In Early Trial, Targeted Therapy Fights Advanced Melanoma

By probing deeper into the biological mechanisms that go awry in melanoma, scientists have come up with an experimental drug that has had an effect in a surprising number of patients with advanced melanoma.

The drug, PLX4032, just completed a phase 1 clinical trial in which 81 percent of participants with a particular gene mutation had a partial response, meaning at least some shrinkage of the tumor.

The current standard treatments for metastatic melanoma -- chemotherapy and interleukin-2 (IL2) -- only have response rates in about 15 percent of these patients, said Dr. Paul Chapman, senior author of a study in which the findings are described.

The average survival time for someone diagnosed with melanoma is nine to 11 months, added Chapman, who is an attending physician in the Melanoma Sarcoma Service at Memorial Sloan-Kettering Cancer Center in New York City.

One expert cautioned that it's too early to say whether the drug will actually prolong patient's lives, or if it might be helpful to patients in earlier stages of the disease.

"I don't want to say this is going to change survival rates but they're working with the most ill people, so you can't really generalize [to other patient populations]," said Dr. Alice Pentland, chair of dermatology at the University of Rochester Medical Center. "I think the most important part of this breakthrough is the bigger percentage of people who responded."

The study, which is published in the Aug. 26 issue of the New England Journal of Medicine, was funded by drug makers Plexxikon and Roche Pharmaceuticals.

About nine years ago, scientists discovered that the tumors of about half of patients with melanoma have a mutation in a gene called BRAF.

The gene appears to help drive the runaway cell division that is a hallmark of cancer. "It's always on. It's always signaling to the nucleus [of the tumor cells] that it's time to divide," Chapman explained.

That finding opened the door to potential targeted, molecular therapies for melanoma, which has been sorely lacking in effective treatments.

PLX4032 is the first potent inhibitor of BRAF that has made it to the clinical trial stage, Chapman said.

In the trial, 55 patients received escalating doses of the drug. Ten of 16 patients who had the BRAF gene mutation had a partial response to the drug, meaning the tumor shrank by at least 30 percent, while one had a complete response, with the tumor disappearing altogether.

Among 32 patients with BRAF-mutated melanoma in the second phase of the study, 24 had a partial response and two had a complete response.

"It worked: 81 percent had a partial response -- which has never been seen. I don't know of any solid tumors that have a response rate that high," said Chapman. "What's different here is that we've discovered a molecule that is responsible for driving the melanoma cell. It turns out that the melanoma really cares if we block the gene BRAF. It matters. It's addicted to this pathway."

There are some important caveats, however. It's not known at this time if the drug can improve overall survival, and a sizable proportion of participants developed resistance to the drug, the researchers say.

The findings join other recent reports of potential treatments for melanoma in what appears to be an exciting time for the field. Progress in this field has essentially been stalled for decades, experts say.

Recently, scientists reported that another experimental drug, ipilimumab, prolonged median survival in patients with metastatic melanoma from 6.4 months to 10 months.

"[Existing therapy] is not good for melanoma, so this is really a new opportunity that I think may have some importance to people," Pentland said.

However, she stressed that the best defense against melanoma is to get your skin examined regularly by a professional who knows what to look for.

"Our most successful treatment is to get [the lesion] early, get it before it's thick, get it before it spreads," she said.

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Findings May Lead to First Approved Treatment for Myelofibrosis

Myelofibrosis is a rare but serious disorder in which the bone marrow is replaced by scar tissue. There is no currently approved treatment for the disease, but a phase I/II clinical study of an experimental drug produced by Incyte Corp. of Delaware may possibly lead to the first medical option to reduce spleen size.

One of the primary symptoms of myelofibrosis is an enlarged spleen. Because the scarring of the bone marrow causes anemia, both the liver and the spleen attempt to make blood cells, which causes the organs to swell.

The new pill, called INCB18424 was found in a small study of 153 patients to reduce the size of the spleen of over half of the patients by 50% in an average of two weeks to one month, avoiding surgery to remove the organ called a splenectomy.

Also, fewer patients than expected progressed to a more severe form of the disorder called acute myeloid leukemia, a cancer that starts in the bone marrow and affects the normal production of white blood cells.

“This is a disease for which patients don’t have a therapy,” said Srdan Verstovsek, lead author and an associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston. The results, particularly the reduction of spleen size, have been “unbelievable,” he said.

The pill was also found to lessen other common symptoms, such as weight loss, fatigue and night sweats. Unfortunately, however, the medicine did not effectively address anemia, which in myelofibrosis patients often requires blood transfusions and medications called recombinant erythropoietin to help stimulate red blood cell production.

Incyte plants to initiate the third and final stage of human trials required for US approval of INCB18424.

If approved, the drug will likely be marketed by Novartis outside the US, according to Reuters.

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Scientists In Singapore Discover New Drug Against Malaria

Scientists from the Singapore Immunology Network (SIgN) of Singapore’s Agency of Science, Technology and Research’s (A*STAR) led by Dr Laurent Renia have made a breakthrough concerning a drug that is effective against malaria.

Their work, carried out with industry leader Novartis, the Swiss Tropical and Public Health Institute, and The Scripps Research Institute, was published in top scientific journal Science.

The discovery and validation of the new drug, spiroindolone NITD609, is timely as many strains of drug-resistant malaria are emerging.

Dr Renia and his team of scientists from SIgN played a significant role in the testing and validation of the drug. With the help of a pioneering technology, Dr Renia tested spiroindolone NITD609 against field isolates – samples of the parasite isolated directly from patients.

This enabled researchers to obtain a clearer picture of how the drug would perform in a real life situation. In addition, Dr Renia’s team also tested the drug against a strain of malaria, P. vivax, that cannot be cultured in a lab, showing that the drug was also effective against another important species of malaria parasites.

Said Dr Renia, “We are excited to be able to contribute to the fight against malaria with our expertise and know-how. Our technology enabled Novartis to obtain a clearer picture of how their drug might perform in the field, giving them a better idea of the effectiveness of their spiroindolone NITD609. Moving forward, we will continue to collaborate with Novartis in the necessary steps to bring the drug closer to a medical reality. ”

Prof Paola Castagnoli, Scientific Director of SIgN, commented, “Malaria is a threat that kills approximately one child every 45 seconds. This kind of collaboration between SIgN and Novartis represents how the talent and know-how of our researchers can be applied to problems as pressing and urgent as malaria. SIgN will continue to explore ways in which we can work together with the private sector (biotech and pharma companies) to fight against human infectious diseases.”

Dr Renia and his team plan to continue the fight against malaria by assisting Novartis in the further testing of other possible drug candidates against field isolates.

They are also planning to further develop SIgN’s expertise in technologies that can be used in the fight against malaria by developing a new, fast, and robust assay using portable flow cytometer to test drugs in field conditions

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New Drug Speeds Response in multidrug-resistant TB

Patients with multidrug-resistant TB (MDR-TB) given a new anti-TB drug -- TMC207 -- combined with a background regimen, responded almost twice as fast as those on placebo with the background regimen, a researcher reported here.

