Researchers pinpoint a new enemy for tumor-suppressor P53

Author: staff

Researchers at The University of Texas M. D. Anderson Cancer Center have identified a protein that marks the tumor suppressor p53 for destruction, providing a potential new avenue for restoring p53 in cancer cells.

The new protein, called Trim24, feeds p53 to a protein-shredding complex known as the proteasome by attaching targeting molecules called ubiquitins to the tumor suppressor, the team reported this week in the Proceedings of the National Academy of Sciences Online Early Edition.

“Targeting Trim24 may offer a therapeutic approach to restoring p53 and killing tumor cells,” said senior author Michelle Barton, Ph.D., professor in M. D. Anderson’s Department of Biochemistry and Molecular Biology.

The discovery is based on an unusual approach to studying p53, which normally forces potentially cancerous cells to kill themselves and is shut down or depleted in most human cancers. Studies of the p53 protein and gene tend to focus on cancer cell lines or tumors, where the dysfunction already is established, Barton said. “We wanted to purify p53 from normal cells to better understand the mechanisms that regulate it.”

The team developed a strain of mice with a biochemical tag attached to every p53 protein expressed. After first assuring that the tagged p53 behaved like normal p53, the team then used the tag, or hook, to extract the protein. “We could then identify proteins that were attached to p53, interacting with it, through mass spectrometry,” Barton said.

They found Trim24, a protein previously unassociated with p53 that is highly expressed in tumors and is a target of two known oncogenes in distinct forms of leukemia and thyroid cancer.

Subsequent experiments showed that decreased levels of Trim24 led to increased levels of p53 expression in the cell nucleus, and increasing Trim24 expression reduced p53 levels. Loss of Trim24 expression in a breast cancer cell line caused spontaneous programmed cell death – apoptosis. A similar response was confirmed in human lung, colon and prostate cancer cells.

Treating cells with a proteasome inhibitor also led to increased p53 expression. Removing an important binding domain of Trim24 or depleting it completely both led to greatly reduced ubiquitin targeting of p53.

An analogous system in fruit flies showed that a simpler version of Trim24 in the flies plays a similar role regulating p53, demonstrating that the relationship is evolutionarily conserved.

1. Co-authors with Barton are first author Kendra Allton, Abhinav Jain, Ph.D., Hans-Martin Herz, Ph.D., Wen-Wei Tsai, Ph.D., Andres Bergmann, Ph.D., and Randy Johnson, Ph.D., all of M. D. Anderson’s Department of Biochemistry and Molecular Biology; and Sung Yun Jung, Ph.D., and Jun Qin, Ph.D., of the Department of Molecular and Cellular Biology at Baylor College of Medicine. Allton completed the paper as her master’s degree thesis for The University of Texas Graduate School of Biomedical Sciences, a joint program of M. D. Anderson and The University of Texas Health Science Center at Houston. Allton, Jain, Tsai, Johnson and Barton also are with M. D. Anderson’s Center for Stem Cell and Developmental Biology.

2. Funding for the project was provided by M. D. Anderson’s Kleberg Fund for Innovative Research, grants from the National Institutes of Health, CellCentric, Ltd., the Kadoorie Foundation, the Welch Foundation, the National Cancer Institute and the Laura and John Arnold Foundation Odyssey Fellowship (for Abhinav Jain).

3. About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

University of Texas M. D. Anderson Cancer Center

U.S. scientists say Lilly Erbitux cancer drug not worth price

Source: Bloomberg
Author: Lisa Rapaport

Eli Lilly & Co.’s tumor-fighter Erbitux doesn’t prolong lung cancer patients’ lives enough to justify its $80,000 cost, U.S. scientists said in commentary published today.

Erbitux added to other cancer drugs extends survival about 1.2 months more than chemotherapy alone, making the price too high for a “marginal benefit,” commentary in the Journal of the National Cancer Institute said. Erbitux, which Lilly markets with Bristol-Myers Squibb Co., generated $1.3 billion last year as treatment approved for other malignancies.

The high price of some of the newest cancer medicines are coming under scrutiny as part of an effort by lawmakers and health officials to rein in overall medical costs. President Barack Obama has set aside $1.1 billion in the U.S. economic stimulus bill to study the comparative effectiveness of treatments for cancer and other diseases.

“We must avoid the temptation to tell a patient that a new drug is available if there is little evidence that it will work better than established drugs that could be offered at a miniscule fraction of the cost,” wrote the commentators, Tito Fojo with the National Cancer Institute and Christine Grady at the National Institutes of Health.

