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Utah-based Myriad Genetics turned a loss into a record $21.2 million

Myriad Genetics: Diagnostic product maker thrives despite economy

The Salt Lake Tribune, February 4, 2009, by Tom Harvey — Utah-based Myriad Genetics turned a loss into a record $21.2 million profit in its fiscal second quarter, its stock soaring Tuesday about $12, or 17 percent, on the news.

“The severe recession that grips the country appears to be affecting most companies but not Myriad,” Peter Meldrum, CEO and president, said during a conference call after the company announced earnings for the quarter that ended Dec. 31.

In the same quarter of its fiscal 2008, Myriad had reported a net loss of $5.1 million, or 11 cents a share. The turnaround to the profit that amounted to 46 cents a share was tied to revenue growth that Chief Financial Officer James Evans called “explosive.”

The company with offices and laboratories in South Salt Lake markets tests for genetic conditions that may cause or contribute to cancer, as well as to the risk of developing a reaction to chemotherapy.

Myriad had a 58 percent increase in revenues for its diagnostic products, to $84 million, for the fiscal second quarter. Company officials attributed the growth to an expansion of its sales force for women’s health products, plus its efforts to market directly to consumers, as well as to health-care providers.

Michael Yee, who analyzes Myriad for RBC Capital Markets, raised his share target price to $95. Myriad closed Tuesday at $84.22.

“Basically I thought the quarter was spectacular,” Yee said. “The results exceeded not only my expectations, which were above [analysts’] consensus, but even the highest expectations out there on The Street.”

The company has been running an ad campaign in Florida and Texas, sometimes in conjunction with ads from major breast cancer centers and OB/GYN clinics, touting its test for genes that cause hereditary breast and ovarian cancer.

“The campaign has the goal of convincing physicians of the need to routinely identify patients in their practices that benefit from molecular diagnostic testing,” said Gregory C. Critchfield, president of subsidiary Myriad Genetics Laboratories.

For its fiscal 2009, Meldrum said the company was confident revenue for the diagnostic business would exceed analysts’ consensus predictions of $325 million.

The company also has available funds-on-hand of $497 million and no debt.

Yee said the risks for the company are that it has set high expectations it will be expected to meet.

“Any dramatic falloff in the economy I would suspect at some point would affect everybody,” he said.

For the six months that ended Dec. 31, Myriad Genetics reported a net profit of $35.7 million, or 78 cents a share, compared to a net loss of $13.1 million or 30 cents a share for the comparable period of its fiscal 2008.

The company also said it would launch its seventh genetic test this summer.

“We are an early pioneer in this field, and our goal is to become the dominant player in predictive medicine, prognostic medicine and personalized medicine,” Meldrum said.

Complex Biology of CNS Diseases Continues to Hamper Development of Effective Drugs

GenEngNews.com, February 5, 2009, by Allan B. Haberman PhD — Central nervous system (CNS) diseases are a major focus of the pharmaceutical industry, with CNS drugs representing some of its most successful products. These include Pfizer’s Zoloft, Eli Lilly’s Cymbalta, and Abilify from Bristol-Myers Squibb and Otsuka.

Drug discovery and development researchers, however, have experienced difficulty developing CNS drugs that can complete clinical trials and win regulatory approval. This is especially true for drugs that address major unmet needs in the CNS area such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), stroke, brain cancers, and metastases to the brain.

A major bottleneck in successful development of CNS drugs is the discovery or design of drugs that can cross the blood-brain barrier (BBB).

Researchers believe that the function of the BBB is to protect the CNS from toxic molecules, including toxins that may be ingested in food, and endogenously formed toxic molecules. Unfortunately, the BBB also serves as a barrier to potentially beneficial drugs for treatment of CNS diseases. About 98% of small molecule drugs fail to cross the BBB and, no large molecule drugs cross the BBB, except for a few natural peptides and proteins such as insulin, and those specifically designed to do so.

Most current CNS drugs are small molecule drugs that cross the BBB via passive diffusion. These drugs are either old compounds that were discovered via traditional drug discovery methods (involving serendipity and animal studies), or newer drugs discovered via high-throughput screening (HTS) and medicinal chemistry.

Small molecule drugs that can cross the BBB via passive diffusion must have physicochemical properties that allow them to do so. Such drugs have a more restricted set of physicochemical properties than the universe of oral drugs. For example, the molecular weight cutoff for CNS penetrant drugs appears to be 400 daltons, as opposed to 500 daltons for all drug-like compounds. Companies such as Pfizer and GlaxoSmithKline have developed computational models, based on the physicochemical properties of compounds, which allow medicinal chemists to predict the ability of small molecule drugs to cross the BBB via passive diffusion, and to design compounds that can do so.