Final results from the first part of a stage IIb trial among 47 patients, found the median time to culture conversion was 11 weeks for those treated for eight weeks with TMC207 and the five-drug MBR-TB background regimen, according to Andreas Diacon, MD, of the University of Stellenbosch in South Africa.

In contrast, the median time for patients assigned to placebo combined with the five-drug background regimen was 18 weeks, Diacon reported here at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Importantly," Diacon said, "these patients were only treated with TMC207 for eight weeks and still there is a significant reduction in the median time to culture conversion compared with placebo."

The drug has been closely followed (See ICAAC-IDSA: Novel Drug Shows Power in MDR-TB) but Diacon presented the final results of the first stage of the trial, which involved eight weeks of therapy with TMC207 and two years of the background regimen alone.

A second stage of the trial, with a different and larger cohort of patients treated for 24 weeks, is currently under way, he added.

TMC207 interferes with synthesis of adenosine triphosphate in Mycobacterium tuberculosis cells, but not in other cells, even those of closely related bacteria. Inhibiting the compound reduces the energy available for the TB bacteria to combat other drugs or to reproduce.

The researchers were looking at the safety and tolerability of the drug, as well as efficacy, in 47 patients with multidrug-resistant TB, defined as a strain resistant to the first-line drugs isoniazid (Nydrazid) and rifampin (Rifadin).

They were treated with a five-drug background regimen, which varied from patient to patient but usually included ethionamide (Trecator), pyrazinamide, kanamycin (Kantrex), and ofloxacin (Floxin). TMC207 was given daily at 400 milligrams for two weeks, followed by 200 milligrams three times weekly for six weeks.

At the end of the first stage of the trial, Diacon said, 81% of those treated with TMC207 were considered cured, defined as two consecutive negative cultures at least 28 days apart and no recurrence of the disease.

In contrast, 57% of those getting the background regimen alone were considered cured, a difference that was significant at P=0.03, he said.

The drug was generally well tolerated, Diacon said. No patients stopped the drug because of adverse events, and the proportions of patients with grade 3 and 4 adverse events were similar between the arms -- 26% for TMC207 and 21% for placebo.

The results are exciting, according to Patrick Charles, MD, PhD, of Austin Health in Heidelberg, Australia, who moderated the session at which the study was presented but who was not involved in the research.

"It's really the first new drug to treat these extremely resistant cases," he told MedPage Today.

For patients with multidrug-resistant TB, he said, treatment options are "very limited and very expensive, so to have a new drug is very exciting."

According to the abstract, preliminary results from the second stage of this trial, involving 161 MDR-TB patients with TMC207 administered for six months, are expected soon.

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Promising Treatment for Metastatic Melanoma

Researchers from the John Theurer Cancer Center at Hackensack University Medical Center played an important role in a study that led to the Food & Drug Administration's (FDA) recent fast tracking of ipilimumab, a promising treatment for metastatic melanoma.

The FDA based its decision largely on the results of a pivotal study published in the New England Journal of Medicine on August 19, 2010 - the same day the agency accepted Bristol-Myers Squibb's application for the drug's approval and granted the application priority review status.

Ipilimumab is the first drug shown in randomized, placebo-controlled trials to improve survival in stage IV melanoma.

"This study, and the FDA's decision, provides new hope for people with this devastating cancer," said Andrew L. Pecora, M.D., F.A.C.P., C.P.E., Chairman and Executive Administrative Director, John Theurer Cancer Center, who led the study at the John Theurer Cancer Center. "We are proud to have played a role in helping move another promising cancer treatment closer to market."

The incidence of metastatic melanoma has increased over the last three decades, and the death rate continues to climb faster than that of most other cancers. According to the American Cancer Society, there were approximately 68,000 new cases of melanoma in the United States in 2009, and 8,700 melanoma-related deaths. Melanoma accounts for about three percent of all skin cancers, but 80 percent of skin cancer deaths. Melanoma is difficult to treat once it has spread beyond the skin to other parts of the body (metastasized). Very few treatment options exist for people with metastatic melanoma.

In this phase III study, researchers randomly assigned patients to one of three treatment groups: those receiving ipilimumab plus an inactive (placebo) version of gp 100, a cancer vaccine; those receiving ipilimumab plus gp 100; and those receiving gp 100 plus ipilimumab placebo. The treatments were administered once every three weeks, for a total of four treatments. The study was double blinded: neither the researchers nor the patients knew which medications the patients were being given.

To participate in the study, patients must have had stage III or IV (metastatic) melanoma, and must have been previously treated unsuccessfully with another cancer drug. They must also have had a life expectancy of at least four months. 676 patients participated in the study at 125 cancer centers.

Those who received ipilimumab, both by itself and with gp 100, lived a median of about 10 months, while those who received only gp 100 lived about 6.4 months. After two years, approximately 23 percent of those who got ipilimumab were alive, while 14 percent of those who did not receive this drug survived. Ten to 15 percent of those who received ipilimumab suffered attacks on their bodies' immune systems (autoimmune reactions), and seven of the 540 patients who got this drug died from these attacks. Most adverse events suffered by study participants, however, were reversible with treatment.

A monoclonal antibody, ipilimumab activates the body's immune system to fight cancer by blocking a protein called CTLA-4. CTLA-4 is a molecule on T-cells, white blood cells that play a critical role in regulating immune responses. CTLA-4 suppresses the immune system's response to disease, so blocking its activity stimulates the immune system to fight the melanoma.

The FDA grants priority review status to drugs that offer major advances in treatment, or that provide treatment where no adequate therapy exists. The projected FDA action date for the ipilimumab application is December 25, 2010.

The John Theurer Cancer Center has more than 100 clinical trials under way for all types of cancer and life-threatening blood disorders. Clinical trials test the safety and effectiveness of new medications, therapies, treatment regimens, devices, and adjuvant treatments in human patients. These clinical trials are conducted independently or in cooperation with pharmaceutical companies, universities, other cancer centers, and national organizations such as the National Cancer Institute, the American Cancer Society, the National Science Foundation, and the National Institutes of Health.

"Our commitment to providing outstanding patient care and leading edge treatments extends to our leadership or participation in major clinical trials," said Dr. Pecora. "We are dedicated to improving treatment outcomes not just for our patients, but for all of those with cancer."

Results of this study were originally presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2010, and published online by the New England Journal of Medicine to coincide with the presentation.

About the John Theurer Cancer Center at Hackensack University Medical Center

The John Theurer Cancer Center at Hackensack University Medical Center is New Jersey's largest and most comprehensive center dedicated to the diagnosis, treatment, management, research, screenings, and preventive care as well as survivorship of patients with all types of cancer. The 15 specialized divisions covering the complete spectrum of cancer care have developed a close-knit team of medical, research, nursing, and support staff with specialized expertise that translates into more advanced, focused care for all patients. Each year, more people in the New Jersey/New York metropolitan area turn to the John Theurer Cancer Center for cancer care than to any other facility in New Jersey. Housed within a 775-bed not-for-profit teaching, tertiary care, and research hospital, the John Theurer Cancer Center provides state-of-the-art technological advances, compassionate care, research innovations, medical expertise, and a full range of after care services that distinguish the John Theurer Cancer Center from other facilities.