Lilly, of Indianapolis, and marketing partner Bristol- Myers, of New York, withdrew an application to extend the Erbitux’s use to lung tumors in February after the Food and Drug Administration questioned differences in American and European versions of the treatment.

$10,000 a Month

The authors projected that Erbitux costs $80,000 based on a typical course of treatment for lung tumors, 18 weeks. If all 550,000 U.S. patients who die of cancer each year took 12 months of Erbitux, the total cost would be $440 billion, 100 times the annual budget of the National Cancer Institute, the authors said.

Bristol-Myers estimated Erbitux’s cost to be lower, at about $10,000 a month, according to company spokesman Brian Henry. The drug is approved to treat head, neck and colon cancer. A Lilly spokeswoman referred questions to Bristol-Myers.

“Erbitux isn’t indicated for all cancer patients, nor would all cancer patients for which Erbitux is indicated necessarily receive the medicine for one year,” Henry said in an e-mailed statement.

Lilly gained Erbitux in its $6.5 billion purchase of ImClone Systems Inc. last year. German drugmaker Merck KGaA markets Erbitux outside the U.S.

Cancer medicines are the best-selling and fastest-growing group of drugs in the U.S., and sales will surge 12 to 15 percent each year to top $75 billion by 2012, according to IMS Health Inc., a pharmaceutical industry research company in Norwalk, Connecticut.

About 220,000 people will be diagnosed with lung cancer in the U.S. this year, and 160,000 will die, according to the National Cancer Institute.

To contact the reporter on this story: Lisa Rapaport in New York

Oral Cancer Foundation praised for its social media efforts

Source: The Oral Cancer Foundation
Author: John Pohl

Social Media Guru Cites Organizations Using Social Media for Public Good

The Oral Cancer Foundation was recently praised by a leading Internet media website in an article discussing non-profit organizations that are effectively using Internet based social media for the public good.  Mashable, the world’s largest site focused exclusively on Web 2.0 and social media such as blogs, Facebook, YouTube and Twitter, touted the online efforts of several organizations in a recent story entitled, 5 Unique Social Good “Finds”.  Other organizations cited included The National Suicide Prevention Hotline and the ASPCA.

Founded in July 2005, Mashable is the most prolific source for information and reviews of new websites and services, publishes breaking news on new web developments, and provides social media resources and guides. Mashable’s audience includes early adopters and influencers, social media enthusiasts, entrepreneurs, large and small corporations, marketing, PR and advertising agencies, Web 2.0 aficionados, and technology journalists.

“We are flattered that our social media efforts have generated the attention and kind words of such a leading edge organization,” said Brian Hill, Founder and Executive Director of the Oral Cancer Foundation.  “We dedicate a great deal of time and focus to social media, which we believe allows us to connect with younger members of our audience in a way that is richer, more meaningful, and more relevant than we can achieve using more traditional media. This is particularly important to us, as individuals impacted by oral cancers have been increasingly young people, previously not thought to be at risk. Learning from Mashable’s expertise has helped us to reach out to this younger, technology savvy population, with information we hope will help them avoid risk factors for oral cancers, and understand that the perception that this is a disease that only smokers get, is incorrect.”

The blog post can be found at

The Oral Cancer Foundation’s social media pages can be found at the following addresses:


Blueberries: cancer-fighting flowers in disguise

Author: Julie LeBlanc


I can’t say I’ve been one for gardening. Or just liking plants, in general, for that matter. I’m the person that killed two rose bushes within two weeks while living in the school dormitories last year.

It’s things like this that make you contemplate becoming a super-villain.

Even I was amazed to find out that blueberries are not, in fact, berries at all. They’re not even fruit. claims they are “epigynous fruits” which, aside from having a name that could tongue-tie Mr. Ed, means that they are actually flowers. Tiny, blue, delicious flowers that go fabulously with vanilla ice cream.

Instead of parts like the stamen and petals falling off when the bud is ready to ripen, these organs stay attached and actually form alongside the plant ovary to create these little “false fruits.” Other veggies in this genre of plants include cucumbers, melons, bananas and figs.

Sneaky little buggers.

“The health properties of blueberries” or “Why you need another reason to eat these for dessert”:

Containing only about 40 calories in ½ a cup, blueberries have ascended to the superfood pantheon which includes, among other things, açai berries, red wine and plums. Like their cancer-fighting counterparts, blueberries contain high levels of anthocyanins and antioxidants, two phytonutrients which amp up the body’s immune system and to detoxify harmful chemicals. Some species even contain reservatrol, another phytonutrient that aids in fighting cancer and Alzheimer’s.  Red grapes and red wines are well-known for containing high amounts of reservatrol.