A particular challenge to the development of CNS-penetrant small molecule drugs is the action of efflux transporters. These are a class of ATP-dependent membrane glycoproteins that actively expel molecules that have crossed the BBB back across endothelial cell membranes and out of the brain. Researchers consider the P-glycoprotein (P-gp) to be the most important of these transporters. In addition to designing compounds that have the physicochemical properties needed to enable passive diffusion across the BBB, medicinal chemists must also ensure that these compounds are poor substrates for P-gp.

Small molecule compounds that are designed to cross the BBB via passive diffusion seem to be particularly ill-suited to address tempting new disease targets in indications with high unmet need. For example, researchers have identified the enzyme beta-secretase as being critically involved in the amyloid pathway of Alzheimer’s disease. Because of the physicochemical nature of the active site of beta-secretase, it is difficult to design small molecule inhibitors that readily cross the BBB via passive diffusion.

Nutrient Transporter
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Figure 1. Dopamine cannot cross the BBB.

Researchers have been developing novel technologies that enable the design of drugs that cross the BBB via active transport. The permeation of the brain by drugs that are actively transported across the BBB is approximately an order of magnitude greater than for compounds that cross the BBB via passive diffusion. Moreover, most small molecule compounds do not cross the BBB at therapeutically significant concentrations at all. This problem might be overcome by developing versions of these compounds that can be actively transported across the BBB.

One technology for enabling active transport of small molecule drugs across the BBB involves targeting endogenous nutrient transporters. These transporters are members of the solute carrier (SLC) transporter superfamily. Transport of small molecules across the BBB by these membrane proteins is known as carrier-mediated transport (CMT).

CMT is responsible for transport of such nutrients as glucose, other sugars, lactate, nucleosides, fatty acids, and vitamins, as well as certain hormones (such as thyroid hormones) into the brain. These substances are vital for brain function. Many of the SLC transporters found in brain endothelium that are involved in CMT are also found in intestinal endothelium, where they are involved in transport of nutrients—and drugs—from the intestine into the bloodstream.

In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson’s disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.

Dopamine itself cannot cross the BBB. It can, however, be modified to produce L-DOPA, an amino acid that is recognized by the large neutral amino acid transporter. This SLC family member transports L-DOPA into the brain, where it is converted to dopamine by the enzyme aromatic amino acid decarboxylase. L-DOPA thus serves as a prodrug that crosses the BBB and is converted into the active agent in the brain. The structures of L-DOPA and dopamine are shown in Figure 1.

XenoPort has been designing small molecule drugs that exploit CMT to enable improved absorption from the gut or transport across the BBB. The company refers to its products as Transported Prodrugs. These are prodrugs that target SLC nutrient transporters, either in the BBB or in the intestine. XenoPort’s main therapeutic focus is on CNS drugs, but it is also developing a drug for gastroesophageal reflux disease.

All of Xenoport’s clinical-stage drugs target SLCs in the intestine. They are Transported Prodrugs that are derivatives of FDA-approved drugs and are modified to target an SLC. Once they are transported from the intestine into the bloodstream, they are converted into the active drug, analogous to the conversion of L-DOPA to dopamine.
Xenoport’s research aimed at development of drugs that cross the BBB similarly involves the design of Transported Prodrugs that target SLCs in brain capillaries. Once they are transported through the BBB, they are converted into active drugs.

Receptor-Mediated Transport

The other major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).

In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.

William Pardridge, M.D., professor of medicine at UCLA, has been exploiting RMT to develop large molecule CNS drugs that can cross the BBB. Such large molecule drugs may include peptides, recombinant proteins, monoclonal antibodies (mAbs), and small interfering RNAs (siRNAs).

In designing such large molecule drugs, researchers use what are called molecular Trojan horses (MTHs). MTHs are either peptide or protein ligands that target RMT systems (e.g., receptor-binding sequences of insulin) or MAbs that are specific for target receptors. In designing protein drugs that can transit the BBB, researchers typically construct fusion proteins between the desired therapeutic protein and the MTH. BBB receptors that are typically targeted with MTHs include the receptors for insulin, transferrin, IGF, leptin, and LDL.

ArmaGen has an MTH technology that utilizes RMT to cross the BBB. The company is a spin-off of Dr. Pardridge’s laboratory. ArmaGen and the Pardridge laboratory have developed fusion proteins between mAbs to the transferrin and insulin receptors with various therapeutic proteins that cannot themselves cross the BBB. They have demonstrated that these MTH-based agents cross the BBB in animal models, including nonhuman primates.

ArmaGen’s lead product, AGT-120, is a fusion protein between a human transferrin receptor mAb and brain-derived neurotrophic factor. It is in the pre-IND stage and is intended for treatment of stoke and neurodegenerative diseases.

