Drug Discovery Short-Circuits Cancer Growth

The discovery is reported in the Feb. 10, 2009 edition of "PLoS Biology," a journal published by the Public Library of Science.

We were trying to synthesize compounds that could help us learn more about how cancer exploits normal growth controls

Once we made it, though, we found it was even better than we thought it would be at blocking mTor signaling. It does everything that rapamycin does and more.

I hope the new drug can be used to treat a range of cancers

We will work with clinicians to test it against a number of types of cancer - colorectal, lung, breast, multiple myeloma and others. We want to first find the cancer that is most sensitive to it.

We are extremely excited about the potential of targeting mTOR in this way to treat a number of cancers, although we are aware that there are many hurdles to reaching the finish line

A new drug that blocks cancer's main source of growth has been created in the lab and proven effective in mice, scientists are reporting. It is now being readied for clinical trials in patients.

Far more potent than similar compounds already in clinical trial, the drug short-circuits the normal ability of cells to sense the need to grow and divide -- a signal that cancer cells exploit to spread in the body.

The scientists are working with clinicians to test the drug's effectiveness against a range of cancers that have proven difficult to treat.

The discovery is reported in the Feb. 10, 2009 edition of "PLoS Biology," a journal published by the Public Library of Science.

The research was led by scientists at the University of California, San Francisco (UCSF) and the UCSF Helen Diller Family Comprehensive Cancer Center. Senior author of the paper is Kevan Shokat, PhD, Howard Hughes Medical Investigator and professor of cellular and molecular pharmacology at UCSF.

Normally, in response to growth signals, a multi-protein unit in cells called mTOR integrates information about the cell's nutritional and energy needs, and prompts the cell to manufacture key proteins for cell growth. But cancer exploits this signal for its own growth.

Clinical trials are underway to stymie cancer proliferation by using a drug called rapamycin--marketed as Rapamune--or related compounds to block the growth signal cycle. The new drug greatly improves on rapamycin's effectiveness, the scientists reported. The name mTOR stands for "mammalian target of rapamycin."

Of serious concern to clinicians, rapamycin and related drugs can actually promote cancer at the same time they thwart it. This happens, the scientists found, because the drugs only partially block the cells response to a growth signal. When this happens, the drugs end up augmenting the growth signal itself because a feedback process in the cell kicks in to assure adequate nutrition. With the feedback system in play, cancer cells can regain needed nutrients and continue to proliferate.

The new drug totally blocks this feedback loop, said Shokat, who also is a faculty affiliate at the California Institute for Quantitative Biosciences, known as QB3, which is headquartered at UCSF.

"We were trying to synthesize compounds that could help us learn more about how cancer exploits normal growth controls," he explained. "Once we made it, though, we found it was even better than we thought it would be at blocking mTor signaling. It does everything that rapamycin does and more."

The new drug succeeds because there are two mTOR signal pathways, and it blocks both, the scientists found. Rapamycin only blocks one, and so allows the growth-signaling system to still function.

The scientists think that the drug's total blockage of the nutrient-sensitive mTOR and its feedback loop offer a major advance over rapamycin based drugs, which have been approved to treat only renal call carcinoma effectively.

"I hope the new drug can be used to treat a range of cancers," Shokat said. "We will work with clinicians to test it against a number of types of cancer - colorectal, lung, breast, multiple myeloma and others. We want to first find the cancer that is most sensitive to it."

The new compound has been dubbed a TORKinib because it inhibits the mTOR signal. UCSF has applied for a patent and licensed the patent to a startup biotech company, co-founded by Shokat and colleagues, to advance its use in clinical trials to treat cancer.

mTOR is known as a kinase, a ubiquitous type of signaling molecule - there are more than 500 different kinases in the body - that essentially switches proteins on or off. The switch is one of the most common interactions in the body. The kinase adds a small molecule known as a phosphate group to the protein, and that single action either turns on the protein or dampens its activity.

Like all signaling systems in the body, the one involving mTOR goes through many steps to accomplish its duties. The different steps form a cascade that can ramp the signal up or down, depending on the conditions of the cells or tissues. These kinase cascades are embedded within complicated feedback loops, such as the one activated by rapamycin.

Research on the mTOR pathway is of increasing interest to drug companies, Shokat said.

Since mTOR acts "upstream" and "downstream" of other key kinases that are found to cause cancer-- such as the much-studied kinases PI3K and Akt-- he thinks blocking it will short-circuit the many feedback loops cancer cells use to generate and maintain a growth signal.

"We are extremely excited about the potential of targeting mTOR in this way to treat a number of cancers, although we are aware that there are many hurdles to reaching the finish line," Shokat said.

Lead author on the paper is Morris E. Feldman, a graduate student in Shokat's lab.

Shokat's colleague, Davide Ruggero, PhD, who studies cancer's effect on protein synthesis, is also a coauthor. Ruggero is assistant professor of urology in the UCSF Helen Family Comprehensive Cancer Center.

Other coauthors are Beth Apsel, PhD, a graduate student in chemistry and chemical biology; and Zachary Knight, PhD, a postdoctoral scientist in Shokat's lab during the research project.

