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(PSYCHIATRIC TIMES) - Pharmacotherapeutic

Advances for Brain Cancer

An estimated 18,500 cases of primary cancer of the brain and CNS will be diagnosed this year, according to the American Cancer Society (Cancer Facts and Figures 2005;, and thousands (98,000 to 170,000) more cases of secondary (metastatic) brain cancers are expected to be diagnosed in any given year, according to various reports. Two separate studies that appear to illustrate significant advances in the treatment of a particularly aggressive glioma, glioblastoma multiforme, were reported at the recent annual meeting of the American Society of Clinical Oncology (ASCO), held May 13 to 17 in Orlando, FL. The tumor is diagnosed in an estimated 40,000 persons each year, according to the North American Brain Tumor Coalition. A significant number of those affected are under the age of 30 years. Prognosis is poor, especially for patients who have recurrent disease.

One study, an ongoing phase 2 trial, is looking at the value of the protein kinase C-b isozyme inhibitor, enzastaurin (Eli Lilly); the other, also a phase 2 study, is investigating temsirolimus (Wyeth), a mammalian target of rapamycin (mTOR) kinase inhibitor.

Enzastaurin had the distinction of making headlines in the Wall Street Journal on May 17 after preliminary results of the trial were reported at the ASCO meeting. The agent appears to have the ability to either shrink or stabilize gliomas by inhibiting protein kinase C-b and phosphatidylinositol 39-kinase/Akt cell pathways, thereby inhibiting angiogenesis and encouraging tumor cell apoptosis.

The study, which is expected to be completed next year, is looking at the agent in the treatment of recurrent glioblastoma and anaplastic astrocytoma, a less aggressive glioma that may progress to glioblastoma. In all, 92 patients are receiving treatment, and a response rate of 20% to 25% is being seen. Findings reported at the ASCO meeting by Howard Fine, MD, chief of the neuro-oncology branch at the National Cancer Institute's Center for Cancer Research and the National Institute of Neurologic Disorders and Stroke, focused on a cohort of 87 patients. So far, tumors shrank by 30% or more in 14 (22%) and stabilized in 5 (8%) of 63 patients who had recurrent glioblastomas and shrank by 30% or more in 6 (25%) and stabilized in 3 (12.5%) of 24 patients who had anaplastic astrocytomas.

Touted in the press as a "smart drug" because of its targeted ability to interrupt cancer cell metabolism and, primarily, interfere with cell division, temsirolimus also is showing promise in arresting progression of glioblastomas.

Evanthia Galanis, MD, an oncologist at the Mayo Clinic in Rochester, MN, reported results at the ASCO meeting of a phase 2 trial that tested the drug in 65 patients with recurrent glioblastoma. The effect: tumors regressed in 36% of patients treated.

"Treatment was well tolerated, and imaging responses were observed in a significant portion of patients with glioblastoma multiforme. . . . These early results suggest that we are on to a promising new treatment strategy that could potentially help us improve treatment for patients with recurrent glioblastoma," said Galanis.

In addition to recording response rate, the Mayo Clinic team led by Galanis analyzed tumor characteristics to define which patients afflicted by glioblastomas would probably benefit from temsirolimus therapy. It was determined that patients with activation of the tumor protein p70s6 kinase were most likely to respond to treatment. This knowledge could be translated into a screening tool, according to Galanis.

The team intends to study the drug in combination with radiation therapy and in combination with other small-molecule cell cycle inhibitors. *

Mapping Therapeutic

Response in Brain Cancer

Another recently reported advance in the treatment of brain cancer is an MRI-based assessment tool described by its developers at Ann Arbor's University of Michigan Comprehensive Cancer Center as a functional diffusion map (fDM). This tool uses MRI technology to track diffusion of water in the brain and map changes that occur between the start of a given therapy and 3 weeks into its course.

Because tumor cells block encephalic water diffusion, resulting in death of normal cells, the mapping of changes provides a picture 3 weeks into therapy about whether the therapy is inhibiting tumor growth and its effects, according to the research team, members of which successfully tested their hypothesis in a rodent model more than a de- cade ago.

In studying fDM in 20 patients as they began chemotherapy and/or radiation therapy for an encephalic malignancy (including glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, anaplastic oligodendroglioma, germ cell tumor, and primitive neuroectodermal tumor), the team found a 100% rate of accuracy in predicting whether and to what degree a therapeutic response would be achieved. Of significance is that this insight into therapeutic response occurred 10 weeks before the traditional evaluation method--an MRI scan to check tumor growth obtained 6 weeks after the end of treatment--would detect it.

