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BioAlliance Pharma SA (Paris:BIO)(Euronext Paris – BIO), a company dedicated to the supportive care and treatment of cancer patients, announces the launch in the United States of Oravig® (known as Loramyc® in Europe) for the treatment of oropharyngeal candidiasis (OPC) in adults by its commercial partner, Strativa Pharmaceuticals, the proprietary products division of Par Pharmaceutical Companies, Inc. (NYSE:PRX).

With a US FDA approval in April 2010, BioAlliance Pharma is the first small medium-sized innovative French company to have access to the American market, the largest worldwide market.

Oravig® is already available on the US market. The national sales force meeting of Strativa is being held this week in the United States to prepare the promotion of the product to the prescribers.

«The US launch of Oravig® is the ultimate step of a process that confirms our expertise in development and registration of products at the international level. It represents a major achievement that will generate significant revenues for BioAlliance Pharma», declares Dominique Costantini, its CEO. « We are very confident in Strativa sales team’s commitment and know-how to ensure Oravig® success in the US, a product presenting a strong synergy with the product portfolio already commercialized by our US partner».

Source:
BioAlliance Pharma
Strativa Pharmaceuticals
Par Pharmaceutical Companies, Inc.

A novel mechanism used by adenovirus to sidestep the cell’s suicide program, could go a long way to explain how tumor suppressor genes are silenced in tumor cells and pave the way for a new type of targeted cancer therapy, report researchers at the Salk Institute for Biological Studies in the Aug. 26, 2010 issue of Nature.

When a cell is under stress, the tumor suppressor p53 springs into action activating an army of foot soldiers that initiate a built-in “auto-destruct” mechanism that eliminates virus-infected or otherwise abnormal cells from the body. Just like tumor cells, adenoviruses, which cause upper-respiratory infections, need to get p53 out of the way to multiply successfully.

“Instead of inactivating p53 directly, adenovirus renders the ‘guardian of the genome’ powerless by targeting the genome itself,” explains Clodagh O’Shea, Ph.D., an assistant professor in the Molecular and Cell Biology Laboratory, who led the study. “It literally creates zip files of p53 target genes by compressing them till they can no longer be read.”

The p53 tumor suppressor pathway is inactivated in almost every human cancer, allowing cells to escape normal growth controls. Yet there is still no rationally designed targeted cancer therapy to treat patients based on the loss of p53.

“All of the targeted therapies we have are based on small molecules that inactivate oncogenes, but cancer is not solely caused by the gain of growth-promoting genes,” says O’Shea. “The loss of tumor suppressors is just as important. The big question is how do you target something that’s no longer there?”

Adenovirus seemed to provide the answer. It brings along a viral protein, E1B-55K, which binds and degrades p53 in infected cells. Without E1B-55K to inactivate p53, adenovirus should only be able to replicate in p53-deficient tumor cells. Then, each time it bursts open the host cell to release thousands of viral progenies, the next generation of viruses is ready to seek out remaining cancer cells while leaving normal cells unharmed.

“This makes adenovirus a perfect candidate for oncolytic cancer therapy,” says O’Shea. “Although these viruses did their job, to everybody’s surprise, the patients’ responses did not correlate with the p53 status of their tumors,” says O’Shea. Intrigued, she and her team followed up on this unexpected finding.

Conrado Soria, Ph.D., a research assistant and co-first author of the study, quickly realized that E1B-55K was only half of the story. “The inability of the E1B-55K-mutant virus to replicate in normal cells was not because the virus failed to degrade p53,” he explains.

In unstressed normal cells, p53 is only found at low levels due to rapid degradation. In response to DNA damage, the activation of oncogenes or infection by DNA viruses, p53 degradation is halted and as a result p53 protein levels accumulate. This increase activates p53 target genes, which arrest the cell cycle or induce apoptosis.

Just as predicted, p53 started to build up in normal cells that had been infected with adenovirus lacking E1B-55K but it was still unable to turn on its target genes and start the cell on the path to apoptosis. He eventually discovered why: Adenovirus brings along another protein, E4-ORF3, which neutralizes the p53 checkpoint through a completely different mechanism.

