California Pacific Currents 2005
Charles S. Cobbs, MD: A Clinician and Researcher's Hybrid Approach to Understanding Brain Tumors
Performing brain surgery remains the classic example of the ultra-demanding task. The ability to reach deep within the human brain to extract a tumor or repair a blood vessel requires a total commitment to learning and practice. The training and technical sophistication required to hone those motor and visual skills can take a decade of 14-hour workdays to develop.
That all-consuming focus on patients and surgical technique leaves, it would seem, little time for more research-oriented pursuits-such as finding the molecular and genetic causes of those same brain tumors. But this is the exact combination of hands-on neurosurgery and highlevel laboratory research now being pursued by Charles S. Cobbs, MD, one of the latest additions to the California Pacific Medical Center and the Research Institute. "They are very different skills," admits Cobbs, "but I wanted to do both, and so now I go from surgery on a patient to the lab where I try to figure out what's happening at the cellular level."
Still in the Dark Ages
This impulse to delve deeper into the fundamental causes of brain tumors is understandable. After all, none of the treatment advances of the past 40 years since the introduction of radiation have changed the grim prognosis for most patients with brain cancers. This is especially true for patients with malignant glioma-a fast spreading growth of the glial cells that normally protect and support the nerve cells that perform the actual information processing in the brain.
Malignant gliomas are the most lethal of these Central Nervous System (CNS) tumors, often killing patients within months of diagnosis. Surgery usually can't "get it all" but is often needed for an accurate diagnosis or to relieve symptoms such as headaches, vomiting, or seizures.
"Unfortunately, it remains a bad prognosis," says Cobbs. "We're still in the Dark Ages in understanding these tumors, and my belief is that any new advances in treatment will need to come from thinking outside the box-from considering alternative causes."
For Cobbs, the hybrid approach to attacking these cancers began early in his career. After working for a year with the researchers who had discovered the human immunodeficiency virus (HIV), he entered medical school at the University of Alabama in his hometown of Birmingham. His final-year rotation in neurosurgery convinced him that this was the specialty for him; yet he still had the research bug.
"I reached a crossroads," he recalls, "and fortunately the University of California at San Francisco was a place that encouraged people in the neurosciences to mix bedside care with bench research." This is how, as part of his neurosurgical training at UCSF in the mid 1990s, he came to work in the brain tumor molecular oncology laboratory of Mark Israel, MD. After his residency, he returned to Birmingham, and while establishing his clinical practice, embarked on a series of studies that explored the role of viral infections and immune responses in brain tumor pathobiology. Along the way he picked up several grants and research awards and began to build a novel hypothesis: Cobbs suggested that a common virus might push cancer cells into an unstable or hyperactive mode that contributes to tumor progression.
A Common Virus May Promote Tumor Growth
Cytomegalovirus (CMV) is an extremely widespread, but usually harmless infection, in humans. It is passed along at birth, or in breast milk, or by sexual transmission. Blood tests for antibodies, which provide evidence of a past immune response to a specific microorganism, show that more than half the population has been infected. Like other members of the herpes virus family, CMV will often lie dormant inside certain cells long after the initial mild infection. The immune system can keep the virus in check for a lifetime.
However, just as the herpes varicella zoster (chicken pox) virus can reawaken in older or immunocompromised patients to cause painful shingles, CMV is now suspected by Cobbs and others of reactivating in certain patients to contribute to malignancy. Researchers had connected persistent viral infections with cancers of the blood, liver, and cervix but no one had focused on CMV and brain tumors. Cobbs was lead author on the 2002 article in Cancer Research that first reported the association between CMV and malignant gliomas. In this key study, all 10 of the tumor specimens from glioma patients tested positive for CMV genetic material, while none of 14 brain biopsy samples taken from patients without tumor had any trace of CMV.
Since then, Cobbs and his colleagues have also found evidence of active CMV in colon and prostate cancer cells. They are now exploring the mechanisms by which the virus may promote aberrant signaling pathways in susceptible cells. One theory, for example, holds that brain stem cells with premalignant traits are particularly vulnerable to the cancer-promoting effects (as opposed to the cell-killing effects) of CMV activation. To test this theory, Cobbs and his colleagues have recently snipped out certain CMV genes and placed them into tumor cells to show that even single components of the virus's genetic signature can cause tumor cells to proliferate more rapidly.
From Utter Complexity to Hope for a Cure
Cobbs cautions that the CMV theory is preliminary and needs to be confirmed by other researchers. Because the virus is so widespread, the method of measurement affects the results. He also acknowledges the difficulty of peering inside the cell's complex machinery to pinpoint any single factor that might serve as a tipping point for malignancy. "You can write a diagram of intracellular cancer signaling pathways that would take up a wall of my office," he says. And this is precisely what he has done.
In his freshly painted Research Institute office, that wall is already crowded with the lines and arrows connecting those signaling pathways with inflammatory molecules, drops in blood flow, surges in toxic chemicals ("free radicals"), and immune cells capable of turning on or off programmed cell death sequences. As he tries to figure out where CMV reactivation fits into this convoluted diagram of cellular events leading to malignancy, Cobbs is well aware of the question marks and hasty erasures in this evolving picture of cancer.
"Scientists and drug companies have tried to keep pace with the advances in our knowledge about specific pathways of disease," he says, "and in recent years we've thought on several occasions that we had developed a slam dunk treatment for cancer. But then we find out that inhibiting certain pathways may work only for small subpopulations of patients or for very specific tumor types."
But the researcher is also quick to cite some recent history as reason for hope that this line of work will lead to new antiviral drugs or a vaccine that will reduce the risk or impact of CNS and perhaps other cancers.
"Twenty years ago," says Cobbs, "the concept that vaccinations for human papilloma virus (HPV) and hepatitis B might prevent two of the world's major cancers was considered absurd. The idea that treating an infection with an antibiotic would prevent certain gastric cancers was not discussed. But now that's the reality. A recent study in The New England Journal of Medicine showed that the HPV vaccine prevented cervical dysplasia-the precursor of cervical cancer in high-risk adolescent girls- and this vaccine is now about to be mass produced. And the hep B vaccine is already used worldwide to prevent liver cancer. My kids have been vaccinated. These advances have been underappreciated, and the fact that these major malignancies are now going to be eradicated with vaccines has given me hope that this line of work will lead to a better way of preventing or eradicating gliomas."
Back to San Francisco
Having returned to the Bay Area, Cobbs and his wife and three children are now settling back into San Francisco. He says they are looking forward to reconnecting with their network of friends and colleagues and taking advantage of all the opportunities for outdoor activities like hiking and skiing.
According to Cobbs, the Research Institute will provide him with exactly the type of hybrid opportunity he was seeking. "I was interested in a somewhat nontraditional situation," he explains, "something like Mayo or Scripps, where I could develop a private clinical practice and yet still pursue my research."
Cobbs will join the California Pacific neurosurgery practice of Brian Andrews, MD, who is also co-director of the Neuroscience Institute at the Medical Center. At the Research Institute Cobbs' new laboratory will adjoin that of his former colleague Garret L. Yount, PhD, who directs a molecular and cellular biology laboratory.