Head And Neck Cancers: Common Genetic Alteration May Not Be Key To Effective Treatment
Although a large majority of head and neck cancers have a deregulation of the PI3K/AKT/mTOR pathway, data recently published in Cancer Research, a journal of the American Association for Cancer Research, indicated that deregulation of this pathway does not necessarily signify that the tumor is dependent on it for survival and progression.
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Since: Dec 05
#1 Jan 31, 2013
With several hundred compounds currently in development for the treatment of cancer, how will scientists and clinical oncologists match these drugs to patients in need? According to Dr. Robert A. Nagourney, only 8 percent of drugs entering Phase I ever make it through the highly unproductive Phase II and Phase III trial mechanisms to win FDA approval, with 50 percent failing at the Phase III final stage of development. He believes that ex vivo analysis of programmed cell death is a critical pathway and can serve to streamline drug development.
There are "real-time" insights that can only be achieved using human tissue in its native state. Ex vivo analyses offer these insights. The information moves us from the realm of prognostics to one of predictives, and it is after all, predictive measures is what patients are most desperately in need of today. We need the guidance of more global measures of human tumor biology, measures that incorporate the dynamic interplay between tumor cells, their stroma, vasculature and the inflammatory environment.
By expanding the application of ex vivo analyses to targeted therapies, they are able to explore new classes of compounds that function by inhibiting survival signals in cancer cells. Many signaling pathways have extracellular domains that function as cellular switches activating downstream phosphorylations following receptor ligation by proteins like EGF, amphiregulin and TGF alpha. These mitogen activated protein kinases (MAPK) induce additional cascades of phosphorylations ultimately signaling transcription factors at the level of DNA.
While these phenomena were originally thought to represent mitotic events, it is now recognized that most cells are not actively dividing, yet require all of these signalling pathway activations to remain alive. What was once described as growth factors are more likely better described as anti-death factors. It is evident that effective therapies induce cell death, not growth inhibition in the patient. This is why it is critical to apply lab analyses that measure cell death. As most of the signals for cell survival emanate from the extracellular environment, it is clear that cancer cells must be maintained in their native state to provide clinically relevant information.
The ex vivo analysis focuses upon the complexity of human tumors by measuring cell death, the end result of all cellular mechanisms of response and resistance acting in concert. By incorporating cell-cell, vascular, stromal and inflammatory elements into the tumor response assessment, the platform provides a robust surrogate for human tumor response. As Dr. Nagourney reiterates, while much of modern cancer research pursues the question of "Why" cancer arises, the clinical oncologist must confront the more practical question of "How" the best outcome can be achieved. Assay-directed therapy is truly personalized cancer care providing treatment unique to the individual.
Source: Nagourney, RA. Ex vivo programmed cell death and the prediction of response to chemotherapy. Current Treatment Options in Oncology 2006, 7:103-110
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