AGT-181, a fusion protein between a human insulin receptor (HIR) mAb and the enzyme alpha-L-iduronidase (IDUA), is an enzyme-replacement therapeutic for treatment of the lysosomal storage disease Hurler’s syndrome (Mucopolysaccaridosis Type 1).

ArmaGen is also developing a product for treatment of Alzheimer’s disease. This is a trifunctional fusion antibody, which consists of moieties that bind to HIR, Abeta peptide (which makes up amyloid plaques that researchers believe causes Alzheimer’s disease), and the neonatal Fc receptor. The anti-HIR moiety serves as an MTH to enable the agent to cross the BBB, the anti-Abeta peptide moiety binds to anyloid plaque and disaggregates it, and the anti-neonatal Fc receptor moiety enables the Abeta-bound agent to exit the brain via the BBB.

The Pardridge laboratory and ArmaGen have also developed a delivery system to enable siRNAs to cross the BBB. This agent consists of an mAb to the transferrin receptor, linked to streptavidin. This carrier is designed to bind biotinylated siRNAs (via streptavidin-biotin binding), and transfer them across the BBB.

Another company that has been developing MTH technology is to-BBB, a spin-off of the Blood-Brain Barrier Research group of Leiden University. to-BBB’s technology platform, 2B-Trans, is based on the use of the nontoxic diphtheria toxin mimetic CRM197. CTRM197 binds to a receptor on capillaries of the BBB, which is a membrane-bound precursor of heparin-binding epidermal growth factor. This receptor is also known as the diphtheria toxin receptor (DTR). DTR is constitutively expressed on brain capillaries and in neurons and glial cells of the brain.

to-BBB’s lead product, 2B3-101, is a liposome-encapsulated ribavirin conjugated to CRM197. It is intended as a therapeutic against Japanese encephalitis virus (JEV).

The Immune Disease Institute at Harvard Medical School has been developing a MTH for delivery of siRNAs to the brain. This MTH, called the CORVUS peptide, is a fusion peptide between a 29-amino acid peptide from the rabies virus glycoprotein (RVG) and a 9-amino acid peptide made up entirely of D-arginine units.

The CORVUS peptide is designed to bind the negatively charged si-RNAs via its nona-D-arginine moiety, and to bind the receptor for the virus, the nicotinic acetylcholine receptor (nAChR). nAChR is expressed on capillaries of the BBB and on neurons of the brain. CORVUS thus serves to transport the siRNAs across the BBB and into neurons. The CORVUS MTH is in the research stage. The researchers showed that intravenously injected CORVUS complexed with an siRNA specific for the JEV envelope gene gave mice 80% protection from JEV infection.

Outlook

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CNS drug researchers generally agree that design and discovery of drugs that can readily cross the BBB is a major bottleneck for the development of new CNS drugs, especially those that address major unmet needs. Academic and corporate researchers have been developing technologies that enable the design of small and large molecule drugs that are actively transported across the BBB, and have demonstrated the feasibility of these technologies in animal studies.

Nevertheless, the majority of companies developing CNS drugs continue to rely on traditional medicinal chemistry-based methods for design of small molecule drugs that cross the BBB via passive diffusion (and which are poor substrates for P-gp), or they have no specific programs on crossing the BBB at all.

This is seen in the results of a survey carried out by Cambridge Healthtech Institute in conjunction with our recent BBB report. Despite the traditional orientation of most companies’ BBB research programs, many of them are focusing on CNS indications such as neurodegenerative diseases that are underserved by current CNS drugs, and for which drugs that cross the BBB via passive diffusion have so far been poorly applicable.

However, the survey indicates that a substantial minority of companies are working on development of large-molecule (protein, peptide, or nucleic acid) drugs that can cross the BBB via use of MTH technology. Others are using another early-stage technology, naonparticle carriers, to enable their large molecule drugs to cross the BBB (Figure 2).

Thus, although most companies developing CNS drugs are not applying novel technologies that enable active transport of drugs across the BBB, these technologies have begun to penetrate the industry. As these early-stage technologies prove themselves in the clinic, we expect that there will be a great interest in utilizing them, including partnering between large pharmaceutical and biotechnology companies and BBB specialty companies, and commercialization of academic research in this area. We expect that, as this occurs, those companies that are already utilizing these technologies will have an advantage over others.

Researchers cite the BBB as a major challenge to developing novel CNS drugs, and some see the BBB as the major bottleneck in this area. However, understanding the complex biology of CNS diseases is an equally important challenge. Thus, although development of clinically proven BBB transport technologies will represent a major breakthrough, the biology of CNS diseases will still challenge CNS drug developers.

TOKYO — USNews.com, 02/05/2009, by Yomiuri Shimbun — A group of researchers has developed a new vaccine effective against many types of influenza, a breakthrough that could be a possible silver bullet against new strains of the virus.

Although practical application of the vaccine is still several years away, trials conducted on mice have shown promising results even on flu strains that can quickly mutate.