The growing season for blueberries typically peaks between May and June. If you’ve got a farm in your area, look into picking some on your own. You’ll never buy berries from the supermarket again. Bring your significant other, or kid sister, or your Grandma Maybelline. It’s more fun to pick berries together and you can pass the time gorging on the occasional tempting berry or pelting each other with the green, unripe ones.

Not that I condone of that sort of thing, mind you.

What this means for you: claims that the average adult should take in roughly two cups of fresh fruits a day. If possible, said fruits should range the colour spectrum. Darker fruits in reds and blues contain more antioxidants and, thus, your diet should include them as often as possible. Yes; believe it or not, the universe has colour-coded your diet. Does it get any easier? Not really. Does it get more delicious? You bet your cookie dough it does.

Cancer researchers “play it safe” due to grant system

Source: NYTimes
Author: Gina Kolata

Among the recent research grants awarded by the National Cancer Institute is one for a study asking whether people who are especially responsive to good-tasting food have the most difficulty staying on adiet. Another study will assess a Web-based program that encourages families to choose more healthful foods.

Many other grants involve biological research unlikely to break new ground. For example, one project asks whether a laboratory discovery involving colon cancer also applies to breast cancer. But even if it does apply, there is no treatment yet that exploits it.

The cancer institute has spent $105 billion since PresidentRichard M. Nixon declared war on the disease in 1971. TheAmerican Cancer Society, the largest private financer of cancer research, has spent about $3.4 billion on research grants since 1946.

Yet the fight against cancer is going slower than most had hoped, with only small changes in the death rate in the almost 40 years since it began.

One major impediment, scientists agree, is the grant system itself. It has become a sort of jobs program, a way to keep research laboratories going year after year with the understanding that the focus will be on small projects unlikely to take significant steps toward curing cancer.

“These grants are not silly, but they are only likely to produce incremental progress,” said Dr. Robert C. Young, chancellor at Fox Chase Cancer Center in Philadelphia and chairman of the Board of Scientific Advisors, an independent group that makes recommendations to the cancer institute.

The institute’s reviewers choose such projects because, with too little money to finance most proposals, they are timid about taking chances on ones that might not succeed. The problem, Dr. Young and others say, is that projects that could make a major difference in cancer prevention and treatment are all too often crowded out because they are too uncertain. In fact, it has become lore among cancer researchers that some game-changing discoveries involved projects deemed too unlikely to succeed and were therefore denied federal grants, forcing researchers to struggle mightily to continue.

Take one transformative drug, for breast cancer. It was based on a discovery by Dr. Dennis Slamon of the University of California, Los Angeles, that very aggressive breast cancers often have multiple copies of a particular protein, HER-2. That led to the development of herceptin, which blocks HER-2.

Now women with excess HER-2 proteins, who once had the worst breast cancer prognoses, have prognoses that are among the best. But when Dr. Slamon wanted to start this research, his grant was turned down. He succeeded only after the grateful wife of a patient helped him get money from Revlon, the cosmetics company.

Yet studies like the one on tasty food are financed. That study, which received a grant of $100,000 over two years, is based on the idea that since obesity is associated with an increased risk of cancer, understanding why people have trouble losing weight could lead to better weight control methods, which could lead to less obesity, which could lead to less cancer.

“It was the first grant I ever submitted, and it was funded on the first try,” said the principal investigator, Bradley M. Appelhans, an assistant professor of basic medical sciences and psychology at the University of Arizona. Dr. Appelhans said he realized it would hardly cure cancer, but hoped that “it will provide knowledge that will incrementally contribute to more effective cancer prevention strategies.”

Even top federal cancer officials say the system needs to be changed.

“We have a system that works over all pretty well, and is very good at ruling out bad things — we don’t fund bad research,” said Dr. Raynard S. Kington, acting director of theNational Institutes of Health, which includes the cancer institute. “But given that, we also recognize that the system probably provides disincentives to funding really transformative research.”

The private American Cancer Society follows a similarly cautious path. Last year, it awarded $124 million in new research grants, with some money coming from large donors but most from events like walkathons and memorial donations.

Dr. Otis W. Brawley, chief medical officer at the cancer society, said the whole cancer research effort remained too cautious.

“The problem in science is that the way you get ahead is by staying within narrow parameters and doing what other people are doing,” Dr. Brawley said. “No one wants to fund wild new ideas.”

He added that the problem of getting money for imaginative but chancy proposals had worsened in recent years. There are more scientists seeking grants — they surged into the field in the 1990s when the National Institutes of Health budget doubled before plunging again.