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Researchers try new approaches to preventing HIV

Tablets, insertable rings and dissolving films can effectively deliver drugs to help protect women and perhaps men from infection with the AIDS virus, researchers reported on Monday.

They also found evidence that using such an approach -- called a microbicide -- may help overcome some of the risks of drug resistance that can come with taking pills to prevent infection.

Here are some of the findings from the International Microbicides Conference being held in Pittsburgh:

* A flexible ring designed for use in the vagina can continually deliver two AIDS drugs for up to a month. Andrew Loxley of Bethlehem, Pennsylvania-based Particle Sciences, Inc., and colleagues lab tested a vaginal ring that time-released dapivirine, a drug made by Johnson & Johnson's Tibotec Inc and licensed to the International Partnership for Microbicides, and the entry inhibitor maraviroc sold by Pfizer under the brand name Selzentry. It has not been tested in people yet.

* A vaginal tablet worked in similar fashion, time-releasing maraviroc and another experimental HIV drug called DS003, licensed to the International Partnership for Microbicides by Bristol-Myers Squibb, Sanjay Garg of the University of Auckland in New Zealand told the conference. The tablet uses a polymer designed to attach to the moist lining inside the vagina.

* A third approach uses a film, Anthony Ham of ImQuest BioSciences of Frederick, Maryland reported. ImQuest is testing the HIV drug IQP-0528 in a film smaller and thinner than a stick of gum, similar to a mouthwash strip.

* Susan Schader of McGill University in Montreal, Canada, and colleagues said tests of these and other HIV drugs used as microbicides showed that drug resistance emerged only if HIV was in the lab dish first -- which suggests people would only develop drug-resistant infections by using microbicides when they were already infected.

* The AIDS virus infects more than 33 million people globally and it has killed 25 million, according to the United Nations AIDS agency UNAIDS. Globally, more than half of those with HIV are women, most infected by husbands or steady partners and many of whom who are unable to insist on use of a condom.

* AIDS experts have long been searching for a microbicide -- a cream, gel or vaginal ring that women or men could use as a chemical shield to protect themselves from sexual transmission of the deadly and incurable virus.

* Microbicides using HIV drugs would represent a large new market for the companies that make the drugs, which are now used only to treat infection.

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New theory of Alzheimer's explains drug failures

Brain plaques, long considered the chief killer of brain cells and the cause of Alzheimer's disease, may actually play a protective role under a new theory that is changing the way researchers think about the disease.

Instead of sticky plaques, free-floating bits of a toxic protein called amyloid beta may be what's killing off brain cells in Alzheimer's patients, U.S. researchers say.

If the theory is right, then drugs that target plaque, including bapineuzumab -- being developed by Pfizer, Johnson & Johnson and Elan -- may be aiming at the wrong target, they say.

"The plaque is not the main culprit in terms of toxicity," said Dr. Scott McGinnis of Harvard Medical School and Brigham and Women's Hospital in Boston, who treats Alzheimer's patients and runs clinical trials testing new Alzheimer's drugs.

For more than two decades, the prevailing plan of attack for researchers and drug companies has been to find a way to remove sticky clumps of a protein called amyloid beta from the brain.

But several recent studies in mice and rats now suggest that floating pieces of amyloid beta called oligomers are the real bad actors in Alzheimer's disease.

And instead of being the chief toxin, several teams suspect, the plaques may be the body's way of trapping and neutralizing oligomers.

"If you say Alzheimer's, everyone immediately thinks that it's the plaques that actually cause the disease. That couldn't be further from the truth," Andrew Dillin, of the Salk Institute in California and the Howard Hughes Medical Institute, told reporters in London this week at a conference on aging.

"The data actually suggest these plaques are a form of protection that the body tries to put on. So this is a sign that your brain was trying to do something very useful and helpful to you, and the remnant was the formation of amyloid plaques," Dillin said.

A Good Thing?

Adrian Ivinson, who directs the Harvard NeuroDiscovery Center in Boston, a drug discovery center affiliated with Harvard Medical School working on new Alzheimer's drugs, said scientists are beginning to think plaque is a good thing.

"It actually sequesters all of that amyloid," he said, adding that oligomers are "the really toxic substance."

In the latest study, a team led by Dr. Sam Gandy of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine in New York genetically engineered mice that form only oligomers, but never brain plaques.

They found these mice developed the same level of memory and thinking problems as genetically engineered mice that get both plaques and oligomers.

And when the team added a gene that converted the oligomers to plaques, the mice got no worse.

"That suggests that plaques were not necessary and the addition of plaque did not make the oligomer-induced memory problems any worse," said Gandy, whose study appeared last month in the Annals of Neurology.

The findings may help explain the stunning failure of drugs designed to remove plaques from the brain of patients, which do little to improve thinking in Alzheimer's patients.

Alzheimer's is the most common form of dementia in which patients progressively lose their ability to think and care for themselves. Current drugs only treat symptoms.

Lack of Effects

Gandy points to a recent imaging study in Lancet Neurology looking at the drug bapineuzumab -- now in late-stage clinical trials.

The team used an imaging agent called Pittsburgh Compound B or PiB that can be used in brain scans to identify amyloid plaques. Using these scans in 28 patients, the team found that bapineuzumab shrank brain plaques by 25 percent, but Gandy said the drug had no effect on patients' ability to think and reason.

"We don't know whether bapineuzumab sees oligomers or not," Gandy said in a telephone interview.

And because PiB can only see amyloid deposits and not floating clumps of oligomers, there is no way to know whether the drug is having any effect.

Gandy said the Lancet Neurology study may simply mean that patients need to be treated longer to benefit from bapineuzumab. Or, it may mean that the drug -- an engineered immune-system molecule called a monoclonal antibody -- is targeting the wrong thing.

Bapineuzumab has had mixed results in a mid-stage clinical trial, and some researchers were encouraged by the Lancet Neurology study because it reduced plaque levels in patients.

But Dillin said the drug, like several others aimed at trying to stop plaques from forming, is destined to fail.

"This hypothesis is actually completely wrong, and we need a new way to start looking at this disease. This is actually not a viable therapeutic avenue," Dillin said.

Pfizer this month said results of its U.S. phase 3 trials would be released in mid-2012 and the European phase 3 trials would be done in 2014, a bit later than analysts had expected.

Many investors have already written off bapineuzumab, but since Alzheimer's afflicts 26 million people worldwide, any success could mean billions of dollars in revenue.

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New drug type developed to kill lymphoma cells

Scientists have developed a new type of drug designed to kill non-Hodgkin lymphoma tumour cells.

The breakthrough could lead to potential non-toxic therapies for cancer patients.

The researchers, including Dr. Ari Melnick, of Weill Cornell Medical College, Dr. Alexander MacKerell, of the University of Maryland and Dr. Gilbert Prive, of the University of Toronto, have identified a drug that targets an oncogene known as BCL6.CL6 functions as a master regulatory protein.

"It's a protein that controls the production of thousands of other genes. Because of that, it has a very profound impact on cells and is required for lymphoma cells to survive and multiply," said Melnick.

BCL6 causes the majority of diffuse large B cell lymphomas, the most common form of non-Hodgkin lymphoma.

