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New drug target & biomarker for advanced childhood cancer discovered

American Association For Cancer Research (AACR) : 19 November, 2003  (Company News)
Scientists announced today that they have discovered a protein produced by advanced childhood cancers that provide s a new target for treatments and a new marker for the disease. Separately, researchers reported data on the crystal structures of two kinase proteins implicated in multiple cancers. The data on structure provides valuable information for the design of cancer therapeutics targeted at these proteins.
The studies were presented today at the International Conference on Molecular Targets and Cancer Therapeutics organized by the American Association for Cancer Research, National Cancer Institute and European Organisation for Research and Treatment of Cancer in Boston.

Identification of a novel secretory protein specific to neuroblastoma: Abstract 1216

A new protein found only in the cells of neuroblastoma, a common childhood cancer, could provide clues to differentiating between aggressive tumors and those that are more likely to respond to treatment, said Baylor College of Medicine researchers who discovered it.

The gene that codes for the protein, called neuroblastoma-derived secreted protein or NDSP, is most active in severe cases of neuroblastoma, said Dr. Jianhua Yang, assistant professor of pediatrics/hematology and oncology, at Baylor College of Medicine in Houston. As such, the protein could provide important information about the recurrence of disease after first treatment, said Dr. Jed Nuchtern, associate professor of pediatrics/surgery at Baylor College of Medicine.

'We know there are some tumor cells left after surgery and chemotherapy because of the high relapse rate,' Dr. Nuchtern said. 'This gene may make possible a sensitive means of detecting those.'

Dr. Yang discovered the gene, a novel structure, during a screening using microarray technology. He subsequently discovered the gene was only expressed in neuroblastoma cells. So far, Dr. Yang has only tested neuroblastoma cell lines in the laboratory, but he plans to check for the protein in clinical samples as well. He also hopes to determine the role the protein plays in the growth and spread of neuroblastomas, as well as other biological functions.

Crystal structure of an inhibitor complex of Aurora A kinase and preliminary in vitro SAR analysis of quinazoline inhibitors: Abstract 446

Scientists have discovered selective and potent inhibitors of key protein kinases implicated in a variety of cancers. Researchers from AstraZeneca led the study, and are investigating these inhibitors to determine their potential role in the treatment of cancer.

The Aurora kinases, commonly overexpressed in breast, colon, pancreas and bladder tumors and correlated with poor prognosis for these diseases, are important in regulating mitosis and the process of cell division. Because they are only expressed in cells that are actively dividing, these kinases could be an important new target in cancer.

'As part of our broad-based development program in cell cycle directed therapies, we've determined the crystal structure of Aurora A kinase, and have been able to use this to develop selective and potent inhibitors of Aurora kinase activity,' said Dr. Nick Keen, associate director, cancer & infection, AstraZeneca. 'We are excited because pre-clinical studies have shown these inhibitors to be highly effective and selective in killing proliferating tumor cells. We are hopeful that this research will lead to a new class of therapeutics in the fight against cancer.'

Structure-based design and X-ray crystallographic analysis of a potent and selective Src tyrosine kinase inhibitor for the treatment of cancer: Abstract 1176

Researchers have identified a potent small-molecule inhibitor of a protein important both to the growth and spread of tumors. The compound, known as AP23464, was discovered by ARIAD scientists using structure-based drug design and X-ray crystallography. The research team described the crystal structure of the drug bound to its target, Src tyrosine kinase.

'Overexpression of the Src enzyme has long been recognized as a driver of the accelerated growth and proliferation, and extended survival of numerous types of cancer cells,' said Dr. Tim Clackson, senior vice president and chief scientific officer at ARIAD. 'In addition, its key role in metastasis, the spread of cancers from primary tumors and successful implantation at distant sites, was discovered in the past few years. Thus, AP23464 uniquely combines in a single drug both anti-tumor and anti-metastatic activity.'

AP23464 is also a potent inhibitor of Abl tyrosine kinase, an enzyme implicated in certain forms of leukemia. AP23464 is also designed to inhibit mutant forms of the protein that are resistant to the drug imatinib (Gleevec), making it an attractive drug candidate to treat resistant leukemia patients. ARIAD plans to begin Phase 1 clinical trials of AP23464 in 2004, initially in cancer patients for whom there currently is no alternative therapy.
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