That makes many researchers, who need grants not just to run their labs but also sometimes to keep their faculty positions, even more cautious in the grant proposals they submit. And grant review committees become more wary about giving scarce money to speculative proposals.

Philanthropies, which helped some researchers try outside-the-box ideas, are now having financial problems. And advances in technology have made research more expensive.

“Scientists don’t like talking about it publicly,” because they worry that their remarks will be viewed as lashing out at the health institutes, which supports them, said Dr. Richard D. Klausner, a former director of the National Cancer Institute.

But, Dr. Klausner added: “There is no conversation that I have ever had about the grant system that doesn’t have an incredible sense of consensus that it is not working. That is a terrible wasted opportunity for the scientists, patients, the nation and the world.”

A Big Idea Without a Backer

For 25 years, Eileen K. Jaffe received federal grants to run her lab. As a senior scientist at the Fox Chase Cancer Center, with a long list of published papers in prestigious journals, she is a respected, established researcher.

Then Dr. Jaffe stumbled upon results that went against textbook explanations, suggesting that it might be possible to find an entirely new class of drugs that could disable proteins that fuel cancer cells. Now she wants to find chemicals that might be developed into such drugs.

But her grant proposal was rejected out of hand by the institutes of health, not even discussed by a review panel. She had no preliminary data showing that the idea was likely to work, something reviewers always want to see, and the idea was just too unprecedented.

Dr. Jaffe epitomizes the scientist who realizes that if she were to single-mindedly pursue her unorthodox idea, her “career may be ruined in the process,” in the words of Dr. Brawley of the American Cancer Society.

Dr. Jaffe is just conceiving her project; it is much to soon to know whether it will result in a revolutionary drug. And even if she does find potential new drugs, it is not clear that they will be effective. Most new ideas are difficult to prove, and most potential new drugs fail.

So Dr. Jaffe was not entirely surprised when her grant application to look for such cancer drugs was summarily rejected.

“They said I don’t have preliminary results,” she said. “Of course I don’t. I need the grant money to get them.”

Dr. Young, chancellor at Fox Chase, said Dr. Jaffe’s situation showed why people with bold new ideas often just give up.

“You can’t prove it will work in advance,” he said. “If you could, it wouldn’t be a high-risk idea.”

It is a long haul, Dr. Jaffe knows. And she has already had to downsize her lab. But, she said, she will persist.

Angels Outside Government

At the Dana-Farber Cancer Institute in Boston, Dr. Ewa T. Sicinska knew she would have a similar problem with her research. She wanted to grow human cancers in mice. Unlike Dr. Jaffe, though, Dr. Sicinska did not even apply for government money.

It is not that the project was unimportant.

“Rather than have to start a human clinical trial to test new drugs, we want to test them first in mice with real human tumors,” said Dr. George D. Demetri, who leads the research group supporting Dr. Sicinska.

Researchers have studied mouse cancers but, they acknowledge, they are just not the same as human cancers — they are much easier to treat, and drugs that cure mice often do nothing in people. So, over the years, scientists have tried to implant human cancer cells in mice, but with little success.

“Everyone told us that if you take tumors out of patients and put them in mice, they don’t grow,” Dr. Demetri said. The tumor cells usually were put in a plastic dish before being implanted in mice. “We said — wait a minute. The cells are not growing in the plastic dish. They probably are dying. What if we bypass the dish?’”

With that idea in mind, Dr. Demetri, convinced it was too speculative to get federal money, tapped an unusual source, the Ludwig Fund. Endowed by Daniel K. Ludwig, one of the world’s richest men in the 1960s and 1970s, the fund supports unfettered cancer research at six medical centers in the United States, including Dana-Farber, to be used at the institutes’ discretion. That put Dr. Sicinska in a very different position from that of Dr. Jaffe. She could try something chancy without a grant.

Dr. Sicinska used a quarter of a million dollars of Ludwig money for this project, buying mice without immune systems, which meant they could not reject human tumors, and housing them in a germ-free basement lab. She spent months learning to implant tumors in the mice and enlisted geneticists to study the implanted tumors, making sure they did not mutate beyond recognition.

She spends her days in the lab, using a miniature ultrasound machine to scan the mice, hairless creatures with prominent ears. Four types of sarcomas — cancers of fat, muscle or bone — are growing in them and look genetically identical to the tumors removed from patients.

Dr. Elias A. Zerhouni, former director of the National Institutes of Health, said he was not sure that a grant for the project would have been turned down. The N.I.H., he said, does finance research on mouse models for human cancer.