Currently, about 60 percent of diffuse large B cell lymphomas can be cured with chemo-immunotherapy, said Melnick.

"The hope is that we can improve that to a higher percent, and in the long term reduce the need for chemotherapy," he added.

Traditional cancer drugs target enzymes, which have small pockets on their surfaces that can be blocked with molecules.

Until now, pharmaceutical companies have been reluctant to create drugs that target a protein like BCL6 because they function through a different mechanism involving interactions with cofactor proteins involving extensive protein surfaces.

"And because the real estate covered by these interactions is so large, the drug companies have viewed these as being not druggable targets," said Melnick.

The researchers could identify a "hot spot" on BLC6 that they predicted would play a critical role in protein interactions.

They showed that their BCL6 inhibitor drug was specific to BCL6, and did not block other master regulatory proteins.

The drug had powerful lymphoma killing activity and yet was non-toxic to normal tissues.

"This is the first time a drug of this nature has been designed and it shows that it's not actually impossible to target factors like BCL6," he said.

Emerging data from other investigators suggests that BCL6 is important in many other tumor types, including forms of leukemia.

The study has been published in a recent issue of Cancer Cell. (ANI)

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Researchers discover metabolic vulnerability in TB and potential drug target

Tuberculosis (TB) has been present in humans since ancient times. The origins of the disease date back to the first domestication of cattle, and skeletal remains show prehistoric humans (4,000 B.C.) had TB. Although relatively rare in the United States, it is the single leading bacterial cause of death worldwide. Approximately 8 million people are infected each year and 2 million people die from TB.

The cause of tuberculosis is Mycobacterium tuberculosis (Mtb), a slow-growing aerobic bacterium that divides every 16 to 20 hours. Scientists know that carbon metabolism plays a significant role in the ability of Mtb to replicate and persist in the body and that fatty acids are the major source of carbon and energy during infection. However, the specific enzymes required for the metabolism of fatty acids have not been completely defined.

New research conducted at Weill Cornell Medical College and published online in the Proceedings of the National Academy of Sciences (PNAS) sheds light on a previously unrecognized aspect of fatty acid metabolism that could potentially lead to new targets for drug therapy. A team led by Dr. Sabine Ehrt, professor of microbiology and immunology at Weill Cornell Medical College, reported that Mtb relies primarily on gluconeogenic substrates for in vivo growth and persistence, and that phosphoenolpyruvate carboxykinase (PEPCK) plays a pivotal role in the growth and survival of Mtb during infections in mice, making PEPCK a potential target for drugs that fight tuberculosis.

Dr. Ehrt and her colleagues found a way to silence the gene encoding PEPCK in Mtb during mouse infections to assess the importance of gluconeogenesis for Mtb's ability to maintain a chronic infection. According to Dr. Ehrt, "Silencing a gene when the pathogen is not or only slowly replicating, after an infection has established, is an important tool for studying diseases such as TB, which can be dormant for years only to become active again years later."

Dr. Ehrt, the lead author on the paper, conducts basic research on the pathogenesis of tuberculosis. She and her team investigate the role of the macrophage in the immune response to Mtb and the molecular mechanisms used by the pathogen to establish and maintain persistent infections. A goal of Dr. Ehrt's research is to validate novel drug targets that may facilitate the development of new therapies against active and chronic TB.

"Tuberculosis is very difficult to treat," says Dr. Erht. "It is especially challenging as the infection can lay dormant in the body even though there are no symptoms. We investigated the metabolic requirements of Mtb during acute and chronic infections and found that the gluconeogenic enzyme PEPCK is critical for both."

The study used a novel mass spectrometry-based metabolic profiling tool, developed at Weill Cornell (in collaboration with Agilent Technologies) by Dr. Kyu Rhee to biochemically examine Mtb carbon metabolism. The tool has provided the first direct insights into the metabolic architecture of Mtb. Dr. Rhee is a co-author and assistant professor of medicine, microbiology & immunology, and the Hearst Clinical Scholar in Microbiology & Infectious Diseases at Weill Cornell Medical College.

Dr. Ehrt hopes that her work will eventually lead to new drug therapies to treat tuberculosis. "Although the current treatments we have to treat Mtb are effective, the treatment times are too long and the regimens too complex. This leads to treatment failures, due to poor adherence and multidrug resistance. We need new, safer drugs that work faster to eliminate tuberculosis."

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Research helps end guesswork in prescribing ADHD drug

Children with ADHD who carry a specific type of dopamine receptor gene respond better to the drug methylphenidate (MPH) than those without the genotype, according to new research from Cincinnati Children's Hospital Medical Center.

The findings come from the first-ever placebo-controlled pharmacogenetic drug trial for Attention Deficit/Hyperactivity Disorder in school age children to evaluate variants of the DRD4 dopamine receptor gene using teacher ratings of children's symptoms.

The research makes progress toward ending the guesswork now involved in prescribing effective ADHD medications that deliver the greatest symptom improvement and fewest side effects, according Tanya Froehlich, M.D., a physician and researcher in the division of Developmental and Behavioral Pediatrics at Cincinnati Children's.

"We don't have a good way of predicting who will experience great improvement in ADHD symptoms with a particular medication, so we use a trial-and-error approach. Unfortunately, as a result finding an effective treatment can take a long time," Froehlich said. "With more information about genes that may be involved in ADHD medication response, we might be able to predict treatment course, tailor our approach to each child, and improve symptom response while decreasing health care costs."

The study was presented May 1 at the annual meeting of the Pediatric Academic Societies in Vancouver, Canada.

Dr. Froehlich and her colleagues tested 89 children between the ages of 7 and 11 who were not already taking stimulant medications for their ADHD. The researchers analyzed DNA from saliva samples to see if the children carried the 7-repeat version of the DRD4 gene, an increasing target of ADHD gene-based studies that has been linked to increased risk for the condition.

Children in the double-blind four-week trial were given one week each of placebo and three different doses of MPH for their ADHD. Parents and teachers assessed and scored the children's behavioral symptoms based on the Vanderbilt ADHD Parent and Teacher Rating Scales. In children with at least one copy of the 7-repeat DRD4 gene who took MPH, teachers reported greater improvement in symptoms with increasing doses compared to children who did not have any copies of the 7-repeat gene.

Going forward, Dr. Froehlich said researchers will be studying additional gene variants and their relationship to ADHD medication response. This includes genes that encode MPH drug targets, such as the dopamine transporter, as well as enzymes that help the body metabolize the drug. MPH (which goes by several brand names, including Ritalin and Concerta) is a stimulant frequently used to treat ADHD.

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Parents Try Alternative Treatments for Autism

Many families are turning toward to special diets and/or psychotropic medications to help better manage autism spectrum disorder and its symptoms in their children, two new studies show.

The CDC estimates that about one in 110 children in the U.S. have an autism spectrum disorder, the umbrella name given to a group of disorders that can range from the mild to the severe that often affect social and communication abilities.

One study shows that 21% of children with autism spectrum disorder are using complementary and alternative medical therapies. Of these, 17% were on special diets, most commonly a gluten-free or casein-fee diet.