Instead of inactivating p53 directly, the tiny protein prevents the tumor suppressor from binding to its target genes in the genome by modifying chromatin, the dense histone/DNA complex that keeps everything neatly organized within the cells’ nucleus. “These modifications cause parts of chromosomes to condense into so-called heterochromatin, burying the regulatory regions of p53 target genes deep within,” says graduate student and co-first author Fanny E. Estermann. “With access denied, p53 is powerless to pull the trigger on apoptosis.”

O’Shea hopes to exploit these new insights to understand how high levels of wild type p53 might be inactivated in cancer as well as the mechanisms that induce aberrant silencing of tumor suppressor gene loci in cancer cells. “Our study really changes the longstanding definition of how p53 is inactivated in adenovirus-infected cells and will finally allow us to develop true p53 tumor selective oncolytic therapies.”

The work was funded in part by the Alliance of Cancer Gene Therapy, the American Cancer Society, the Sontag Foundation, the Beckman Foundation and the National Cancer Institute.

Source: Salk Institute for Biological Studies

Keystone Symposia on Molecular and Cellular Biology will convene its conference on “Immunological Mechanisms of Vaccination” in Seattle, Washington from October 27 to November 1, 2010 at Sheraton Seattle Hotel. This is the first conference of Keystone Symposia’s 40th meeting season and its first in Seattle. It will be held at the conclusion of the Grand Challenges in Global Health conference, also taking place in Seattle for that program’s grant recipients earlier in the week.

Part of the Keystone Symposia Global Health Series, supported by the Bill & Melinda Gates Foundation, the meeting will begin with keynote addresses on the evening of October 27, 2010 by Anthony S. Fauci of NIH and Tadataka Yamada of Bill & Melinda Gates Foundation, as well as a joint reception with the Grand Challenges in Global Health conference attendees.

Additional speakers over the course of the following four days will include Rafi Ahmed of Emory University School of Medicine, Norman Baylor of the US FDA, Robert L. Coffman of Dynavax Technologies, Stefan H.E. Kaufmann of Max Planck Institute for Infection Biology, Lalita Ramakrishnan of the University of Washington and many others. Concluding remarks on the evening of October 31 will be delivered by Peter C. Doherty of the University of Melbourne, one of two 1996 winners of the Nobel Prize in Medicine or Physiology for discovering how white blood cells recognize and kill virus-infected cells.

The four-day conference will bring together more than 400 researchers from around the world confronting a range of different diseases that would benefit from vaccine development. Included among the attendees will be 58 researchers and students originating from 27 developing countries who have received Keystone Symposia Global Health Travel Awards to attend the conference.

The goal of the meeting is to bring together, and encourage crosstalk between, vaccinologists, immunologists, virologists and systems biologists. Since these groups do not always interact, such interaction, it is hoped, will encourage the rational design of future vaccines against pandemics such as HIV, malaria and tuberculosis, and against emerging infections such as swine influenza and dengue. Because of recent advances in immunology, human genetics and systems biology – particularly in our understanding of the role of innate immunity in shaping an adaptive immune response, the time is ripe for progress in this area.

The conference’s scientific organizers are Bali Pulendran of Emory University, Rino Rappuoli of Novartis Vaccines & Diagnostics and Bruce A. Beutler of The Scripps Research Institute. Bali Pulendran is one of six scientists recently selected by the US Government to share $100 million over the next five years to conduct infectious disease and vaccination research.

Further information about the conference program can be found here. Early registration, which saves US$100 on later registration fees, ends August 27, 2010.

Source:
Yvonne Psaila
Keystone Symposia on Molecular & Cellular Biology

In the vast majority of patients with advanced cancer, their muscles will gradually waste away for reasons that have never been well understood. Now, researchers reporting in the August 20 issue of Cell, a Cell Press Publication, have found some new clues and a way to reverse that process in mice. What’s more, animals with cancer that received the experimental treatment lived significantly longer, even as their tumors continued to grow.

“This is the first demonstration that muscle mass plays a key role in cancer survival,” said H.Q. Han of Amgen Research.

