The pathway is involved in angiogenesis, cell growth, differentiation, and survival. In addition, it is part of the PI3/AKT/mTOR pathway, which plays a key role in cancer, according to the December issue of GEN (www.genengnews).

"The good news about cancer is that a report last month from the National Cancer Institute indicated that there is a decline in both cancer incidence and death rates in the U.S.," says John Sterling, Editor in Chief of GEN . "But the American Cancer Society estimates that there will still be over half a million cancer deaths in America in 2008 so novel therapies remain critical."

Exelixis, for example, has developed several potential cancer compounds, two of which (XL147 and XL765) target the PI3-kinase pathway. Company scientists say they are studying the pathway because there are a number of feedback loops that emanate from m-TOR and downstream kinases that circle back to the top of the pathway and turn on AKT, an enzyme that drives tumor survival signals.

Investigators at the University of London are exploring the role of PI3-kinase isoforms in normal physiology and disease. A team led by Dr. Bart Vanhaesebroeck isolated the PI3-kinase genes in various mammals and developed models to better understand gene function.

Also covered in the GEN article is research taking place at Eli Lilly, the Multiple Myeloma Research Foundation, Semafore Pharmaceuticals, Calistoga Pharmaceuticals, and Harvard Medical School.

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"Why do organisms have reactions they don't use? Presumably so they have the flexibility to adapt to different conditions. One optimization situation will engage a certain set of reactions, while another situation will require a different set. It remains to be demonstrated, however, whether different conditions alone can justify the presence of all available reactions. The fact that this question is yet to be answered makes the entire problem even more attractive," Motter said.

Motter and his team used computational results to re-interpret and explain specific recent experimental results. First they gathered extensive experimental information on the metabolic networks of four different single-celled organisms: three bacteria ( H. pylori , S. aureus and E. coli ) and yeast ( S. cerevisiae ). Then the researchers built general quantitative models of the organisms that allowed them to predict cellular behavior. With those models, the researchers conducted mathematical analyses and computer experiments, simulating the organism and its metabolic function under optimal and non-optimal conditions.

They observed that for all four organisms in a typical non-optimal state, all utilizable reactions in the metabolic network, with a few exceptions, were active. In contrast, when the four organisms were growing at their optimal rate, each of them spontaneously silenced a large number of metabolic reactions. The number of active reactions, around 300, was the same for all four, despite differences in the size and complexity of each organism's genome and metabolic network. And the number stayed around 300 for a variety of quite different optimization scenarios.

"Mathematical abstraction of the problem suggests that spontaneous shutdown may not be limited to metabolic networks," said Nishikawa, who led the mathematical part of the effort. "What appears to be essential for this phenomenon is that a complex network that is under constraints and locally in balance is 'trying' to optimize its function. There are other important systems, like transportation networks, where the same type of analyses could be useful."

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