Preserving the Mind

 

Dr. W. K. Alfred Yung (left) and Dr. Peter Steck are working together to uncover the genetic mechanisms associated with brain tumor development.
 
It was the frequent, yet mild headaches and strange smells that told Mary Ann Bashem something was wrong.
 
What the mother of two didn't know was that a golf ball-sized tumor lay insidiously hidden in the right temporal lobe of her brain, the center for smell and a region associated with memory, learning and thought processing.
 
Thanks to successful surgery, aggressive chemotherapy, radiation and adjuvant therapy, the 48-year-old Bashem has been cancer-free for two years.
 
While standard cancer therapies still give people with brain tumors the best possible chance of survival, in many cases, they still do not cure the cancer completely, often causing some disability and suffering.
 
For Dr. Victor Levin, that's simply not acceptable.
 
"I want the future to change for people with brain tumors," says Dr. Levin, director of the Brain Cancer Research Program and Brain Tumor Center. "I want the suffering to stop. I don't want to use cytotoxic drugs anymore. I don't want to give radiation therapy. I want to prescribe therapy that is simple, direct and non-toxic."
 
To do this gains must be made in the laboratory.
 
"I believe real progress will be made in the laboratory and then translated into new therapies," says Dr. Levin, chairman of the Department of Neuro-Oncology. "I think our chances of making a big impact in the disease are probably as good as they were when the astronauts decided they were going to the moon."
 
Much of the Brain Cancer Research Program's activities center on understanding the molecular genetic changes that lead to the malignant phenotype and, in particular, the signaling pathway that controls cell division and invasion in angiogenesis (blood vessel formation), says Dr. Levin, who holds the Bernard W. Biedenharn Chair in Cancer Research.
 
In a most recent development, Dr. Peter Steck and his team, along with researchers at Myriad Genetics, Inc., have discovered a candidate gene that is believed to be involved in tumor progression. Ironically, researchers at Columbia University's College of Physicians and Surgeons seem to have isolated the same gene.
 
According to Dr. Steck, associate professor of neuro-oncology, the MMAC1 (Mutated Multiple Advanced Cancers) tumor suppressor gene is either missing or malfunctioning in more than 90 percent of patients who have glioblastoma multiforme, the most common and malignant form of brain tumors in children and adults. The gene also is mutated in a number of other cancers, including breast, ovarian, prostate, lung and skin. The nature of the gene does not determine whether people will get cancer, but instead indicates how aggressive their cancer may be, he says.
 
"The discovery of the MMAC1 gene is a most exciting breakthrough in brain tumor research," Dr. Steck says, "because this gene will increase our understanding of the progression process in glioblastoma multiforme and help us develop new targets for therapy."
 
In the past decade, researchers at M. D. Anderson and elsewhere also have found other genes and enzymes to be associated with brain tumor development. A lot of the research at the cancer center has focused on the tumor suppressor gene known as p53, which is abnormal in 50-60 percent of people with malignant astrocytoma, and certain enzymes responsible for tumor invasion and blood vessel formation.
 
With knowledge gained from research, scientists at the Brain Tumor Center are developing new and innovative therapies that aim to restore normal cell functioning by applying therapies that either correct or destroy abnormal cells.
 
While standard chemotherapy drugs like CCNU, procarbazine and timodal are effective in treating brain tumors, researchers are looking towards newer, less-toxic drugs and therapies that will target the cancer cell specifically and selectively, leaving normal cells alone.
 
Gene-based therapies also are increasingly being evaluated in cancer today. The ongoing therapies being explored involve replacing tumor suppressor genes that inhibit tumor growth; transporting "suicide" genes via a virus that kills tumor cells directly; transferring apoptosis-promoting genes that instruct tumor cells to die; inserting genes that block tumor blood vessel formation and invasion; and delivering antisense constructs that alter DNA or RNA in such a way that specific cancer proteins are not produced, allowing cells to become less malignant.
 
"If we can find the right genetic switch and we can deliver the genes only to the tumor cell, then we will be able to kill the tumor in a highly efficient and specific manner. That's the goal," says Dr. W. K. Alfred Yung, deputy chairman and medical chief of the Neuro and Supportive Care Center and holder of the Florence Maude Thomas Cancer Research Professorship.
 
In addition to gene therapy, scientists are translating research information into what someday may be promising new drugs, as well as using some of the knowledge to enhance standard drug therapy.
 
Besides cytotoxic drugs, researchers also are investigating drugs that block angiogenesis and tumor cell invasion. Many older and newer drugs have been shown to block tumor blood vessel growth. Marimastat, a protease inhibitor which can block tumor cell invasion and may also have an angiogenic effect, is one example of several drugs being clinically investigated, according to Dr. Levin.
 
Another group of chemotherapeutic agents under investigation are differentiating agents such as retinoids, a vitamin A derivative. Well-known for their use in treating acne, these drugs may be helpful in renewing cells damaged by tumors. Clinical trials have shown them to be active in treating glioblastoma multiforme, Dr. Levin says.
 
Also under investigation is the development of a small molecule that can be taken orally and that is not expected to have systemic toxicity, but which can specifically block specific enzyme signaling pathways known as Src in many cancers, Dr. Levin says. This research is currently funded by a five-year national cooperative drug discovery group grant from the National Cancer Institute.
 
At M. D. Anderson, brain tumor research is advancing on many fronts. "But despite the progress being made, there is still no cure," says Dr. Raymond Sawaya, chairman of the Department of Neurosurgery and holder of the Mary Beth Pawelek Chair in Neurosurgery. "And until there is a cure, there is no rest."

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