But Dr. Demetri said he did not apply “because we have lots of experience in what’s fundable.” His mouse work, he said, is exploratory, and he cannot predict what he will find or when. He certainly could not lay out a road map of what he would do and promise results in a few years.

Studies With a Different Goal

Researchers like Dr. Appelhans, who is studying weight control and tasty foods, do not expect to change the outlook for cancer patients anytime soon. But, they say, that does not mean their work is unimportant.

Dr. Appelhans will study 85 overweight or obese women, measuring how much the tastes and textures of food drive their eating. Then they will be given a weight loss diet and nutritional counseling. Dr. Appelhans will ask whether those who are most tempted by the tastes and textures also have the most trouble following the diet.

As for the grant to assess a Web-based program to improve food choices, it is predicated on studies indicating that what people eat in childhood and adolescence may have an impact on cancer risk in middle and old age, said the grant recipient, Karen Weber Cullen, associate professor ofpediatrics at Baylor College of Medicine. Some studies have found that people who reported having eaten fruits and vegetables when they were younger and maintaining a healthy weight were less likely to have cancer.

Of course, it would not be feasible to follow participants for 30 or 40 years to see if their cancer risk was altered, Dr. Cullen noted. But, she added, “we try to achieve improvements in diet and physical activity behaviors that become permanent and will make a difference in later years.”

In the study asking whether a molecular pathway that spurs the growth of colon cancer cells also encourages the growth of breast cancer cells, the principal investigator ultimately wants to find a safe drug to prevent breast cancer. She received a typical-size grant of a little more than $1 million for the five-year study.

The plan, said the investigator, Louise R. Howe, an associate research professor at Weill Cornell Medical College, is first to confirm her hypothesis about the pathway in breast cancer cells. But even if it is correct, the much harder research would lie ahead because no drugs exist to block the pathway, and even if they did, there are no assurances that they would be safe.

Dr. Howe said she hoped that she would find such drugs, or that companies would. Then she wants to develop a way to selectively deliver the drugs to precancerous breast cells. If it all works and the treatment is safe, women with precancerous conditions could avoid developing cancer.

Dr. Howe has reviewed grants for the cancer institute herself, she said, and realizes that, among other things, those that get financed must have “a novel hypothesis that is credible based on what we know already.”

Trying to Change the System

The National Institutes of Health has started “pilot experiments” to see if there is a better way of getting financing for innovative projects, its acting director, Dr. Kington, said.

They include “pioneer awards,” begun in 2004 for “ideas that have the potential for high impact but may be too novel, span too diverse a range of disciplines or be at a stage too early to fare well in the traditional peer review process.” But only 3 percent to 5 percent of the applicants get funded. Now the institutes have decided to set aside up to $25 million for “transformative R01 grants,” described as “proposing exceptionally innovative, high risk, original and/or unconventional research with the potential to create or overturn fundamental paradigms.”

About 700 proposals have come in, but only a small number are expected to be financed, according to Dr. Keith R. Yamamoto, a molecular biologist and executive vice dean of the school of medicine at the University of California, San Francisco, and co-chairman of the committee that reviewed the proposals last week.

“From reading the applications so far, there are really some fantastic things,” Dr. Yamamoto said.

There also is new money from the federal economic stimulus package passed by Congress, which gives the National Institutes of Health $200 million for “challenge grants” lasting two years or less.

But the N.I.H. has received about 21,000 applications for 200 challenge grants, and researchers who have applied concede there is not much hope.

“I did submit one of these challenge grants recently, like the rest of the lemmings,” said Dr. Chi Dang, professor of medicine, cell biology, oncology and pathology at the Johns Hopkins University School of Medicine. But, he added, “there are many, many more applications than slots.”

Some experienced scientists have found a way to offset the problem somewhat. They do chancy experiments by siphoning money from their grants.

“In a way, the system is encrypted,” Dr. Yamamoto said, allowing those in the know to wink and do their own thing on the side.

Great discoveries have been made with N.I.H. financing without manipulating the system, Dr. Klausner said.

“But,” he added, “I actually believe that by and large it is despite, rather than because of, the review system.”

New cancer treatment shows promise in testing

Author: Nicholas Wade

A new method of attacking cancer cells, developed by researchers in Australia, has proved surprisingly effective in animal tests.

The method is intended to sidestep two major drawbacks of standard chemotherapy: the treatment’s lack of specificity and the fact that cancer cells often develop resistance.

In one striking use of the method, reported online Sunday in Nature Biotechnology, mice were implanted with a human uterine tumor that was highly aggressive and resistant to many drugs. All of the treated animals were free of tumor cells after 70 days of treatment; the untreated mice were dead after a month.