Researchers from the National Institute of Infectious Diseases, Hokkaido University, Saitama Medical University and chemical maker NOF Corp. developed the groundbreaking vaccine. The team was working under Japan’s Health, Labor and Welfare Ministry.

Previous vaccines were developed based on proteins that look like barbs covering the outer surface of the virus. After a virus enters the body of a person who had been inoculated, antibodies detect the barbs and try to suppress and fight off the virus.

However, the shape of these proteins differs between influenza strains.

New vaccines must be formulated almost every year because these proteins can quickly change their shape, a problem that becomes all the more troublesome when several strains of influenza with differently shaped proteins are making the rounds.

When predictions about which strain will become an epidemic miss the mark, inoculations lose much of their effectiveness.

The researchers this time targeted the proteins inside the virus, which change little over time compared with those on the outer surface. The vaccine consists of an artificial version of the protein developed by the team that is attached to a special lipid membrane. When the vaccine is injected, immune system cells attack the cells infected by the virus.

The researchers examined the proteins of three common influenza strains — the Hong Kong A strain, the Soviet A type, and the highly pathogenic H5N1 bird flu.

The team inoculated mice implanted with human genes that boost immunity and then infected them with the three viruses. The mice showed no symptoms of the illness, and the vaccine suppressed the viruses’ ability to multiply.

Research will continue into whether the revolutionary vaccine causes any serious side effects in humans.

A group of researchers at England’s Oxford University reportedly is conducting trials of a similar universal flu vaccine.

GoogleNews.com, February 5, 2009, by Rob Youngblood – The number of flu cases around the state is increasing and health officials are urging people to be prepared.

“We are in the infancy stages of influenza. We actually just confirmed our first case last week and we have seen several cases come in this week,” said Shawn Richards of the health department. “We are seeing a mixed bag of lots of respiratory diseases being passed this season — RSV, paraflu, influenza and lots of other just colds.”

The Centers For Disease Control just moved Indiana from the “sporadic” designation to “regional”. It means that cases are now coming in from all over the state. As always, prevention is the best defense. People should wash hands frequently, exercise, and eat well.

A lot of people say they don’t get flu shots because they don’t think they actually work. But this year, the health department said the flu shots should do a lot of good because they match the strain of flu that is going around.

“The flu vaccine is the best protection in our arsenal right now,” said Richards.

Officials say to watch out for the basic flu symptoms: a fever over 100, sore throat and cough are the first signs that you should see your doctor.

Obama poised to lift restrictions, and Texas scientists stand ready

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Melissa Phillip Chronicle

UT Health Science Center-Houston professor Rick Wetsel, with assistant professor Eva M. Zsigmond, is leading a team working with stem cell lines approved by the Bush administration.

Houston Chronicle, February 3, 2009, by Todd Ackerman — More than a decade after the discovery of human embryonic stem cells, Texas scientists are poised to finally ramp up research involving the cutting-edge but controversial science.

With President Barack Obama expected to lift federal restrictions on the field as early as this week, scientists in the Texas Medical Center and around the state have expressed their delight and predicted a long-awaited scientific renaissance will follow.

“Opening up the research is going to have an enormous benefit,” said Bill Brinkley, a Baylor College of Medicine professor of molecular and cellular biology. “After being diminished and pushed to the side for a decade, embryonic stem cell research will become mainstream — most every lab will take advantage of it.”

In the minds of many, stem cell research promises nothing less than the future of medicine, youthful tissue replacing that which is old or damaged. From animal studies, scientists tout research suggesting stem cells can replace brain cells lost in Parkinson’s disease, restore function to defective muscles in muscular dystrophy and regenerate parts of the pancreas that don’t work in diabetes.

The question is, how quickly can scientists turn the promise into reality? The first attempt is about to start in California. A biotech company there recently got clearance from the Food and Drug Administration for the first human trial of a therapy based on embryonic stem cells, injecting them into the spinal cords of paralyzed people.

Local stem-cell leaders are Baylor and the University of Texas Health Science Center at Houston, both of which boast centers dedicated to the science. The centers have focused mostly on adult stem cells but also feature work with embryonic stem cells, work that their leaders say will mushroom once Obama overturns the policy of former President George W. Bush.

Origins of the debate

Already, teams at Baylor, UT-Houston and Rice University are planning grant applications to build on their ongoing embryonic stem cell research on Parkinson’s disease, lung disease and joint replacement cartilage, respectively. Biotechnology industry observers say Texas can become a leader if the Legislature adds its support.

The political debate over embryonic stem cells dates to 2001, when Bush agreed to allow the use of federal funds for research but limited support to existing cell lines, which numbered less than two dozen. Most were in far from ideal condition and unsuitable for clinical work.