Another study shows that more than one-quarter of children with autism spectrum disorder receive at least one psychotropic medication to treat some of their behavioral symptoms such as hyperactivity or irritability.

Both studies were presented at the Pediatric Academy Societies annual meeting in Vancouver, British Columbia, and were sponsored by the Autism Treatment Network, a network of 14 centers across the U.S. and Canada that is focused on developing standards of care for treating children with autism spectrum disorder.

"Complementary medicine is used for all sorts of things such as arthritis and attention deficit hyperactivity disorder (ADHD), so to see it being used for children on the spectrum is pretty much expected," says Daniel Coury, MD, chief of developmental behavioral pediatrics at Nationwide Children's Hospital in Columbus, Ohio, and the medical director of the Autism Treatment Network.

"Families may be looking at complementary treatment because traditional medical treatments may not be doing the job for their child," he says. There is some anecdotal evidence that these diets may improve symptoms among some children with autism.

Parents need to make sure that their child's doctors are aware of what they are taking as some alternative therapies may have side effects on their own or when used in combination with other therapies, he says.

Psychotropic Medications

The study shows that younger children with autism were less likely than older kids to receive psychotropic medications. Sixty percent of children aged 11 and older took one psychotropic drug, compared with 44% of children aged 6 to 10, 11% of children ages 3 to 5, and 4% of children under age 3. The most commonly used medications were stimulants to help treat ADHD symptoms and a drug called risperidone, which is prescribed to treat irritability. Older children were more likely to be taking more than one psychotropic drug, the study shows.

The study raises some questions about how, when, and even why these medications are being used in autism treatment, Coury says.

"It may be that parents and doctors are not treating these children when they are first diagnosed, which usually occurs at very young ages," Coury says. But "as the diagnosis is established, there is a higher likelihood of medications being prescribed. Or the use of these drugs may reflect those children who are more severely affected or don't have access to other nonmedical treatments such as intensive behavioral therapies," he says.

Children who are diagnosed with autism often see numerous specialists several times a week for various types of speech and behavioral therapy.

But "if these therapies are not available, parents may reach for plan B or plan C," he says.

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Promise Seen in Drug for Fragile X Syndrome

An experimental drug succeeded in a small clinical trial in bringing about what the researchers called substantial improvements in the behaviors associated with retardation and autism in people with fragile X syndrome, the most common inherited cause of these mental disabilities.

The surprising results, disclosed in an interview this week by Novartis, the Swiss pharmaceutical giant that makes the drug, grew out of three decades of painstaking genetic research, leaps in the understanding of how the brain works, the advocacy of families who refused to give up, and a chance meeting between two scientists who mistakenly showed up at the same conference.

“Just three years ago, I would have said that mental retardation is a disability needing rehab, not a disorder needing medication,” said Dr. Thomas R. Insel, director of the National Institute of Mental Health, who was told of the Novartis trial results. “Any positive results from clinical trials will be amazingly hopeful.”

Dr. Mark C. Fishman, president of the Novartis Institutes for BioMedical Research, cautioned against too much optimism. The trial involved only a few dozen patients, only some of whom benefited from treatment. The drug is likely to be years away from being commercially available and could fail in further clinical trials, he said.

“We have been reluctant to make this public because we still need to do more experiments, do them correctly and in a bigger way,” Dr. Fishman said. “But our group feels pretty good about the data.”

If authenticated in further, larger trials, the results could also become a landmark in the field of autism research, since scientists speculated that the drug may help some patients with autism not caused by fragile X, perhaps becoming the first medicine to address autism’s core symptoms.

One child in five thousand is born with fragile X syndrome, with mental effects ranging from mild learning disabilities to retardation so profound that sufferers do not speak, and physical effects that include elongated faces, prominent jaws, big ears, and enlarged testes. It mostly affects boys and earned its name because, under a microscope, one arm of the X chromosome seems nearly broken, with part hanging by a thread.

The gene for fragile X was discovered in 1991. Work since then has found that fragile X patients seem to experience an overload of unchecked synaptic noise — synapses being the junctions between brain neurons. The Novartis drug and others like it are intended to lower the volume of this noise so memory formation and high-level thinking can take place, allowing children to develop normally.

The Novartis trial, which began in 2008 in Europe with data analysis completed this year, was too brief to observe effects on basic intelligence. Instead, researchers measured a range of aberrant behaviors like hyperactivity, repetitive motions, social withdrawal and inappropriate speech. They gave one set of patients the drug and another a placebo, and after a few weeks switched treatments, with both doctors and patients unaware of which pill was which.

The results of the trial were something of a jumble until Novartis scientists noticed that patients who had a particular, undisclosed biological trait improved far more than others. “The bottom line is that we showed clear improvements in behavior,” Dr. Fishman said.

Told of the results, two parents of a fragile X patient were euphoric.

“This is what we have been working for and hoping for since our son was diagnosed with fragile X 17 years ago,” said Katie Clapp, president and co-founder of the Fraxa Research Foundation, a nonprofit organization dedicated to financing fragile X research. “This may be the key to solving the mystery of autism and other developmental disorders.”

Geraldine Dawson, chief science officer at Autism Speaks, the world’s largest autism advocacy organization, said that a growing body of research suggests that the many genetic causes of autism all seem to affect synapses, suggesting that a treatment for one form of the disease might help others.

“The exciting thing about these results is that it is our hope that these same medications may have similar positive benefits for people with autism who don’t have fragile X syndrome,” Dr. Dawson said.

Between 10 percent and 15 percent of autism cases result from fragile X syndrome or some other known genetic defect. While fragile X is the most common inherited cause of mental retardation, Down syndrome — which also causes retardation — is more common but is not inherited.

The Novartis trial results were not published or peer reviewed, and for commercial reasons Dr. Fishman refused to divulge many details. Dr. Luca Santarelli, head of neuroscience at Roche, confirmed that Roche is in the midst of testing a similar medicine in fragile X patients at four sites in the United States.

“So far we like what we see,” Dr. Santarelli said in his only characterization of their study.

One reason for the euphoria surrounding the Novartis trial is that it was seen as an especially difficult test of the drug’s effects. For ethical reasons, Novartis tested the drug only in adults. But the company and outside researchers believe that such compounds may prove most effective in young children, whose brains are far more likely to respond rapidly when barriers to learning are removed.

“This is perhaps the most promising therapeutic discovery ever for a gene-based behavioral disease,” said Dr. Edward M. Scolnick, former research chief at Merck and now director of the Stanley Center for Psychiatric Research at the Broad Institute at Harvard and the Massachusetts Institute of Technology.

Dr. Scolnick has not seen the results of the Novartis trial, but was told of them and concluded that if the drugs work in fragile X, “there’s nothing to say that they won’t work in some cases of broader autism-spectrum disorders.”

An Unlikely Beginning

The roots for the Novartis results began in 1982 when Stephen T. Warren, then a graduate student in genetics at Michigan State University, was looking for a job and something to research. A friend told him about fragile X and, with the same reflection he might use to pick a novel for a long flight, he decided that he wanted to find the gene that caused it.

