Combining Two Peptide Inhibitors Might Block Tumor Growth

A new study suggests that combining two experimental anticancer peptide agents might simultaneously block formation of new tumor blood vessels while also inhibiting the growth of tumor cells.

This early test of the two agents in a breast cancer model suggests that the double hit can stifle tumor progression, avoid drug resistance and cause few side effects, say researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) who developed the agents and evaluated their effectiveness in laboratory and animal tests.

The scientists designed one of the agents to prevent human epithelial growth factor from interacting with HER-2, a molecule that marks a particularly aggressive form of breast cancer. The other inhibitor blocks the action of vascular endothelial growth factor (VEGF), which stimulates the growth of new blood vessels that tumors need to grow beyond a certain size.

The findings are described in two papers published online in the Journal of Biological Chemistry. One presents the development of a novel VEGF inhibitor; the other describes the HER-2 inhibitor and the preclinical testing of the two agents together.

“When we combined our peptide HER-2 inhibitor with the VEGF peptide that inhibits angiogenesis, we observed significant additive benefits in reducing tumor burdens in preclinical studies,” says principal investigator Pravin Kaumaya, professor of obstetrics and gynecology, of molecular and cellular biochemistry, and of microbiology, and director of the division of vaccine development at the OSUCCC – James.

The strategy of targeting both HER-2 and VEGF pathways should also discourage the development of drug resistance, Kaumaya says, because it simultaneously inhibits two pathways that are essential for tumor survival. “Combined peptide inhibitors might be appropriate in several types of cancer to overcome acquired resistance and provide clinical benefit,” he adds.

Peptide inhibitors consist of short chains of amino acids (the VEGF inhibitor is 22 amino acids long) that conform in shape to the active site of the target receptor. In addition, Kaumaya engineered the VEGF peptide to be resistant to protease, an enzyme, thereby increasing its efficacy. The shape of the peptide HER-2 inhibitor engineered by Kaumaya and his colleagues, for example, is highly specific for the HER-2 receptor. It physically binds to the receptor, which prevents another substance, called epithelial growth factor, from contacting the receptor and stimulating the cancer cells to grow.

Other categories of targeted drugs in clinical use are humanized monoclonal antibodies and small-molecule TKI inhibitors. Both groups are associated with severe side effects and are very expensive, Kaumaya says. “We believe peptide inhibitors offer non-toxic, less-expensive alternatives to humanized monoclonal antibodies and small-molecule inhibitors for the treatment of solid tumors, with the potential for improved efficacy and better clinical outcomes,” he says.

Funding from NIH supported this research.

Other Ohio State researchers involved in the two studies were Kevin C. Foy, Daniele Vicari, Eric Liotta, Zhenzhen Liu, Gary Phillips and Megan Miller.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The James is the 205-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.

Source:
Darrell E. Ward
Ohio State University Medical Center Continue reading

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Living Vascular Grafts: Pitt Team Grows Arteries With Most Elastic Protein Reported

University of Pittsburgh researchers have grown arteries that exhibit the elasticity of natural blood vessels at the highest levels reported, a development that could overcome a major barrier to creating living-tissue replacements for damaged arteries, the team reports in the Proceedings of the National Academy of Sciences.

The team used smooth muscle cells from adult baboons to produce the first arteries grown outside the body that contain a substantial amount of the pliant protein elastin, which allows vessels to expand and retract in response to blood flow. Lead researcher Yadong Wang, a professor of bioengineering in Pitt’s Swanson School of Engineering, his postdoctoral researcher Kee-Won Lee, and Donna Stolz, a professor of cell biology and physiology in Pitt’s School of Medicine, cultured the baboon cells in a nutrient-rich solution to bear arteries with approximately 20 percent as much elastin as an inborn artery.

The Pitt process is notable for its simplicity, Wang said. Elastin – unlike its tougher counterpart collagen that gives vessels their strength and shape – has been notoriously difficult to reproduce. The only successful methods have involved altering cell genes with a virus; rolling cell sheets into tubes; or culturing elastin with large amounts of transforming growth factor, Wang said. And still these previous projects did not report a comparison of elastin content with natural vessels.