“Essentially, Bush’s policy has made us operate with one hand tied behind our back,” said Robert Lanza, of Massachusetts-based Advanced Cell Technology.

The wonder of embryonic stem cells is that they have the capacity to become any sort of tissue the body needs — nerves, blood, heart, bone, muscle. They morph from microscopic spheres to full body parts, a process scientists hope to take control of after retrieving the cells from 5-day-old embryos. So promising is the research that the 1998 discovery gave birth to a whole new specialty, regenerative medicine. But the science also raises ethical concerns. Because the embryo is killed in the retrieval process, it has been called “a direct attack on innocent human life.”

Bush objected to further research on those grounds. He prohibited the use of federal funding on research involving cell lines from any embryos destroyed after his 2001 policy announcement, calling for research to instead emphasize adult stem cells, which pose no ethical concerns, because they require no destruction of life.

Some defenders of Bush’s policy say it spurred scientists to more aggressively pursue adult stem cell research, resulting in a 2007 breakthrough that could ultimately make the controversy moot. Two teams of scientists independently reported developing a method of converting human adult stem cells into the equivalent of embryonic stem cells, seemingly capable of becoming any of the 220 cell types of the body. Researchers previously believed adult stem cells lacked the unlimited ability to turn into other types of human tissue.

But scientists, noting the breakthrough would have been impossible without knowledge gained through embryonic stem cell research, said last week it’s too early to assume that the technique is the answer. For one,the method entails the use of genetically engineered viruses, which can trigger tumors.

“We still don’t know whether that technique, still far from perfected, will be able to faithfully reproduce all of embryonic stem cell properties in adult stem cells,” said Paul Simmons, director of UT-Houston’s Center for Stem Cell Research and an adult stem cell researcher. “Embryonic stem cells are the gold standard to conduct that study and make a determination. It may turn out that adult stem cells are good for some things and embryonic are better for others.”

Legislation is next in line

Obama campaigned on a promise to lift Bush’s restrictions and allow research on stem cells taken from embryos that otherwise would be discarded by fertility clinics. Congressional sources said last week he plans to make the change as soon as the economic stimulus package is passed. Legislation codifying the policy will follow.

The policy should provide the most immediate boost to three teams here working with Bush’s federally approved cell lines. Their leaders say they can hardly wait to work with any of the more than 1,000 lines created with private money since Bush’s policy was adopted. Those lines, expected to be eligible for federally supported research, are more robust and clinically useful than the currently approved lines.

Advocates of stem-cell research also call for a state investment. A report commissioned by Texans for the Advancement of Medical Research says the state could generate $88 billion in economic activity if Texas’ share of U.S. biotechnology spending increases to 6 percent from 2.9 percent by 2014.

“ Obama’s new policy will change the game dramatically,” said Dr. Ray Dubois, provost at the University of Texas M.D. Anderson Cancer Center. “Texas may not have the state or private money that some states have for stem-cell research, but the stage could quickly change quite a bit.”

ADVANCES IN HOUSTON

Three Houston groups are working with stem cell lines approved by the Bush administration:

Lungs : A team led by UT-Houston professor Rick Wetsel has coaxed embryonic stem cells to become tissue that lines the inside of the lungs, a possible treatment for chronic obstructive pulmonary disease and some genetic diseases.

Memory: A team led by Baylor Stem Cells and Regenerative Medicine Center professor Thomas Zwaka is using embryonic stem cells to study Parkinson’s disease.

Joints: A team led by Rice University bioengineering professor Kyriacos Athanasiou has developed a technique for growing cartilage from embryonic stem cells, a possible treatment for the surgical repair of joints.

Stanford University School of Medicine, 02/05/09 — Cancer stem cells — tiny powerhouses that generate and maintain tumor growth in many types of cancers — are relatively resistant to the ionizing radiation often used as therapy for these conditions.

Part of the reason, say researchers at Stanford University School of Medicine, is the presence of a protective pathway meant to shield normal stem cells from DNA damage. When the researchers blocked this pathway, the cells became more susceptible to radiation.

“Our ultimate goal is to come up with a therapy that knocks out the cancer stem cells,” said Robert Cho, MD, a clinical instructor of pediatrics. “If you irradiate a tumor and kill a lot of it but leave the cancer stem cells behind, the tumor has the ability to grow back.” As a result, patients can relapse months or years after seemingly successful treatment.

Cho and radiation oncologist and post-doctoral fellow Maximilian Diehn, MD, PhD, are co-first authors of the research, which will be published on Feb. 4 in Nature. They collaborated with scientists at Stanford and City of Hope National Medical Center to conduct the research. They studied breast epithelial stem cells from humans and mice to unravel why cancer stem cells are more resistant to radiation than other cancer cells.