“I had no idea how hard this would be,” Dr. Warren said. Nine years later, Dr. Warren, then at Emory University, was part of an international team that won a fierce competition by isolating the gene. The discovery was front-page news around the world, and experts predicted that widespread fetal testing and therapies were in the offing.

The predictions were premature because, like most of genetic research, discovering how the flawed gene caused disease was far harder than anticipated and required multiple leaps in neurology and biology. And even with those, much remains mysterious.

Fragile X is caused by a genetic stutter in which a portion of the gene gets repeated like a scratched album. With each subsequent generation, the number of repeats tends to rise. So if a mother has 10 repeats, her child might have 11 or 12. For reasons that are not well understood, however, this process of repeat amplification can suddenly go haywire. So mothers who have 55 or more repeats tend to have children with hundreds.

In anyone with 200 or more repeats, the body shuts off the gene. Since genes are used to make proteins, this genetic silencing means the encoded protein is never made. The absence of this protein in cells causes the wide-ranging effects of fragile X syndrome. Those with 55 to 200 repeats are considered carriers, and recent research shows they can have severe neurological declines late in life that mimic Alzheimer’s and Parkinson’s.

Many geneticists would have moved on to other research topics after finding a disorder’s underlying gene. But Dr. Warren met affected children and their parents. Instead of family pictures, Dr. Warren’s desk displays a framed photo of a fragile X chromosome.

“I could not imagine telling someone like Katie Clapp that we were not going to pursue this research anymore,” he said.

So he kept on. Years of work by him and others found that the protein missing in those with fragile X normally seems to act as a sort of traffic cop at brain synapses, helping to stop or slow brain signaling at crucial intervals. It does this by sopping up the genetic instructions needed to produce proteins that encourage brain signaling. Regulating this flow of electronic pulses across the brain is crucial for the brain’s ability to learn and mature.

Dr. Warren was puzzling over how to recreate that synaptic traffic cop when, because of a scheduling conflict, he showed up in 2001 at the wrong scientific conference and happened to sit next to Mark F. Bear, a neuroscience professor at M.I.T. who had just given a presentation about compounds that seemed to work in synapses to speed the creation of proteins — including the one missing in fragile X patients.

The two got to talking and decided to collaborate. They found that if Dr. Bear reverse-engineered his compounds, they seemed to slow brain transmissions. Instead of a traffic cop, the brain would get speed bumps. Not ideal, but perhaps adequate in lowering the synaptic noise enough to encourage learning and the moderation of the kind of synaptic traffic jams that in fragile X children can lead to seizures.

Sure enough, mice, fish and fruit flies that through genetic engineering were made to have fragile X seemed to become normal when given Dr. Bear’s compound. The Novartis compound is a member of the same drug family.

“We have been promising for a long time that unlocking the molecular basis for hereditary diseases would lead to dramatic therapeutic advances, and that promise is finally coming true,” said Dr. Francis S. Collins, director of the National Institutes of Health, in discussing the science leading up to the trial. “But it has not been easy.”

A Search for Treatment

A hundred years ago, Katie Clapp would have died giving birth to Andy, her child with fragile X.

“Andy’s head was too big to get out without a C-section, he would have killed me, and that would have taken care of the fragile X gene,” she said.

But Ms. Clapp and Andy did survive. And despite going to some of the best hospitals in the country, four years would pass before Andy’s condition was properly diagnosed.

When a doctor finally thought to do a fragile X test, Ms. Clapp and her husband, Dr. Michael Tranfaglia — both Harvard graduates with post-graduate degrees — researched the disease and came to two conclusions: fragile X was potentially treatable; and only about five researchers in the world were working toward a cure.

“And I thought, what if all five walk across the street at the same time and get hit by a Mack truck?” Ms. Clapp said. “That is not going to get us there.”

So the two started the Fraxa Research Foundation. Remarkably, their efforts seem to be paying off and may finally offer hope not only to those who with fragile X but to carriers like Andy’s sister, Laura.

“I’ve always known my kids have a chance of having it,” Laura, 18, said in a recent visit to the family’s house. “But I’m not going to have kids for at least 10 years anyway, and they’ll have a cure for by then.”

She paused, looked at her mother and said: “You’ve got 10 years.”

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New Drug May Treat Cystic Fibrosis

Inherited diseases such as cystic fibrosis can be caused by genetic "nonsense mutations" that disrupt the way human cells make proteins. David Bedwell, Ph.D., a professor in the University of Alabama at Birmingham (UAB) Department of Microbiology, says scientists are now closer to producing drugs that will fix this disruption and drastically improve treatment of genetic disease.

Bedwell is a renowned researcher on the select group of genetic alterations called nonsense mutations - DNA alterations that can lead to nonfunctional or missing proteins. He presented recent findings on an experimental drug that may help to treat some cystic fibrosis patients during the Experimental Biology 2010 conference in Anaheim, Calif., April 26. This drug ataluren (formerly called PTC124) also holds promise in treating more than 2,400 different genetic disorders caused by nonsense mutations.

"When you treat a genetic disease, the bottom line is how much of the missing protein do you need to restore to have a therapeutic benefit," Bedwell says. "It comes down to the threshold of protein rescue. For some diseases, it might be 1 percent of protein you need restored, and for other diseases you may need 50 percent of protein restored."

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New Pathways In The Treatment Of Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States and throughout the world. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Sadly, most cases of lung cancer are diagnosed at an advanced stage, conferring a poor prognosis.

Should Phase III results be positive, the next step is filing a New Drug Application, for eventual FDA approval. Occasionally Phase IV trials are run, to evaluate the side effects, risks, and benefits of an already approved drug over a longer period of time, and in a larger number of people than in phase III clinical trials.

Typical first-line therapy (the initial treatment used) for advanced NSCLC patients in the United States is paclitaxel plus carboplatin. There are many possible side effects including nausea, increased risk of infection, anemia, and hair loss. Carboplatin can cause kidney damage, while paclitaxel can cause aching joints and muscles, and lowered blood pressure.

An examination of Phase III clinical trials published from 2001-2008 reveals that the one-year survival rate for patients receiving paclitaxel and carboplatin first-line therapy was on average only about 40%, the weighted average for median survival was 9.7 months, and the objective tumor response (defined as greater than 30% tumor shrinkage) rate was about 27%.

Could the efficacy of these agents be improved, and the side effects lessened? Novelos Therapeutics, Inc., a New England-based biopharmaceutical company [www.novelos.com], certainly thinks so. The company's lead product, NOV-002, is presently in a Phase III clinical trial, with top-line trial results expected later in the first quarter of 2010.

NOV-002 acts in conjunction with paclitaxel plus carboplatin as a chemopotentiator and a chemoprotectant. Thus, NOV-002 makes the chemo more effective, while lessening the side effects. NOV-002 is already approved in Russia, where excellent results have been observed. Related Russian Phase II trials demonstrated that NOV-002 increased the one-year survival of advanced NSCLC patients from 17% to 63%, and improved tolerance of chemotherapy.

Additional studies suggest that NOV-002 efficacy is not limited to particular types of tumors, or chemotherapy agents.