The lead researchers, Jennifer A. MacDiarmid and Himanshu Brahmbhatt, say their company, EnGeneIC of suburban Sydney, has achieved a similar outcome in dogs with advanced brain cancer. “We have been treating more than 20 dogs and have spectacular results,” Dr. Brahmbhatt said. “Pretty much every dog has responded and some are in remission.” These experiments have not yet been published.

Cancer experts who were not involved with the research say that the new method is of great interest, but that many treatments that work well in laboratory mice turn out to be ineffective in patients.

Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, called the method “a creative and promising line of research,” but noted the general odds against success.

“Unfortunately our track record shows that far less than 1 percent of our promising approaches actually make the grade in patients,” he said.

The EnGeneIC researchers said they had conducted successful safety tests in a large number of monkeys and will start safety trials in patients with all kinds of solid tumors in three Melbourne hospitals next month. They said they had discussed licensing their technology with large pharmaceutical companies and others.

Stephen H. Friend, head of cancer research at Merck until early this year, said he had been following EnGeneIC’s work for more than a year, and praised the company for trying a method that others had written off without trying.

“I consider the approach is remarkable and more than intriguing,” said Dr. Friend, who is now at Sage Bionetworks in Seattle. But he warned that cancer cells are very versatile and can “evolve around any pressure you put on them,” so that no single approach is likely to afford a cure.

The EnGeneIC method uses minicells to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumors resistant to toxins.

The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells.

No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80 percent of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor.

The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever cargo the minicells carry.

What also helps direct the minicells toward tumors, the EnGeneIC researchers say, is that the blood vessels around tumors tend to be leaky, and the minicells are small enough to leave the circulation at the leak sites.

The minicells do not seem to be highly provocative to the immune system, even though they are made of bacterial cell membrane. The reason may be that the provocative parts of the membrane are masked by antibodies with which the minicells are coated, Dr. Brahmbhatt said.

In the experiments reported Sunday, EnGeneIC treated cancer-ridden mice with two waves of minicells. The first wave contained an agent that suppressed an important gene for toxin resistance. The gene makes a protein that pumps toxin out of cells, and is a major cause of the resistance that tumors often develop toward chemotherapeutic agents.

After the toxin-expelling gene had been knocked down in the tumor cells, the EnGeneIC researchers injected a second wave of minicells, each loaded with half a million molecules of doxorubicin, a toxin used in chemotherapy.

The two-wave treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether.

“The technology looks very good,” said Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island. It provides a general method of delivering chemicals to tumors, he said, especially those that are usually degraded in the bloodstream.

Dr. Stillman, who has advised EnGeneIC and is a co-author of its report, said the minicells could be particularly helpful for delivering silencing RNAs, a promising new class of drug that is rapidly destroyed in the body unless protected.

Though the minicells can be varied to attack different receptors and to import any gene of interest on elements called plasmids, the method still has several hurdles to jump.

Robert M. Hoffman, of the University of California, San Diego, said that the minicells were “good strategy and good science” but that the researchers had implanted the human tumors under the mice’s skin, a position from which they do not usually spread through the body. So the experiments do not answer the question of whether minicells can attack metastasized cancer, he said.

Dr. Hoffman, who is president of AntiCancer Inc., has obtained striking remissions with metastasized cancers in mice by treating them with salmonella bacteria. The bacteria have been engineered to lack two kinds of amino acid, which makes them unable to grow in normal tissues. In cancer cells, however, where the missing amino acids are in more plentiful supply, the bacteria are highly virulent and kill the cells.

The idea of treating cancer with bacteria goes back to the 19th century, when physicians noticed that cancer patients who became infected sometimes enjoyed a remission. Both Dr. Hoffman’s method and the minicells, in different ways, revisit these old observations. Both may face special scrutiny from regulators concerned at the prospect of putting bacteria into people.

Dr. Hoffman said his studies with the defective bacteria were going well and that his company might be ready to start a safety test in patients in two years if it can find a good partner. Use of bacteria in cancer “is an old story but there is definitely a lot of promise there,” he said.

Oral health suffers in down economy

Author: Katie Anderson

As layoffs and furlough days continue to eat away at pocket books, local dentists say they’ve noticed a decrease in the area’s appetite for oral health care.

Dental health care experts are concerned.

“I think a lot of preventative care has become affected by people’s economic situations,” said Randall Lawson, a doctor of dental surgery and owner of College Avenue Dental in Jacksonville.

“I have two hygienists that do preventive care, cleanings, et cetera, and they have seemed to become less busy as of late.”