“Since cancer stem cells appear to be responsible for driving and maintaining tumor growth in many tumors, it is critical to understand the mechanisms by which these cells resist commonly used therapies such as chemotherapy and radiotherapy,” said Diehn. “Ultimately, we hope to improve patient outcomes by developing therapeutic approaches that directly target cancer stem cells or that overcome their resistance mechanisms.”

The origin of cancer stem cells is still under debate. Some may arise from normal adult stem cells gone awry. Others may represent specialized cells from adult tissues that have acquired a stem-cell-like state through a series of mutations. What’s clear is that cancer stem cells can reconstitute an entire tumor cell population when transplanted into an immune-deficient animal, and destroying them is likely to be critical in order to stop the growth and spread of the disease.

But unlike most cells in the body, which are relatively expendable, stem cells are not that easy to kill. Among the millions of easily replaceable minions that carryout the everyday drudgery of living, the much more rare and versatile stem cells comprise a veritable ruling class. It makes sense to protect such a valuable asset.

Diehn and Cho found that, in this case, the protection takes the form of the increased expression of proteins that can bind and deactivate reactive oxygen species, or ROS. These highly unstable small molecules bounce around wreaking havoc on a cell’s DNA and proteins. Although they occur naturally in dividing cells, they are also important mediators of the therapeutic radiation and some chemotherapies doctors use to fight cancer.

The researchers knew that blood stem cells had previously been found to have lower levels of reactive oxygen species than non-stem cells. They wondered whether the same would be true for breast epithelial stem cells. They found that normal breast stem cells from mice have lower ROS levels than do non-stem cells, and that this characteristic was shared by cancer stem cells from both humans and mice.

They found out why when they looked at gene expression levels: the human breast cancer stem cells were churning out much higher levels of antioxidant proteins than were non-stem cells. Antioxidants capture and disarm ROS before they can cause much damage. This may explain why cultured mouse breast cancer stem cells were less likely than other cancer cells to experience DNA damage after ionizing radiation.

“The resistance observed in the breast cancer stem cells seems to be a similar if not identical mechanism to that used by normal stem cells,” said Michael Clarke, MD, the associate director of the Stanford Institute for Stem Cell and Regenerative Medicine and the Karel H. and Avice N. Beekhuis Professor in Cancer Biology. Clarke, who discovered the first cancer stem cells in a solid tumor, is a member of the Stanford Cancer Center and the senior author of the research.

“Although your body would normally eliminate cells with chromosomal damage, it also needs to spare those cells responsible for regenerating and maintaining the surrounding tissue — the stem cells,” Clarke explained. “It’s protective.”

This protection backfires in the case of cancer, however. The researchers found that, in mice with mammary tumors, cancer stem cells with low ROS levels were about twice as likely as other tumor cells to survive a course of ionizing radiation. Similar results were seen in human head and neck cancers that had been transplanted into mice.

The discovery could lead to a new approach to treating cancer. Blocking the activity of an important antioxidant called glutathione made the cancer stem cells significantly more sensitive to killing by radiation. Figuring out how to do something similar in human tumors could have important therapeutic benefits.

“Basically we need to figure out a way to inactivate that protective mechanism in cancer cells while sparing normal cells,” said Clarke. For many patients, it’s a life-or-death question.

“It’s like battling weeds,” said Cho, of the cancer stem cells’ ability to come back even stronger than before. “You can go through a big field with a weed whacker, but the weeds are going to come back unless you get the roots.”

Additional Stanford collaborators on the research include graduate students Neethan Lobo and Angela Kulp; post-doctoral scholar Tomer Kalisky, PhD; senior research scientist Mary Jo Dorie, PhD; laboratory manager Dalong Quian, MD; Jessica Lam, BS; former post-doctoral scholar Laurie Ailles, PhD; post-doctoral scholar Manzhi Wong, PhD; otolaryngologist Benzion Joshua, MD; professor of otolaryngology Michael Kaplan, MD; associate professor of surgery Irene Wapnir, MD; assistant professor of surgery and director of the Clinical Care Sub-team of Stanford’s Breast Disease Management Group Frederick Dirbas, MD; professor of bioengineering Stephen Quake, PhD; professor of radiation oncology J. Martin Brown, PhD; and the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research Irving Weissman, MD.

The research was supported by the National Institutes of Health, the Virginia and D.K. Ludwig Foundation, the Breast Cancer Research Foundation, the Machiah Foundation, the American Society for Therapeutic Radiology and Oncology and the Radiological Society of North America.

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Virus made to kill cancer stem cells

CINCINNATI, January 2009 — U.S. scientists say they have engineered a virus to target and kill apparent cancer stem cells involved in neuroblastoma tumors.

Cincinnati Children’s Hospital Medical Center researchers say they used a reprogrammed herpes virus to block tumor formation in mice by targeting and killing the cells.

The scientists said their accomplishment adds to a growing body of evidence suggesting early stage cancer precursor cells with stem cell-like properties may explain how some cancers form, are treatment resistant and prone to relapse.