While it has long been recognized that this muscle wasting condition, known as cachexia, affects advanced cancer patients’ quality of life, Han explained, its importance for survival had primarily been a matter of speculation. Nearly 30 percent of cancer-related deaths have been attributed to cachexia, but that was based on correlative evidence only. That is, there has seemed to be a connection in cancer patients between weight loss and mortality.

Still, cachexia had typically been considered a “multi-factorial” process with many causes. “That would make it hard to target,” Han said. Indeed, few therapeutic options are available and efforts to treat this aspect of the disease haven’t been top of mind. Given the new results, that could change.

The researchers suspected that a pathway known as ActRIIB might be involved. ActRIIB is what’s known as an activin type 2 receptor. There was evidence to suggest that tumors secrete activin, such that circulating levels of the protein rise in those with cancer. Activin is closely related to another protein, called myostatin, which is known to be important in muscle. Animals lacking myostatin or taking treatments that block it grow bigger muscles. There was some evidence to suggest that activin blockers might have a similar effect.

Based on that hunch, the researchers treated mice with cancer and associated cachexia with a recombinant and soluble version of the ActRIIB receptor (sActRIIB), a kind of molecular “decoy” that potently inhibited both activin and myostatin activity. That treatment reversed the animals’ muscle loss and prolonged their survival by several weeks on average. That was despite the fact that the tumors appeared to be unaffected. The animals also kept losing fat and still had high levels of inflammatory factors.

“In tumor-bearing mice with profound cachexia, blocking this pathway not only prevents muscle wasting but completely reverses the loss of muscle, strength and anorexia,” Han said. (Anorexia is another symptom of cachexia, but appetite stimulants and nutritional supplements don’t help much.)

The researchers also found something that had apparently gone unnoticed before. Just as the skeletal muscles of mice with cancer withered away, so too did their heart muscle. The ActRIIB inhibiting treatment completely reversed that too.

Han said that finding may point to an unappreciated role for heart atrophy in muscle wasting conditions more broadly.

Further experimentation showed that the ActRIIB blockade prevented muscle proteins from being marked for degradation and markedly stimulated muscle stem-cell growth. Muscle stem cells were successfully activated even in muscle that had lost 50 percent of its weight prior to treatment, Han said.

“This is the first indication that there may be a major medical benefit in extending life span by combating cachexia,” Han said, emphasizing however that there is a long way to go from preclinical studies in mice to clinical trials in human patients.

Still, he added, “as drug discovery scientists, we are very excited by the implications. This suggests a promising strategy for treating cachexia and underscores the need for further investigation and translational research to fully understand this pathway and explore the benefits of its antagonism.”

The researchers say it will be important to explore levels of myostatin and other components of the ActRIIB pathway in various patient groups. “The dramatic, reversible changes in body mass shown here emphasize the importance of obtaining such information not only for understanding disease mechanisms but also to provide a fuller rationale for anti-activin therapies,” they wrote. “However, since the inhibition of ActRIIB signaling by sActRIIB induces growth of normal muscle, this treatment is likely to be anabolic and help combat muscle loss in many catabolic conditions, even if the wasting is not triggered by excessive signaling by activin or related ligands of the ActRIIB pathway.”

Han says he and his colleagues hope the findings will renew interest among cancer researchers and oncologists in cachexia. “Our results argue that blocking the catabolic actions of tumors should be a major therapeutic objective, not only to enhance quality of life but also to prolong survival,” he said.

The researchers include Xiaolan Zhou, Amgen Research, Thousand Oaks, CA; Jin Lin Wang, Amgen Research, Thousand Oaks, CA; John Lu, Amgen Research, Thousand Oaks, CA; Yanping Song, Amgen Research, Thousand Oaks, CA; Keith S. Kwak, Amgen Research, Thousand Oaks, CA; Qingsheng Jiao, Amgen Research, Thousand Oaks, CA; Robert Rosenfeld, Amgen Research, Thousand Oaks, CA; Qing Chen, Amgen Research, Thousand Oaks, CA; Thomas Boone, Amgen Research, Thousand Oaks, CA; W. Scott Simonet, Amgen Research, Thousand Oaks, CA; David L. Lacey, Amgen Research, Thousand Oaks, CA; Alfred L. Goldberg,2 and H.Q. Han, Amgen Research, Thousand Oaks, CA.

Source: Cell Press

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