Wang and his colleagues had strong, functional arteries in three weeks. The team first seeded smooth-muscle cells from 4-year-old baboons – equivalent to 20-year-old humans – into degradable rubber tubes chambered like honey combs. They then transferred the tubes to a bioreactor that pumped the nutrient solution through the tube under conditions mimicking the human circulatory system – the pump produced a regular pulse, and the fluid was kept at 98.6 degrees Fahrenheit. As the muscle cells grew, they produced proteins that fused to form the vessel.

Mechanical tests revealed that the cultured artery could withstand a burst pressure between 200 and 300 millimeters of mercury (mmHg), the standard unit for blood pressure, Wang said; healthy human blood pressure is below 120 mmHg. In addition to containing elastin, the artery also had approximately 10 percent of the collagen found in a natural vessel, Wang said.

The process the Pitt team used to cultivate the artery resembles how it would be used in a patient, he explained. The cell-seeded tube would be grafted onto an existing artery. As the rubber tube degrades, the vascular graft would develop into a completely biological vessel.

The next steps in the project, Wang said, are to design a vessel that fully mimics the three-layer structure of a human artery and to prepare for surgical trials.

The project received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Source:
Morgan Kelly
University of Pittsburgh Continue reading

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First Crystal Structure Of Enzyme That Works Inside Membranes

The structure of an enzyme that has many regulatory functions and breaks peptide bonds of proteins where they pass through membranes within the cell has been described for the first time by Yale School of Medicine researchers in Nature.

The crystallized rhomboid structure, GlpG, provides the first detailed view of the intramembrane protease and correlates with earlier genetic and biochemical studies. Rhomboids are found in almost all organisms and, although little is known about their function in most species, they have been implicated in biological processes as diverse as mitochondrial function, invasion of host cells by parasites, bacterial communication, and, growth factor signaling.

The biochemical reaction of proteolysis within a membrane is very unusual. By definition, proteolysis involves water, but it is not clear where the water comes from in the oily membrane.

“Because there is seemingly no easy explanation, people always wonder if the protein factors involved are indeed proteases, and if mutations in them really affect proteolysis,” said the senior author, Ya Ha, assistant professor of pharmacology. “Our results suggest that the mechanism is real, which opens up more questions for the next phase of research.”

Intramembrane proteolysis has historical links to research on Alzheimer’s disease. The amyloid peptide deposits thought to be responsible for Alzheimer’s disease is derived from the large protein precursor, APP. The APP is chopped by two proteases and the resulting middle fragment is amyloid peptide.

“All known mutations that cause early-onset Alzheimer’s disease are mapped to three genes-APP, presenilin-1 and presenilin-2,” said Ha. “We now know that the presenilins are the intramembrane protease that chops up APP, converting it to amyloid peptide. Therefore, it is obvious that intramembrane proteolysis is really one of the centerpieces constituting what we now call the ‘amyloid hypothesis’ of Alzheimer’s disease.”

Co-authors at Yale include Yongcheng Wang and Yingjiu Zhang. The research was funded by the U.S. Department of Energy and the National Institutes of Health.

Nature: Published online October 11, 2006 doi:10.1038/nature05255

Yale News Releases are available via the World Wide Web at yale/opa

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Global meeting to develop common approach on avian influenza and human pandemic influenza

The H5N1 avian influenza virus is firmly established among animals in Asia and has begun to extend its reach into Europe. From 7-9 November, more than 400 animal and human health experts, senior policy makers, economists and industry representatives will gather in Geneva to work towards a global consensus to control the virus in domestic animals and prepare for a potential human influenza pandemic.

The disease in animals caused by the H5N1 influenza virus has resulted in the culling of at least 150 million birds in the last two years. H5N1 remains for the moment an animal disease, but the World Health Organization (WHO) has warned that H5N1 is a virus that has the potential to ignite a human influenza pandemic.

While no one can predict the timing or severity of the next influenza pandemic, governments around the world are taking the threat seriously. A series of international meetings held over the last ten weeks will culminate in the Geneva meeting. The meeting is co-organized by WHO, the Food and Agriculture Organisation (FAO), the World Organisation for Animal Health (OIE) and the World Bank. The goal of the meeting is to work towards a global consensus for controlling the disease in animals while simultaneously preparing for a potential human pandemic.