The study also underscores the increasing potential of targeted biological therapies to help people with stubborn cancers like neuroblastoma, which often recur and metastasize, said Dr. Timothy Cripe, who led the research.

“The main finding of our study is that pediatric neuroblastomas seem to have a population of cells with stem cell characteristics that we may need to target for therapy,” said Cripe. “We also show that one promising approach for targeted treatment is biological therapy, such as an engineered oncolytic virus that seeks out and kills progenitor cells that could be the seeds of cancers.”

The research is reported in the online journal PLoS One.

GoogleNews.com, February 5, 2009, by Stephanie Nano — Doctors thought that combining two newer drugs that more precisely attack cancer would help people with advanced colon cancer. Instead, it made the cancer worse and made the patients more miserable, a study found. The surprising findings underscore the importance of doing rigorous studies before rushing to mix these pricey, new-generation drugs, the Dutch researchers and other experts said.

The doctors tried combining Erbitux and Avastin because lab tests and an earlier small study had shown promising results.

“This will stand out as a warning,” said Dr. Cornelis Punt, the study’s leader. “You have to do the randomized studies to see what really happens.”

For the study, Eli Lilly & Co.’s Erbitux was added to standard treatment, which includes Genentech Inc.’s Avastin. Since both are “targeted” drugs and attack tumors in different ways, the thinking was that the combo would do a better job of keeping the cancer from growing.

But the results show “more is not always better,” said Dr. Robert Mayer, of Dana-Farber Cancer Institute in Boston. He wrote an editorial published with the study in Thursday’s New England Journal of Medicine.

What makes the results even more compelling, Mayer said, is that another similar study reached the same conclusion. That study, released in December, tested another targeted drug that works the same way as Erbitux.

“This is the first time we’ve seen harm by combining targeted therapies and it tells us we need to be cautious,” said Dr. Jordan Berlin, a gastrointestinal cancer specialist at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Berlin, who had no role in the research, stressed that the drugs do help patients, just not when given together.

Colorectal cancer is the nation’s second leading cancer killer. The disease was expected to kill almost 50,000 Americans last year although death rates are dropping because of screening and better treatment.

The research was done at hospitals throughout the Netherlands and led by Punt at Radboud University Nijmegen Medical Center. The 755 study patients had colon cancer that had spread. They all received Avastin, also known as bevacizumab, and two chemotherapy drugs. Half of them also got Erbitux, also called cetuximab. They were followed for nearly two years.

The group that got Erbitux saw their cancer get worse sooner, the researchers found. On average, their cancer progressed after 9.4 months compared to 10.7 months for those who didn’t get Erbitux. The Erbitux group also had lower quality-of-life scores.

The overall survival in both groups was about the same.

Punt said they are now trying to figure out why the combo didn’t work; it could be an interaction between these two specific drugs, Erbitux and Avastin.

After the study began in 2006, it was shown that Erbitux didn’t help colon cancer patients who had a specific gene mutation. The Dutch researchers said their study confirmed that — the worst results were in those with the mutation who got Erbitux.

Vanderbilt’s Berlin said the results also show doctors need to be careful when using drugs “off-label.” Drugs are approved for specific uses but doctors can prescribe them for other purposes. Medicare has recently expanded its coverage for such use of some cancer drugs, which can cost thousands a month.

Off-label use “needs to be cautious and this proves it,” said Berlin.

The study was supported by a network of Dutch researchers which receives grants from a cancer foundation and drug companies. The two targeted drugs were provided by the companies that market them in Europe. Several of the researchers have consulted for cancer drug companies, as has the editorial writer and Berlin.

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On the Net:

New England Journal: http://www.nejm.org

When mice ate is as important as what they ate in reducing cell division linked to cancer

ScienceNews.com, by Laura Sanders — Fasting every other day reduces some hallmarks of cancer in mice, even when the mice voraciously consume high-fat food between fasts, a study in an upcoming Nutrition shows.

Scientists have known for decades that eating fewer calories — roughly 25 to 50 percent less than recommended — extends life span in animals ranging from worms to dogs. But, “caloric restriction on a daily basis is very hard,” says Eric Ravussin, a physiologist at the Pennington Biomedical Research Center in Baton Rouge, La., who studies caloric restriction.

Last year, researchers including Krista Varady, then of the University of California, Berkeley, published a study suggesting that a less drastic version of caloric restriction provides a constellation of health benefits in mice. Called alternate-day fasting, the regimen of eating as much food, low-fat in this study, as one wants one day but fasting the next confers some of the same anticancer benefits as just cutting calories at a constant rate, the team found.

But for people, eating a low-fat diet one day and fasting the next is still challenging. Varady and her colleagues wanted to know whether the diet could be made easier to swallow and still provide similar benefits.

