Old drugs find new target for treating brain tumor

ScienceDaily (Nov. 18, 2011) — Scientists at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center, in collaboration with colleagues in Boston and South Korea, say they have identified a novel gene mutation that causes at least one form of glioblastoma (GBM), the most common type of malignant brain tumor.

The findings are reported in the online edition of the journal Cancer Research.

Perhaps more importantly, the researchers found that two drugs already being used to treat other forms of cancer effectively prolonged the survival of mice modeling this particular form of GBM. That could be good news for at least some GBM patients. More than 9,000 new cases of the disease are diagnosed each year in the United States and effective treatments are limited. The tumors are aggressive and resistant to current therapies, such as surgery, radiation and chemotherapy. The median survival rate for newly diagnosed GBM patients is just 14 months.

Past studies have identified epidermal growth factor receptor (EGFR) as a common genetically altered gene in GBM, though the cause or causes of the alteration is not known. The research team, led by scientists at the Dana-Farber Cancer Institute in Boston, analyzed the GBM genomic database, ultimately identifying and characterizing an exon 27 deletion mutation within the EGFR carboxyl-terminus domain (CTD). An exon is a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.

"The deletion mutant seems to possess a novel mechanism for inducing cellular transformation," said Frank Furnari, PhD, associate professor of medicine at the UC San Diego School of Medicine and an associate investigator at the San Diego branch of the Ludwig Institute for Cancer Research.

The study researchers determined that cellular transformation was induced by the previously unknown EGFR CTD deletion mutant, both in vitro and in vivo, and resulted in GBM in the animals. The researchers then turned to testing a pair of approved drugs that target EGFR: a monoclonal antibody called cetuximab and a small molecule inhibitor called erlotinib.

Cetuximab, marketed under the name Erbitux, is currently approved for use in treating metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Erlotinib, marketed under the name Tarceva, is used to treat lung and pancreatic cancers.

Both drugs were found to effectively impair the tumor-forming abilities of oncogenic EGFR CTD deletion mutants. Cetuximab, in particular, prolonged survival of mice with the deletion mutants when compared to untreated control mice.

However, neither cetuximab nor erlotinib is an unabashed success story. The drugs work by binding to sites on the EGFR protein and inhibiting activation, but they are not effective in all cancer patients and produce some adverse side effects, such as rashes and diarrhea.

But Santosh Kesari, MD, PhD, Director of Neuro-Oncology at UC San Diego Moores Cancer Center and the UCSD Department of Neurosciences, and co-corresponding author of the study, said the new study points to a more selective, effective use of the drugs for some patients with GBM.

"In the past when we treated brain cancer patients with these drugs, the response rate was very small," Kesari said. "What we now show is that the tumors with CTD mutations respond best to these EGFR targeted agents. If we knew this beforehand, we might have been able to select patients most likely to respond to these agents. We are now trying to put together a prospective clinical trial to prove this. We would select only patients with these tumor mutations and treat them. This kind of research gets us closer to identifying genetic subtypes, to doing better biomarker-based clinical trials, and to personalizing treatments in brain cancers."

"This is a great example of personalized medicine in action," said Webster Cavenee, PhD, director of the Ludwig Institute at UC San Diego. "UCSD has made a concerted effort in the past few years to develop a first-class brain tumor research and therapy group that includes adult neuro-oncology, neurosurgery, neuropathology and their pediatric equivalents to join with internationally-renowned brain tumor research. This is making UCSD a destination for the very best in brain tumor management."

Co-authors of the study are Jeonghee Cho, Department of Medical Oncology, Dana-Farber Cancer Institute, Center for Cancer Genome Discovery, Boston, MA, Genomic Analysis Center, Samsung Cancer Research Institute, Seoul, Republic of Korea; Sandra Pastorino and Ying S. Chao, Department of Neurosciences, Moores Cancer Center, UC San Diego; Qing Zeng and Xiaoyin Xu, Department of Radiology, Brigham and Women's Hospital, Boston; William Johnson, Dana-Farber Cancer Institute, Center for Cancer Genome Discovery, Boston; Scott Vandenberg, Department of Pathology, UC San Diego; Roel Verhaak, Amit Dutt, Derek Chiang and Yuki Yuza, Department of Medical Oncology, Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard; Andrew Cherniack and Robert C. Onofrio, Broad Institute of MIT and Harvard; Hideo Watanabe and Matthew Meyerson, Department of Medical Oncology, Dana-Farber Cancer Institute, Center for Cancer Genome Discovery and Broad Institute of MIT and Harvard; Jihyun Kwon, Genomic Analysis Center, Samsung Cancer Research Institute.