“This virus is very treacherous,” says Dr Margaret Chan, Representative of the WHO Director-General for Pandemic Influenza. “While we cannot predict when or if the H5N1 virus might spark a pandemic, we cannot ignore the warning signs.” Because influenza pandemics have typically caused enormous social and economic disruption, WHO is advising its member states to develop national strategies to cope with such a public health emergency, as well as coordinating with international partners to develop a comprehensive response.

The Geneva meeting will first consider how to contain the H5N1 virus in birds. “There is still a window of opportunity for substantially reducing the risk of a human pandemic evolving from H5N1 by controlling the virus at its source, in animals,” says Joseph Domenech, FAO Chief Veterinary Officer. As the FAO expects avian influenza to reach the Middle East and Africa in the near future, it is essential that the global community and affected countries mobilize more resources to combat the virus, which is thought to be spread in part by migratory birds, before it becomes embedded in new regions.

Strengthening disease surveillance systems worldwide will also be high on the agenda at the Geneva meeting. Early detection and rapid response mechanisms are essential to tracking the evolution of the H5N1 virus. Therefore, delegates will also discuss ways to strengthen veterinary and human health services so that any H5N1 cases–in animals or humans–will be identified quickly. “This is crucial for the prevention of any future global crisis associated with emerging animal diseases potentially transmissible to humans,” says Dr Bernard Vallat, Director-General of the World Organisation for Animal Health (OIE).

At the same time that animal control efforts are to be intensified, several critical issues related to potential human disease remain to be addressed. Meetings in the last several months have identified several key pandemic preparedness issues. For example, many countries are concerned about the lack of access to antiviral medicines and the antiquated production methods for human influenza vaccines. Communication with the public is also a critical issue. These and other topics will be on the agenda for the Geneva meeting.

The meeting comes after a recent gathering of experts in Geneva (2-3 November) to discuss the development of pandemic influenza vaccines. At present, at least ten vaccine developers in about as many countries are carrying out demonstration projects to develop and evaluate vaccines primarily against the H5N1 subtype. Participants expressed the need for continued sharing of technical information, strengthened international coordination of work related to pandemic influenza vaccines so as to avoid duplication of efforts, support to vaccine research initiatives in developing countries and integrating the science into the public health context.

“It’s impossible to exaggerate how important pandemic preparedness is, and how dire the consequences would be for the entire world if some of the worst-case scenarios for a human influenza pandemic were to unfold,” says James Adams, the World Bank’s Vice-President for Operations Policy and Country Services, and head of the Bank’s avian flu taskforce. The Geneva meeting will provide an opportunity for all international partners to mobilize the country commitment and financial resources needed to manage this global threat.

“For the first time in human history, we have a chance to prepare ourselves for a pandemic before it arrives,” says Dr Chan. “It is incumbent upon the global community to act now.”

Mr Dick Thompson – Communications officer
Communicable Diseases
WHO/Geneva
E-mail: thompsondwho.int

Mr Iain Simpson – Communications Officer
Director-General’s Office – WHO
E-mail: simpsoniwho.int

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Ipsogen to present breast cancer program results at the upcoming 96th AACR annual meeting

Marseille, France, March 30, 2005 – Ipsogen SAS, a molecular diagnostic
company developing tests to improve disease management of cancer patients,
announced today that results concerning its breast cancer program have been
selected for presentation in a symposium session at the 2005 AACR Annual
Meeting in Anaheim, California.

The abstract titled “Utilisation of microarray technology to refine
molecular classes and improve clinical management of breast cancer,” is
available on the AACR website (aacr; abstract number: 2628)
and an
oral presentation has been scheduled on Monday, April 18, 2005 at 1:00 PM.
Further results from this program will be separately published in a peer
reviewed journal.

The results concern several gene expression signatures refining molecular
classes of breast cancer. Utilisation of these signatures together with
standard clinical parameters provides a unique combination discriminating
patients responding to standard anthracycline chemotherapy. The test was
validated in an independent cohort with patient samples from distinct
clinical sites. Ipsogen will also release data concerning translation of
these results to its Breast Cancer ProfileChipT, a simple diagnostic device
allowing straightforward utilisation of gene signatures in clinical
pathology laboratories. The study represents part of a research program
Ipsogen is conducting with the Institut Paoli-Calmettes (Marseille, France)
and in partnership with major French and US centres.