He said although the summer time is busier due to children being out of school, his office has seen more cancellations than usual.

William Weller, a doctor of dental surgery with an office on West Lafayette Avenue, has seen a similar trend at his practice.

“Whenever we have a downturn or anything like this there are several things that happen,” Dr. Weller said. “Probably the most significant is people looking for ways to cut corners — looking to delay or postpone their six-month checkups. It’s kind of unfortunate because yes, they’ll save 100 bucks on a checkup but they’ll pay later.”

Dr. Weller said the people he and his fellow dentists treat in the area, for the most part, “are really honest people.”

“If they don’t have the money they don’t want to come in and incur a debt,” he explained. “Which is laudable to some degree, but something that we worry about.”

They worry for many reasons.

One, most patients end up paying more when they do get back in the chair because problems like cavities, gum diseases and cracked teeth go undetected and get worse.

Patients are also skipping an oral cancer screening when they skip a check up, Mr. Weller said. “It’s rare, but serious.”

Dentists also worry from a business perspective. When the economy does turn around, the their offices will face a pile up of patients who avoided care.

Elective dental work has also apparently been affected by the economic slowdown.

“People seem to be delaying elective sorts of things, cosmetic services, whitening procedures,” Dr. Lawson said. “Currently it’s just being delayed but eventually it might end up being abandoned.”

Dr. Weller said he has seen patients cancel appointments to have their teeth capped.

Another indicator of how bad the economic situation is, Dr. Weller added, is the number of patients deciding to have teeth removed rather than treated and saved.

“Root canals and crowns can cost $1,000 to $2,000,” he said. “When insurance first began to become popular, the maximum annual coverage was about $1,000 to $1,500. Today it’s still $1,000 to $1,500. Now, you can easily reach that with one tooth.”

Vanderbilt-Ingram Cancer Center’s research efforts highlighted at annual cancer conference

Author: Dagny Stuart

A new drug which targets a genetic mutation found in more than 50 percent of melanoma cases, 10 percent to 15 percent of colorectal tumors and 8 percent of other solid tumors, caused tumor shrinkage and extended progression-free survival among patients during a recent Phase 1 clinical trial.

Igor Puzanov, M.D., assistant professor of Medicine, and Jeffrey Sosman, M.D., Ingram Professor of Cancer Research, led Vanderbilt-Ingram Cancer Center’s participation in the multi-center study. Puzanov delivered the initial findings during a poster session at the recent American Society of Clinical Oncology (ASCO) conference in Orlando, Fla.

Puzanov and Sosman were among nearly a dozen VICC cancer investigators who were invited to give oral or poster presentations on their latest research findings during the ASCO conference.

PLX4032 is a novel, highly selective drug that targets the BRAFV600E cancer-causing genetic mutation. In addition to tumor shrinkage and delay in tumor progression, some patients reported clinical improvement in symptoms.

“The BRAFV600E mutation activates the MAP kinase signaling pathway, causing cells to proliferate. One of the hallmarks of cancer is this uncontrolled, unregulated cell proliferation,” said Puzanov. “The new drug is a very selective inhibitor which appears to target only this mutation, and it blocks the unregulated cell growth and causes cell death.”

In patients without the mutation, no clinical response to treatment was observed and progression-free survival was less than two months, consistent with historical data.

“This is personalized medicine at its best,” said Sosman. “If continued trials confirm the agent works only in patients with this mutation, we can target those patients for this drug and spare others from undergoing a treatment that won’t work.”

Christine Chung, M.D., assistant professor of Medicine, presented on the use of a mass spectrometry-based algorithm to predict which head and neck cancer patients may benefit from treatment with certain drugs.

Chung’s group found that the same predictive algorithm generated from patients with non small-cell lung cancer treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is also predictive of survival outcome in head and neck squamous cell cancer patients treated with the same types of drugs.

Zila enters into merger agreement with Tolmar

Author: press release

Zila, Inc. today announced that it has entered into a definitive merger agreement with Tolmar Holding, Inc., a privately held, pharmaceutical research, development, manufacturing and commercial operations company. Under terms of the agreement, Tolmar will acquire all of the outstanding shares of Zila for a cash purchase price of $0.38 per share, representing an approximate premium of 18% over the closing price of Zila’s shares on June 24, 2009. Total consideration paid by Tolmar includes the purchase of Zila’s existing $12 million senior secured convertible debt at a discount.

The proposed merger transaction is subject to customary closing conditions, including approval by Zila’s stockholders, but is not subject to any financing contingency.

