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Re: Researchers assess complete landscape of kinome expression in cancer
The decoding of the human genome in 2000, sparked a new era of tailored cancer medicine.
However, 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 ever.
As a result, patients with cancer are still being prescribed medicines on a trial-and-error basis or one-size-fits-all.
In an issue of Nature, scientists reported that surveying the human genome has found that many more gene mutations drive the development of cancer than previously thought.
Genomics are far too limited in scope to encompass the vagaries and complexities of human cancer biology.
The human genome project will give way to the human epigenome project which will give way to the human proteome and human kinome project. The next generation of tests will be biosystematic.
What is needed is to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells actually exposed to drugs and drug combinations of interest.
The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism?
The core understanding 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 of these pathways, it is important to examine the effects of drug combinations within the context of the cell.
Both genomics and proteomics can identify potential therapeutic targets, but these targets require the determination of cellular endpoints. You still need to measure the net effect of all processes, not just the individual molecular targets.
Dr. Robert Nagourney, at Rational Therapeutics, describes the term "Outlier" as a patient's response to a drug or combination that has not achieved statistically significant survival advantage in the general population. While outliers may connote strangeness or removal from the norm, in contemporary cancer therapies being removed from the norm can be a very good thing.
After all, a minority of cancer patients benefit durably from chemotherapy. Those patients fortunate enough to have long-term responses are the happy outliers who populate the scientific community's grab bag of anecdotes.
The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErB2), are promising targets for new treatments.
Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them.
Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown (in assays) to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.
They found another kinase called FGF4, and they found that adding a drug that blocks FGFR4, in combination with Herceptin, improved the anti-cancer effect. What happens if you have MEK, ERK, SHH, LKB1, PI3K, as well as FGFR? There are numerous mutations, insertions and deletions.
A gene mutation, deletion, translocation or amplification could disrupt many cell functions, leading to drug resistance, or could inactivate or damage the doors through which a drug enters a cell.
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