"This is an important issue in terms of quality of life," said researcher Brian Ross, PhD, professor of radiology and biological chemistry at the University of Michigan Medical School. "Do you want to go through 7 weeks of treatment only to find 2 months later that it had no effect? Using MRI tumor diffusion values to accurately predict the treatment response early on could allow some patients to switch to a more beneficial therapy and avoid the side effects of a prolonged and ineffective treatment."

Molecular Therapeutics, a privately owned biotechnology company based in Ann Arbor, is planning development of a workstation for fDM computation that, when completed and if approved by the FDA, would make the assessment tool available to medical institutions nationwide. The University of Michigan holds the patent for the technology.

For more information on the study, see:

* Moffat BA, Chenevert TL, Lawrence TS, et al. Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response. Proc Natl Acad Sci U S A. 2005;102:5524-5529. *

At the Threshold of Gene Therapy for Alzheimer Disease

A small study involving 6 patients with mild to moderate Alzheimer disease (AD) demonstrated that disease progression could be slowed by implanting genetically modified autologous fibroblasts that express nerve growth factor (NGF) in the forebrain. The study has paved the way for a second study that will test delivery of NGF to brain cells via a viral vector.

Findings of the first study, a phase 1 trial conducted by a research team led by Mark Tuszynski, MD, PhD, professor of neurosciences at the University of California at San Diego (UCSD), were recently published in the April issue of Nature Medicine. Researchers harvested skin fibroblasts from a small cohort of volunteers with mild to moderate AD, genetically modified them to express NGF, and then surgically implanted the modified cells into sites in the forebrain.

Six subjects were monitored for an average of 22 months. Therapeutic progress was measured by the Mini-Mental Status Examination and the Alzheimer Disease Assessment Scale, which revealed a 36% to 51% reduction in the rate of AD-associated cognitive decline. Serial positron emission tomography scans also showed significantly increased levels of cortical 18-fluorodeoxyglucose, a radioisotope used to indicate the degree of metabolic activity in the brain.

"If validated in further clinical trials, this would represent a substantially more effective therapy than current treatments for Alzheimer disease. [It] also would represent the first therapy for a human neurologic disease that acts by preventing cell death," said Tuszynski.

Those commenting on the study, including William J. Netzer, PhD, research associate and scientific liaison at the Fisher Center for Alzheimer's Research at Rockefeller University in New York City, and William Thies, PhD, vice president of medical and scientific affairs of the Alzheimer's Association in Chicago, have urged caution in interpreting the findings, noting that significantly larger studies need to be conducted to prove both benefit and safety. Brain surgery would not be a practical treatment for AD, according to Thies, given that AD currently afflicts about 4.5 million Americans and, because of the aging of the population, may affect up to 14 million citizens by 2050. In response to the critique, Tuszynski told Applied Neurology that "time will tell. . . . It is possible that approximately 100,000 to 200,000 people per year could be candidates for growth factor gene therapy. The gene therapy is technically straightforward and can be completed in about 3 to 4 hours by experienced centers."

David Bennett, MD, the Robert C. Borwell Professor of Neurological Sciences and director of the Rush Alzheimer's Disease Center at Chicago's Rush University Medical Center said that if further research confirms that the procedure is effective and safe, "it will likely warrant consideration for some subset of persons with the disease."

Bennett and his colleague Zoe Arvanitakis, MD, assistant professor in the Department of Neurological Sciences, are leading the second trial, which will deliver NGF to targeted sites of AD activity within the forebrain--specifically, the nucleus basalis of Meyner (bilaterally). This trial will deliver NGF via a viral vector, developed by Ceregene, Inc., a small biotechnology company in San Diego that was cofounded by Tuszynski.

The agent, dubbed CERE-110--along with a modified neurosurgical method of implantation--represents an effort to sustain gene expression more efficiently in the brain.

The Rush University study, which began last year, intends to enroll about 6 subjects with mild to moderate AD and observe them for 2 years post-treatment. Clinicians interested in enrollment information can call 866-761-7806.

The full citation for the UCSD study is:

* Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11:551-555. *

TNF-a Inhibitor Halts Progression of Advanced MS

A series of studies--the most recent being a phase 2 placebo-controlled trial--suggest that pirfenidone, a tumor necrosis factor a inhibitor, can halt and even improve symptoms of advanced multiple sclerosis (MS).

The phase 2 trial, the results of which were recently published in Multiple Sclerosis and were reported last October in Toronto at the annual meeting of the American Neurological Association, examined the drug's activity in 43 patients with secondary progressive MS. Twenty-five patients were randomly assigned to receive active treatment and 18 to receive placebo.

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