Also: Aino Uotila and Robbie Loewith in the department of molecular biology, University of Geneva.

The research was funded by the Howard Hughes Medical Institute.

The private company co-founded by Shokat is called Intellikine. He is the chairman of its scientific advisory board and holds stock options in the company.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

NOTE: PLoS Biology (www.plosbiology.org) requests that any reports mention the name of the open-access journal as the source for the study findings and provide a link to the freely-available text. The correct citation is PLoS Biology, not public library of science biology. The link to the published article in online reports is http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.1000038

All works published in PLoS Biology are open-access. Everything is immediately available--to read, download, redistribute, include in databases and otherwise use--without cost to anyone, anywhere, subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.

Comments

[research paper writing]

Well, I have been reading your blog posts daily and the reason I come on your blog frequently is its compelling content… Regards…

[Generic Viagra]

hello congratulation for this excellent blog

[Viagra Online]

Hey
igot a comment to make I hope the new drug can be used to treat a range of cancers," Shokat said. "We will work with clinicians to test it against a number of types of cancer - colorectal, lung, breast, multiple myeloma and others. We want to first find the cancer that is most sensitive to it do they really help against hiv?
John B. Barnhart

[cancer disease]

very nice post !!!!

[Health Care]

Hey guys I really like this post!!!! Keep going your good job!!!

[Viagra Online]

Hello there guys, so can you recomend some drug to treat cancer or some medicine? It would be great!

Regards,
Mike

[cialis canadian pharmacy]

Viagra relaxes the arterial wall, which leads to decreased pulmonary arterial resistance and pressure. Decreased pulmonary arterial resistance minimizes the workload of the right ventricle of the heart and in general improves symptoms of right sided heart failure.

[cancer syndrome]

Bowel Changes: If you experience constipation, diarrhea, blood in the stools, gas, thinner stools, or just a general overall change in bowel habits, see your doctor. These symptoms are most commonly associated with colon cancer, but are also related to other cancer types.

[Viagra Online]

An 87 year old man shows sy,toms of short breath. He has been smoking all his life and has history of chronic bronchitis. To treat the bronchitis he has been on antibiotics and bronchodilater inhaler. He returns to the doctors 1 week later having not improved at all and gets an x ray done which show opacity in his right lung. He also complains of a small growth on his ear which has started to bleed.He is now advised that the abnormal chest x ray is likely to be due to cancer.
The question now is why might it be important to confirm the diagnosis and confirm which type of cancer he has?

[compra viagra]

Very good blog! Thanks!

[Acheter Viagra]

You have a very good blog that the main thing a lot of interesting and useful!

[payday loan]

Interesting blog, the author thanks so much for the interesting explanation!
Keep it up, great success! Bloggy wish a lot of good posts!

[generic viagra online]

Great news I am very thankful to the scientist who has
invented new drug that blocks cancer's main source of growth has been created in the lab and proven effective in mice. Thanks a lot for sharing this news. I would like to share one thing with you I heard that canoderma is also one of the medicine which stop cancer cell.

is it right or wrong pleas give me more information about this medicinal plant.

.....Alex

[cheap chanel handbags]

The more you learn, the more you know, The more you know, the more you forget. The more you forget, the less you know. So why bother to learn.

[Suhagra]

If you have had a prostate biopsy that showed high-grade PIN, there is a greater chance that there are cancer cells in your prostate. For this reason, you will be watched carefully and may need another biopsy.

[Jordan Shoes]

But if muddle and jealousy win out, nuclear proliferation, not restraint, will be the norm—to enduring regret all round.

[coach bags outlet]

Two, I've never said I oppose tax cuts. I've said tax cuts are a less effective than direct federal spending in stimulating demand. I've said tax cuts traditionally advocated by conservatives result in the transfer of wealth from the many to the few, just as tax cuts for the poor and middle class result in the transfer of wealth from the few to the many. I've said that conservative advocacy of tax cuts is intended, as always, to benefit the wealthy few. The consevative notion that enriching the already wealthy is the means to put more money in the rest of our pockets is wrong, morally and in the practical sense.

Fundamentally, I believe the interests of modern conservativsm are fundamentally opposed to the interests of the Ameasdfffffrican people. I believe the behavior of the GOP during this current economic crisis -- itself a legacy of conservative government -- is the latest example of that behavior.

[enwoo]

Enwoo enjoys a leading position among the industry with its advanced technology and management concept after years of hardworking.
Electron beam welding machine China Enwoo
Electron beam,

[cialis online]

hey buddy,this is one of the best posts that I�ve ever seen; you may include some more ideas in the same theme. I�m still waiting for some interesting thoughts from your side in your next post.

[cialis side effects]

Thanks mate... just dropped by. Will look for BIKE STN when we get to Seattle. Still in Buenos Airies.

[chanel bags outlet]

You’re writing a non-fiction book about Islam in America…with your two teenagers? Are you crazy?” This was the standard response I received from various friends and relatives - but I’m grateful that it was the occasional comment of “Oh, that sounds interesting - I think you guys could do a great job!” that we listened to.