2011 at 03:58 AM.