David Bethune, Zila’s chairman and CEO, stated, “We are fortunate to have entered into this merger agreement with Tolmar, given Zila’s current financial condition and our inability to access the financial markets. The Board of Directors conducted a substantial and exhaustive review of Zila’s available alternatives, before concluding that this transaction was fair to and in the best interest of the company and its stockholders. I am gratified that we have found a way to both satisfy our debt obligations and provide value for our shareholders. This merger will provide the resources and platform for Zila’s dedicated employees to realize the true worldwide potential of Zila’s oral cancer screening and periodontal products.”

About Zila, Inc.
Zila, Inc., headquartered in Scottsdale, Arizona, is a diagnostic company dedicated to the prevention, detection and treatment of oral cancer and periodontal disease. Zila manufactures and markets ViziLite® Plus with TBlue® (“ViziLite® Plus”), the company’s flagship product for the early detection of oral abnormalities that could lead to cancer. ViziLite® Plus is an adjunctive medical device cleared by the FDA for use in a population at increased risk for oral cancer.

Detecting subtle changes in cancer cells with nanofluidic biopsy

Author: staff

By taking two standard laboratory techniques—capillary electrophoresis and antibody-based protein detection—and shrinking them to the nanoscale, researchers at the Stanford University School of Medicine have created a new method for detecting miniscule changes in the levels of proteins associated with cancer.

In a study published in the journal Nature Medicine, the investigators used their new device to analyze whether individual cancer-associated proteins were present in the tiny samples and even whether modifications of the proteins varied in response to cancer treatments. Although the study focuses on blood cancers, the hope is that the technique also might provide a faster, less invasive way to track solid tumors.

“Currently, we don’t know what’s going on in a patient’s tumor cells when a treatment is given,” said Alice C. Fan, M.D., who along with Dean W. Felsher, M.D., headed the team that developed this nanofluidic proteomic immunoassay (NIA) system. “The standard way we measure whether a treatment is working is to wait several weeks to see if the tumor mass shrinks. It would be a leap forward if we could detect what is happening at a cellular level.”

Dr. Felsher, who is a member of the Center for Cancer Nanotechnology Excellence Focused on Therapy Response based at Stanford University, added, “This technology allows us to analyze cancer-associated proteins on a very small scale. “Not only can we detect picogram levels—one-trillionth of a gram—of protein, but we also can see very subtle changes in the ways the protein is modified.”

Variations in the way a protein is modified, or phosphorylated, can affect how it functions in tumor progression. Cancer cells often evade common therapies by altering levels of protein expression and degrees of phosphorylation. Analyzing repeated small samples from a tumor undergoing treatment may let doctors head off rogue cells before they proliferate into a more resistant tumor as well as identify patients likely to fail standard approaches to treatment.

Drs. Fan and Felsher collaborated with researchers from Cell Biosciences, Inc., to create the NIA system that separates cancer-associated proteins in narrow capillary tubes based on their charge, which varies according to modifications on the surfaces of the proteins. Two versions of the same protein—one phosphorylated and one not—can be easily distinguished because they travel different distances in the tube. The researchers then use antibodies to identify the relative amounts and positions of the various proteins.

Not only was the technique able to identify oncogene activation in cultured tumor cells, but also it worked in lymphoma samples drawn from mice. Furthermore, it was able to detect varying levels of expression of two common oncogenes in 44 of 49 lymphoma samples from human patients compared with normal controls and even was able to distinguish some types of lymphomas from others. The assay system also detected subtle differences in phosphorylation in several other cancer-associated proteins. “Some of these proteins can exist as five or six phosphorylated variants,” said Dr. Felsher. “With this technology, we can see changes that occur in as little as 10 percent of the total protein pool. Now we have a tool that will help us look at what’s happening in cells over time.”

“Surgical biopsies usually require general anesthesia and large amounts of tissue,” agreed Dr. Fan. “If we can figure out how to go in with a needle and remove just a few cells for analysis, we could repeatedly assess how the tumor is responding to treatment.”

For example, the researchers were able to confirm through serial biopsies of a human lymphoma patient that, as suggested by previous research in the Felsher lab, the lipid-lowering drug atorvastatin reduces phosphorylation of yet another cancer-associated protein. “This is the first time we’ve been able to see that this compound affects the biology of cancer cells in patients,” said Dr. Felsher.

Dr. Fan is now expanding her investigations to include head and neck tumors, which tend to be accessible for cell sampling. Drs. Fan and Felsher caution that more research is needed before the technology would be widely available clinically.

This work, which is detailed in the paper “Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens,” was supported by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An investigator from the Hospital Saint-Louis in Paris, France, also participated in this study.

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