Novelos president and CEO Harry Palmin is enthusiastic. "We are on track for our pivotal Phase III trial to conclude this quarter. "Should this registrational trial be positive, we will proceed with filing a New Drug Application (NDA) in 3Q 2010. Thereafter, based on our Fast Track designation, we would project FDA approval for first-line treatment of advanced NSCLC in combination with chemotherapy in 1Q 2011."

Other promising new approaches in chemotherapy involve attaching the drugs to monoclonal antibodies, which could afford benefits in efficacy and reduction of side effects. These antibodies can be designed to bring the chemo agent directly to the tumor. Similar benefits are said to occur with liposomal therapy, whereby the drugs are packaged inside liposomes (synthetic fat globules).

With annual diagnoses of NSCLC in the United States approaching 200,000 and the annual death toll close to 150,000 any improvements in therapy are surely welcomed, but we still have a long way to go.

Michael D. Shaw
Exec VP
Interscan Corporation

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Drugs during pregnancy being studied

A new public/private research program will study the effects of prescription medications used during pregnancy, U.S. researchers say.

The researchers from the U.S. Food and Drug Administration, the HMO Research Network Center for Education and Research in Therapeutics, Kaiser Permanente's multiple research centers and Vanderbilt University say very few clinical trials test the safety of medications in pregnancy although one study finds two-thirds of women delivering a baby have taken at least one prescription medication during pregnancy. The Medication Exposure in Pregnancy Risk Evaluation Program will address that research gap, they say.

"This program is a great example of FDA and the private sector working together to improve the health of pregnant women and their children," Dr. Margaret Hamburg, commissioner of the Food & Drug Administration, said in a statement. "These data will guide regulatory policy and influence medical practice."

To overcome the challenges presented by the lack of clinical trial data about the use of medications during pregnancy, the research program will link healthcare information for mothers and their babies from 11 participating research sites -- a total of about 1 million births during the past seven years since 2001.

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New German drug saves Aussie baby from brain-melting disease

A "miracle" Australian baby has become the first person cured of a rare and deadly brain-melting condition after doctors gambled on an experimental German drug tested only on mice, they said Thursday.

The child, known only as "Baby Z," was facing a painful death of seizures and brain damage from molybdenum cofactor deficiency, a genetic defect which causes a build-up of toxic sulphite and usually kills in months.

But she made an amazing recovery just three days after first being given the untested treatment which was flown in from Germany and rushed through the courts.

"We are looking at her now and she is just an absolute miracle - she has defied everybody," her mother, who cannot be named for legal reasons, told reporters.

Baby Z started having seizures within 60 hours of her birth in May 2008, prompting her family to appeal to biochemist Rob Gianello to help beat the previously incurable condition which affects just one in a million Australians.

"There was courage and there was death - we opted for courage," the mother said. "If she wasn't treated she would die a very painful death."

Baby Z's doctor Alex Veldman said Gianello discovered an experimental drug which had been successfully used on mice by Germany's Gunther Schwarz, but had never been tested on humans.

As Schwarz couriered his entire stock of the compound from Cologne to Melbourne, doctors were in a race against time to get ethics approval from the hospital and a court order clearing its use, with Baby Z worsening by the hour.

"The team ... managed to get this therapy from bench to bedside in about two weeks, a process which normally takes several years," Veldman said.

Within hours of receiving her first dose of the drug, cyclic pyranopterin monophosphate (cPMP), Baby Z's sulphite levels plunged by more than two-thirds and were at normal levels within about three days.

Veldman said Baby Z's alertness improved and her twitching slowed rapidly, with her seizures dropping by 90 percent in three weeks.

"The response was just amazing," he told AFP. "We can treat this in humans for the first time in (the history of) mankind. It has the potential to save lives all around the world."

Baby Z's development has been slowed by the brain damage she suffered before the treatment, and Veldman said she would need a cPMP injection every day for the rest of her life.

But her mother said the baby, now 18 months old, had started speaking and was physically active.

"Every day just gets better and better. We look at her every day and just think, 'Wow'," she said. "(The procedure) was a tiny bit of hope but, when you have nothing, that is a lot of hope."

Veldman said a second child, "Baby P", had since started cPMP treatment in Germany and was "improving rapidly."

The cases were now being analysed ahead of a planned international human trial of the medication at Melbourne's Monash Medical Centre, he said.

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New Drug for treating spinal muscular atrophy

Scientists have identified a chemical cousin of the common antibiotic tetracycline that might be useful in treating spinal muscular atrophy (SMA), a currently incurable disease that is the leading genetic cause of death in infants.

The finding is based on a study conducted by Adrian Krainer, Ph.D., of Cold Spring Harbor Laboratory (CSHL) and scientists from Paratek Pharmaceuticals and Rosalind Franklin University of Medicine and Science.

SMA is caused by mutations in a gene called Survival of Motor Neuron 1 (SMN1), resulting in a decrease in the levels of SMN protein in the motor neurons of the spinal cord - the cells that control muscle activity.

Without the protein, these neurons degenerate, and infants born with the mutations progressively lose the ability to move, swallow, and breathe.

There are no approved therapies for the treatment of SMA.

The new molecule boosts the levels of SMN protein in cells by fixing a mistake in a cellular processing mechanism called RNA splicing.

In the study, the scientists report this fix in both mouse models of SMA, as well as in cells isolated from SMA patients.

Unlike previously identified molecules that stimulate SMN production, the tetracycline-like compound is a unique therapeutic candidate in that it is a small molecule that specifically alters RNA splicing by directly targeting the splicing reaction.

The research appears in the journal Science Translational Medicine. (ANI)

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New Lupus Drug Heads to FDA for Approval

An experimental lupus drug has just met another key goal in its journey to becoming the first approved treatment for the disease in over 50 years. The target of the new drug, known as Benlysta, is to suppress the response of the body’s immune system to lupus in an attempt to control the actions of a protein that becomes overactive in lupus patients.

Hopes were that the study data from a clinical program called Bliss-76 would confirm the optimistic results of a prior late-stage study. In actuality, the indications of the Bliss-76 data were that a 10-milligram dose of Benlysta, accompanied by therapy with steroids, resulted in improvement among 43 percent of lupus patients taking a higher dose, as well as a 40.6 percent of those taking a lower dose. This is compared to improvements observed in only 33.8 percent of patients taking a placebo.

Makers of the drug, Human Genome Sciences (HGS) based in Rockville, Maryland, and GlaxoSmithKline based in the United Kingdom, now plan to seek the regulatory approval of the U.S. Food and Drug Administration in the early months of 2010. If approved, Benlysta could be available on the market by late next year.

In a statement, HGS President and CEO H. Thomas Watkins said, “The Bliss-76 results confirm our view that Benlysta has the potential to become the first new approved drug in decades for people living with systemic lupus.” He then added, “We take great pride in the innovation and scientific rigor that has made it possible to bring Benlysta to this point.”

The Bliss-76 study was the second of two late-stage studies, and involved 865 patients who were treated and monitored over a period of one year. In October of this year, the first late-stage study, called Bliss-52, involved over 800 patients in Asia, South America and Eastern Europe, and has positive results in meeting several key goals.