In the new study, Varady and other researchers compared mice who fasted every other day, both on high-fat and low-fat diets, to mice that didn’t fast but instead ate a low-fat diet every day. The mice on the ultimate yo-yo diet ate high-fat food, in which 45 percent of the calories came from fat — comparable, Varady says, to human diets of fast food and processed food.

On the fasting days, mice were fed 15 percent of their required calories from either the high- or low-fat food.

The results were surprising, says Varady. Mice that ate the rodent equivalent of Big Macs every other day showed the same anticancer benefits of fasting as the mice that ate the low-fat diet every other day. High rates of cell division — a key feature of cancer — were lower in the mice who fasted every other day than in mice that had not fasted. Mice who fasted every other day also had reduced levels of IGF-1, a protein that induces cell growth and has been linked to cancer.

The new study on mice is the “next installment in a systematic and interesting series of studies” from the researchers, comments James Johnson, a doctor affiliated with the Louisiana State University Health Sciences Center and studies alternate-day fasting in humans.

The option to eat high-fat meals while fasting every other day may make people more likely to stick with the demanding diet regimen, researchers say. To date, only three small studies have examined the effects of alternate-day fasting on people, says Varady, now at the University of Illinois in Chicago.

She says the next step is to see whether an unrestricted high-fat diet one day and a small amount of food the next will confer the same health benefits in humans as it does in mice. Varady and her colleagues are currently conducting a study to test whether humans are able to stick with such a diet. Preliminary data suggest that they can.

“The alternate diet has a lot of potential,” comments Valter Longo, a University of Southern California in Los Angeles researcher who studies aging. But, he adds, “I seriously doubt that very many people would adopt it because it is very tough to do regularly.”

Ravussin knows the difficulty firsthand. When he attempted alternate-day fasting himself, he reported feeling very irritable and hungry. “My wife told me, ‘Don’t do it again.’ ”

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DiscoveryNews.com, by Irene Klotz — A Boston-area company plans to begin flight tests this year of a two-seater airplane that moonlights as a car.

The aptly named Transition takes a stab at bridging the gap between automobiles and airplanes. Some people call it a flying car. The company designing and selling the vehicle prefers the term “roadable aircraft.”

Either way, it boils down to this: You sit down behind the steering wheel, drive to the runway, unfold two wings and take off. You can fly 500 miles on a tank of gas — regular unleaded — and when you land, you simply fold up the wings and drive where you want to go. At the end of the day, you fly back, drive home and park inside your garage.

Terrafugia, of Woburn, Mass., is not the first firm to attempt what may be the ultimate hybrid.

“It’s probably a concept that people have been dreaming up since there have been airplanes and cars,” said Dick Knapinski with the Experimental Aircraft Association, a 55-year-old aviation group based in Oshkosh, Wisc.

A company called Aerocar of Longview, Wash., debuted one of the first flying cars in 1949. The company built six prototypes, one of which is sitting in the EAA’s museum, but never went into production.

Terrafugia, founded in 2006 by a group of MIT students, has taken deposits for more than 40 Transitions and plans to begin deliveries in 2010, said Richard Gersh, vice president of business development.

The vehicles sell for $194,000.

Advances in materials and propulsion technologies are among the reasons why Terrafugia is in position for commercial success. But equally important, says Knapinski, is an easing of government regulations on private aircraft and pilot licensing.

In 2004, the Federal Aviation Administration created a new category of aircraft and license for sport aviation, an attempt to re-awaken interest in flying after steady drops in the number of licensed pilots.

In the United States, about 600,000 people are licensed to fly aircraft, a drop of 25 percent since 1980, Knapinski said.

“The FAA and the aviation industry realized there has to be a way to get people interested in flying. Even the airline pilots of today had to start somewhere with basic flying. There had to be an entry point that was practical and affordable,” he said.

Sport pilot licenses don’t require as many hours of training as private and commercial pilot licenses, though sport fliers are not eligible to take off and land at runways with air traffic control towers. The medical requirements for sport pilots also are less stringent than for other types of pilot licenses, matching what is needed for a driver’s license.

“What the FAA and the government say by having that rule is that these vehicles have the same level of complexity as motor vehicles,” Knapinski told Discovery News. “You fly in non-complex airspace at relatively low speed.”

Regulations covering the new category of sport aviation aircraft likewise are reduced.

“It gives us an opportunity,” said Terrafugia’s Gersh. “We could never compete with Cessna or Boeing.”

One of the biggest obstacles facing a company like Terrafugia in launching a personal aircraft is not technical in nature or even cost, added Knapinski. It’s perception.

“The comfort level for a significant percentage of the population is not there,” Knapinski said. “They just don’t believe they can operate this type of machine.”

Perhaps having an airplane under the same roof as the family car will be just the ticket.