Daily Archives: October 28, 2014

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Newswise PHILADELPHIA A new effort mapping 24-hr patterns of expression for thousands of genes in 12 different mouse organs five years in the making provides important clues about how the role of timing may influence the way drugs work in the body. A study detailing this veritable atlas of gene oscillations, never before described in mammals, is published this week in the Proceedings of the National Academy of Sciences. The research was led by John Hogenesch, PhD, professor of Systems Pharmacology and Translational Therapeutics, in the University of Pennsylvanias Perelman School of Medicine.

The 24-hour rhythms of gene and protein activity govern most biological processes in animal and plant life on Earth. The Penn team found that nearly half of all genes in the mouse genome oscillate on a 24-hour schedule somewhere in the mouse body.

The team didnt stop there. They also determined that the majority of best-selling drugs (based on U.S. sales data from Q1 2013 at Drugs.com) target proteins made from genes whose expression changes daily.

Timing is an important but underappreciated factor in drug efficacy. Many of these drugs have relatively short half lives in the body, notes Hogenesch. The team suggests that the intersection of atlas and drug data can predict which drugs might benefit from timed dosing the essential medicines that directly target the products of rhythmic genes and therefore proteins. This approach is the crux of a growing field called chronotherapy. Whats Under the Lamppost

The genome is under much more clock control than we once thought, explains Michael Hughes, PhD, a former postdoctoral researcher in the Hogenesch lab, who is now an assistant professor of Biology at the University of Missouri-St. Louis. Since only a few organs were studied previously, we were only looking under the lamppost. Now we have the most comprehensive survey to date.

Specifically, the team found that 43 percent of all protein-coding genes showed circadian rhythms in being transcribed into proteins somewhere in the mouse body. The liver was the most rhythmic, having more oscillating genes than any other organ studied. They also found that these oscillations largely occur in an organ-specific manner, with the expression of many oscillating genes peaking during rush hours of transcription (that is, the reading of DNA onto RNA before proteins are made by the cell) preceding dawn and dusk. The non-coding RNAs conserved between mouse and humans show a rhythmic expression in similar proportions as protein-coding genes, helping the researchers to focus on the non-coding genes most likely to be relevant in humans.

Drug targets are even more likely to be under clock control -- 56 of the 100 top-selling drugs and 119 of the 250 World Health Organizations list of essential medicines work on genes with circadian oscillation. Most of these drug targets were not known to be clock-regulated. Many metabolizing enzymes and transporters are too, says Hogenesch. Because this isnt appreciated, few of these drugs have been evaluated for time-of-day dependent efficacy, metabolism, or toxicity.

The study of drug timing has been going on for forty years and has had several successes like chemotherapeutics, short-acting statins, and low-dose aspirin. However, most of these studies were done by trial and error. Now we know which drug targets are under clock control and where and when they cycle in the body. This provides an opportunity for prospective chronotherapy, explains Hogenesch. Benefits of proper drug timing could include better compliance, improved efficacy, fewer drug:drug interactions, and ultimately, better outcomes at lower costs.

Read more:
First Atlas of Body Clock Gene Expression Informs Timing of Drug Delivery

The drug erlotinib is highly effective in treating advanced-stage lung cancer patients whose tumors have a particular gene change, but when the same drug is used for patients with early-stage tumors with the same gene change, they actually fare worse than if they took nothing. A study by researchers at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) and at Cincinnati Children's Hospital might show why.

Oncologists use erlotinib to treat lung cancers that have a mutation in a gene called epidermal growth factor receptor (EGFR). The gene mutation causes EGFR to run like it has a stuck accelerator, and erlotinib blocks the overactive molecule. The study shows that while erlotinib effectively causes tumors to shrink -- suggesting that the drug is helping -- this drug also increases the aggressiveness of the tumor so that growth is accelerated when therapy ends. This study finds that this is due to a secondary and previously unknown effect of inhibiting EGFR.

The researchers found that when erlotinib blocks EGFR, it activates a second signaling molecule called Notch3. Activation of that pathway leads to increased development of cancer stem cells among the surviving tumor cells and to accelerated tumor growth.

"Our findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer," says co-corresponding author David Carbone, MD, PhD, professor of medicine, Division of Medical Oncology at the OSUCCC -- James. "They also suggest that combining an EGFR inhibitor with a Notch inhibitor should overcome the effect."

The study was published in the journal Cancer Research.

Carbone, co-corresponding author Stacey Huppert, of Cincinnati Children's Hospital, and their colleagues conducted the study using several cell lines of non-small-cell lung cancer, the most common form of lung cancer, to learn if inhibiting EGFR enhances the activity of the Notch signaling pathway.

"We found that the activated, mutated EGFR directly inhibits Notch signaling, and that inhibiting EGFR with erlotinib removes this restraint and activates Notch signaling," says Carbone, who is the Barbara J. Bonner Chair in Lung Cancer Research. "It suggests that specific dual targeting might overcome this adverse effect."

The study's key technical findings include:

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The above story is based on materials provided by Ohio State University Wexner Medical Center. Note: Materials may be edited for content and length.

Excerpt from:
Why targeted drug doesn't benefit patients with early-stage lung cancer