Based on these findings and ongoing clinical studies, Ipsogen believes
there is potential for applying this test to identify patients, at
diagnosis, with favorable outcome under standard anthracyclines
chemotherapy to avoid unnecessary intensification.

About Ipsogen

IPSOGEN is an emerging biotechnology company utilising advanced
technologies to analyse gene expression and to improve the disease
management of cancers. IPSOGEN addresses two main markets: (i) The
molecular diagnosis of cancer (i.e.; leukaemia, lymphomas, breast cancer)
to provide innovative diagnostic tools to clinical centres; (ii) the
optimisation of discovery and development of anti cancer drugs, to provide
pharmaceutical companies with high value information at the pre-clinical
and clinical stages, and accelerate drug development through biomarker
discovery and validation. Headquartered in Marseille, France, IPSOGEN has
global partnerships and markets its products worldwide.

This press release contains “forward-looking statements” as defined in the
US Private Securities Litigation Reform Act of 1995. No forward-looking
statement can be guaranteed, and actual results may differ materially from
those projected. Ipsogen SAS does not undertake any obligation to publicly
update any forward-looking statement, whether as a result of new
information, future events, or otherwise. Forward-looking statements in
this document should be evaluated together with the many uncertainties that
affect the business of Ipsogen SAS, among others, the extent to which
Ipsogen’s technology platform can be used in large scale gene expression
analysis, uncertainty of market acceptance of Ipsogen’s technologies or
ability to compete against existing technologies.

CONTACTS
Ipsogen: Vincent Fert, Chief Executive Officer – Tel +33 4 91293090 –
fertipsogen

Global Headquarters
Ipsogen
Luminy Biotech Entreprises
Case 923 – 163 Ave de Luminy
13288 Marseille
France
Tel: +33 4 91 29 30 90
Fax: +33 4 91 29 30 99
infosipsogen

North America – Oncodiagnostics
Ipsogen, Inc
83 Maple Avenue
Windsor
Connecticut 06095
USA
Tel: +1 860 298 0234
Fax: +1 860 298 8586
infosipsogen

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Compounds in plastic packaging act as environmental estrogens altering breast genes

Compounds found in plastic products used to wrap or contain food and beverages have aroused concerns as possible cancer-causing agents because they can sometimes leach out of the plastic and migrate into the food, especially after heating or when the plastic is old or scratched. In two studies funded by the National Institute of Environmental Health Sciences, researchers at Fox Chase Cancer Center in Philadelphia have demonstrated that two plasticizer compounds, BPA and BBP, are environmental estrogens capable of affecting gene expression in the mammary glands of young female laboratory rats exposed to the compounds through their mothers’ milk.

Raquel Moral, Ph.D., a postdoctoral associate in the Fox Chase laboratory of Jose Russo, M.D., presented the results today at the 96th Annual Meeting of the American Association for Cancer Research. Russo is director of the Breast Cancer and the Environment Research Center at Fox Chase. After the morning poster session, he will give an oral presentation on “Estrogens as Carcinogens in the Human Breast.”

“Development of breast cancer entails multiple events, in which estrogen appears to play an important role,” explained Russo. “Our laboratory has pioneered an in vitro system of cell transformation using estrogens and their metabolites as carcinogenic agents in human breast cells. Our data show that each compartment of the breast has specific differentially expressed genes that provide a genomic signature according to the increasing maturation of the organ.

“Estrogenic agents involved in breast development and possibly in breast cancer may include foreign estrogens, or xenoestrogens, that are used in manufacturing a number of products. The studies of BPA and BBP in young rats were designed to see whether exposure to these hormonally active biological compounds could alter the genomic signatures of the mammary gland during critical stages of development.” BPA (bisphenol A) is a synthetic resin used in food packaging, dental sealants and polycarbonate plastic products, which range from CDs and eyeglass lenses to tableware and food and beverage containers, including baby bottles. BBP (n-butyl benzyl phthalate) is a widely used plasticizer used in food wraps and cosmetics.

“In exposing prepubescent female rats to BPA and BBP, our aim was to determine what effects, if any, each compound had on mammary gene expression during at different ages,” said Moral.

“Our results showed that exposure to BPA changes the gene expression profile of mammary tissues as a function of age. That is, there was a significant increase in protein production governed by various genes at increasing ages from 21 to 100 days.”