Funding for this research came, in part, from the National Institutes of Health, the Sontag Foundation Distinguished Scientist Award, James S. McDonnell and the Samsung Cancer Research Institution.

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'New paradigm' in the way drugs can be manufactured: New method to build important heparin drug

ScienceDaily (Oct. 27, 2011) — Robert Linhardt is working to forever change the way some of the most widely used drugs in the world are manufactured. In a new studying appearing in the journal Science, he and his partner in the research, Jian Liu, have announced an important step toward making this a reality.

Linhardt, the Ann and John H. Broadbent Jr. '59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer Polytechnic Institute, and Jian Liu, a professor in the Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill, have discovered an entirely new process to manufacture ultra-low molecular weight heparin.

The research shows that the drug is identical in performance and safety to the current and successful anticoagulant fondaparinux, but is purer, faster, and less expensive to produce.

"This research represents an entirely new paradigm in drug manufacturing," Linhardt said. "With this discovery, we have successfully demonstrated that replacing the current model of drug production with a chemoenzymatic approach can greatly reduce the cost of drug development and manufacturing, while also increasing drug performance and safety, and reduce the possibility of outside drug contamination. It is our hope that this is the first step in the adoption of this method for the manufacture of many other drugs."

The new process uses chemicals and enzymes to reduce the number of steps in production of fondaparinux from approximately 50 steps down to just 10 to 12. In addition, it increases the yield from that process 500-fold compared to the current fondaparinux process, and could decrease the cost of manufacture by a similar amount, according to Linhardt.

Fondaparinux, which is sold as a name-brand drug and was also recently approved by the FDA as a generic drug, is a synthetic anticoagulant used to treat deep vein thrombosis, with over $500 million in annual sales. It is part of a much larger family of anticoagulant drugs known as heparins. But, unlike most heparin products, it is chemically synthesized from non-animal materials. All other heparin-based drugs currently on the market use materials from the intestines of pigs and lungs of cattle as source materials. Such animal materials are more likely to become contaminated, according to Linhardt.

"When we rely on animals, we open ourselves up for spreading viruses and prion diseases like mad cow disease through the use of these heparins," Linhardt said. "And because most of the raw material is imported, we often can't be sure of exactly what we are getting."

But, fondaparinux is extremely costly to produce, according to Linhardt. "The process to produce the drug involves many steps to purify the material and creates tons and tons of hazardous waste to dispose of," Linhardt said.

The new process developed by Linhardt and Liu greatly reduces the number of steps involved in the production of the drug. This reduces the amount of waste produced and the overall cost of producing the drug.

"Cost should no longer be a major factor in the use or production of this drug," Linhardt said.

The process uses sugars and enzymes that are identical to those found in the human body to build the drug piece by piece. The backbone of the material is first built sugar by sugar and then decorated with sulfate groups through the use of enzymes to control its structure and function in the body.

Linhardt and Liu have already begun testing the drug in animal models with successful results and think the drug could be quickly transferred to the market.

"Because the new drug is biologically identical in its performance to the already approved fondaparinux, the approval process for this new drug should work very similar to the approval process used for fondaparinux," Linhardt said. He also thinks that this combined chemical and enzymatic synthesis can be quickly brought to patients in need and adapted for the production of many other improved carbohydrate-containing drugs.

"During this study, we were able to quickly build multiple doses in a simple laboratory setting and feel that this is something than can be quickly and easy commercialized to reduce the cost of this drug and help to shift how pharmaceutical companies approach the synthesis of carbohydrate-containing drugs."

The finding is part of a much larger body of work occurring in the Linhardt lab to completely replace all types of heparin-based or other glycoprotein-based drugs with safer, low-cost, synthetic versions that do not rely on foreign, potentially contaminated animal sources.

The research is funded by the National Institutes of Health.

Linhardt and Liu were joined in the research by Yongmei Xu, Haoming Xu, Renpeng Liu, and Juliana Jing of the University of North Carolina, Chapel Hill; Sayaka Masuko of Rensselaer Polytechnic Institute; and Majde Takieddin and Shaker Mousa of the Albany College of Pharmacy and Health Sciences.

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The above story is reprinted from materials provided by Rensselaer Polytechnic Institute.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Yongmei Xu, Sayaka Masuko, Majde Takieddin, Haoming Xu, Renpeng Liu, Juliana Jing, Shaker A. Mousa, Robert J. Linhardt, Jian Liu. Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins. Science, 2011; 334 (6055): 498-501 DOI: 10.1126/science.1207478

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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