Lupus is an inflammatory, autoimmune condition, in which the body’s defense system against pathogens attacks the body’s own tissue causing health issues such as rashes, mouth sores, arthritis, and kidney damage among other problems. Because the illness manifests itself differently in each patient, it is difficult to develop effective treatments against the disease. According to Watkins, “We’ve got a good chance to redefine the standard of care for patients living with lupus.”

While one recent study estimated that 322,000 Americans most likely have the most common form of lupus known as systemic lupus erythematosus, the Lupus Foundation of America estimates that about 1.5 million Americans have some form of the disease. According to Sandra C. Raymond, the organization's president and chief executive, “Individuals with lupus and their families have waited more than 50 years to hear that it is possible to develop therapies that control the disease.” She went on to say, “We believe that this is a significant first step in developing the full arsenal of therapies and personalized treatment lupus requires.”

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New 'Schizophrenia Gene' Prompts Researchers To Test Potential Drug Target

Johns Hopkins scientists report having used a commercially available drug to successfully "rescue" animal brain cells that they had intentionally damaged by manipulating a newly discovered gene that links susceptibility genes for schizophrenia and autism.

The rescue, described as "surprisingly complete" by the researchers, was accomplished with rapamycin, a drug known to act on a protein called mTOR whose role involves the production of other proteins. The idea to test this drug's effectiveness at rescuing impaired nerve cells occurred to the team as a result of having discovered a new gene that appears to act in concert with two previously identified schizophrenia susceptibility genes, one of which is involved in the activation of the protein mTOR. This piecing together of multiple genes adds support for the idea that susceptibility to schizophrenia and autism may have common genetic fingerprints, according to the researchers.

In a report on the work published in the Sept. 24 issue of the journal Neuron, the scientists are careful to say that the genes in question are not the cause of schizophrenia or any other brain/mind disorder in humans. However, these genes do appear to serve as a blueprint for proteins that consistently pop up in a range of mental illnesses in people.

The newfound gene, dubbed KIAA1212, serves as a bridge linking two schizophrenia genes: DISC1 and AKT. Suspecting KIAA1212 as one of many potential binding partners interacting with DISC1, whose name is an acronym for "Disrupted-in-Schizophrenia," the researchers genetically shut down the production of DISC1 proteins in newly born neurons in the hippocampus region of an adult mouse brain. The hippocampus contains a niche where native stem cells give rise to fully developed new neurons. The idea was to deliberately cause these cells to malfunction and then watch what happened.

The scientists found that the newborn neurons were most noticeably defective 14 days after DISC1 suppression and that they were defective in a variety of ways. By manipulating AKT production, or altering KIAA1212, they discovered the very same abnormalities as with DISC1 deficiency, concluding that KIAA1212 is in the same signaling pathway as DISC1 and AKT.

Because mTOR is a well-known downstream effector of AKT, they treated the adult mice harboring those abnormal neurons with rapamycin, a drug known to alleviate the effects of a faulty AKT pathway. It effectively "rescued" the neurons from their defects.

"Our discoveries give us more of the information we need to understand the function of genes associated with psychological diseases," says Guo-li Ming, M.D., Ph.D., an associate professor of neurology and neuroscience in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. "The next step is to create a good animal model that would allow us to test whether candidate drugs will reverse not only the irregularities of brain cells with deficiency of these genes, but also behaviors."

The new neurons with alterations of DISC1, KIAA1212 or AKT in the brains of the Rapamycin-treated mice developed normally, says Hongjun Song, Ph.D., an associate professor of Neurology in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, who collaborated in the research. "What was amazing to us is how potent the drug is, at least on the cellular level," he says. "A number of the neurons' developmental defects -- from enlarged cell size to the misplacement of cell localization and abnormal neuronal processes involved in receiving and sending messages -- were corrected by this one drug."

This study was supported by the National Institutes of Health, the McKnight Foundation, NARSAD, the International Mental Health Research Organization, the Maryland Stem Cell Research Fund, and the March of Dimes.

Authors on the paper, in addition to Ming and Song, are Ju Young Kim, Xin Duan, Cindy Y. Liu, Mi-Hyeon Jang, Junjie U. Guo, Nattapol Pow-anpongkul and Eunchai Kang, all of Johns Hopkins.

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New Drug Aims To 'Seek And Destroy' Many Types Of Cancer

A new drug designed to “seek and destroy” common cancers such as breast, prostate, endometrial, pancreatic, ovarian, skin and testicular cancers is being tested at TGen Clinical Research Services (TCRS) at Scottsdale Healthcare.

The Phase 1 clinical trial will help determine if EP-100 is safe and effective for use among patients with solid cancer tumors, with fewer side effects than chemotherapy or radiation treatment.

TCRS is a partnership of the Translational Genomics Research Institute (TGen) and Scottsdale Healthcare. The partnership allows molecular and genomic discoveries made by TGen and others around the world to reach the patient bedside in the Virginia G. Piper Cancer Center at Scottsdale Healthcare as quickly as possible through clinical trials with agents directed at specific targets in patients’ tumors.

According to Ramesh K. Ramanathan, MD, principal investigator for the trial in Scottsdale, the drug is a membrane-disrupting peptide (tMDP) designed to “seek and destroy” cancer cells by targeting those with excessive luteinizing hormone releasing hormone (LHRH) receptors.

Excessive LHRH receptors are found in a wide range of cancers, including breast, prostate, endometrial, pancreatic, ovarian, skin and testicular cancers.

Mike Janicek, MD, a Gynecologist Oncologist who practices at the Virginia G. Piper Cancer Center at Scottsdale Healthcare said, “I am looking forward to participating in the study with EP100, especially for ovarian and uterine cancer patients. Often patients with advanced cancer will need new therapies and a targeted treatment like EP100 is the next frontier of research.”

The study is designed to evaluate the safety of EP100 and will enroll as many as 36 adult patients with solid tumors whose tumor biopsies indicate that they have excessive LHRH receptors.

EP-100 will be administered intravenously for three out of four weeks. Once the maximum tolerated dose has been established, additional subjects with specific diagnoses of either breast, ovarian, endometrial, pancreatic or prostate cancer will be enrolled. EP-100 is produced by Esperance Pharmaceuticals of Baton Rouge, La., and was culled from a range of drugs tested at TGen Drug Development Services (TD2) in Scottsdale.

“It brings with it a killer, a toxin. It’s a way of targeting a toxin to the cancer tumor cells,’’ said Dr. Steve Gately, president and chief scientific advisor at TD2. “Our goal would be to find that set of patients who are highly responsive; who have the greatest benefit. We’d like to accelerate the government approval for that agent.’’

The clinical trials could show that EP-100 is effective with certain types of cancer, Dr. Gately said. “Perhaps there is a genetic context under which certain patients may be more responsive. We want to find those patients.’’

Dr. Hector Alila, president of Esperance, said EP-100 has the potential to offer an improved safety and effectiveness over existing therapies, such as radiation or chemotherapy.

“Preclinical studies of EP-100 demonstrated this candidate’s efficacy across multiple indications in oncology, including aggressive cancers known to be resistant to the current standards of care and, importantly, studies of EP-100’s mechanism-of-action support that it targets and selectively kills cancer cells without harming normal cells,” Dr. Alila said.

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