These included proteins regulating cell proliferation and differentiation, including tumor-suppressing proteins and a large number of unknown proteins. The exception was decreased expression of the GAD1 gene. It encodes a key enzyme of the GABA-ergic system, which could be involved in hormonal regulation and breast cancer development. GAD1 has consistently been overexpressed in primary breast cancer.

“In contrast, the BBP exposure modified the genomic signature of the mammary gland primarily at 21 days of age and had less effect later,” Moral said.

Future studies are needed to determine whether exposure to such xenoestrogens leads to breast cancer in rats and whether these estrogens bring about similar gene alterations in human breast tissue.

In addition to Moral and Russo, Fox Chase co-authors of the BPA and BBP studies include research associate Gabriela A. Balogh, Ph.D., postdoctoral associate Daniel A. Mailo, Ph.D., and research pathologist Irma H. Russo, M.D., as well as Coral Lamartiniere, Ph.D., of the University of Alabama at Birmingham.

Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation’s first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at fccc or call 1-888-FOX CHASE.

Contact: Colleen Kirsch
colleen.kirschfccc
215-906-7227
Fox Chase Cancer Center
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Exactech, Inc. Cleared By FDA For U.S. Distribution Of Equinoxe(R) Reverse Shoulder

Exactech Inc.
(Nasdaq: EXAC), a developer and producer of bone and joint restoration
products including orthopaedic implants and biologic materials, announced
today that it has received clearance from the U.S. Food and Drug
Administration (FDA) to market the Equinoxe(R) Reverse Shoulder, the latest
component in the company’s shoulder arthroplasty line.

A “reverse” shoulder is designed for patients who have an irreparable
rotator cuff and osteoarthritis. The Equinoxe Reverse Shoulder is
compatible with the Equinoxe primary stem, allowing surgeons to change from
a primary to a reverse without removing the humeral stem.

Exactech CEO Bill Petty said, “With the introduction of our Equinoxe
Reverse Shoulder, we have continued the precedent of innovation that we
established with the Equinoxe primary and fracture shoulder systems. The
shoulder market is rapidly growing and we are pleased that we have a
prosthesis that will help address the clinical challenges that surgeons
have faced thus far with reverse shoulders.”

Lynn Crosby, M.D., a leading shoulder surgeon and member of the design
team, said, “The Equinoxe Reverse Shoulder is an exciting new product that
has been designed to address some of the limitations or challenges inherent
in other reverse shoulder systems. I’ve been pleased to work with an
international team of surgeons who brought a great deal of clinical and
surgical expertise to this product’s development.”

Exactech plans to initiate targeted clinical evaluation of the Equinoxe
Reverse Shoulder in its second quarter with full-scale release targeted for
the second half of 2007. Reverse shoulders have only recently been
introduced in the U.S. market. According to industry sources, approximately
49,000 shoulder replacements were performed in the U.S. in 2006, which is a
12% increase from 2005. Roughly 6% of that increase is attributed to
reverse shoulder replacement.

About Exactech

Based in Gainesville, Fla., Exactech develops and markets orthopaedic
implant devices, related surgical instruments and biologic materials and
services to hospitals and physicians. The company manufactures many of its
orthopaedic devices at its Gainesville facility. Exactech’s orthopaedic
products are used in the restoration of bones and joints that have
deteriorated as a result of injury or diseases such as arthritis. Exactech
markets its products in the United States and Australia, in addition to
more than 25 countries in Europe, Asia and Latin America. Copies of
Exactech’s press releases, SEC filings, current price quotes and other
valuable information for investors may be found at exac and
hawkassociates.

An investment profile on Exactech may be found at
hawkassociates/exacprofile.aspx.

This release contains various forward-looking statements within the
meaning of Section 27A of the Securities Act of 1933 and Section 21E of the
Securities Exchange Act of 1934, which represent the company’s expectations
or beliefs concerning future events of the company’s financial performance.
These forward-looking statements are further qualified by important factors
that could cause actual results to differ materially from those in the
forward- looking statements. These factors include the effect of
competitive pricing, the company’s dependence on the ability of third party
manufacturers to produce components on a basis which is cost-effective to
the company, market acceptance of the company’s products and the effects of
government regulation. Results actually achieved may differ materially from
expected results included in these statements.

Exactech, Inc.
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