Charles Cobbs, MD
Charles Cobbs, MD is Associate Clinical Professor, UCSF Department of Neurological Surgery, Staff Neurosurgeon, California Pacific Medical Center and Scientist at California Pacific Medical Center Research Institute.
The goal of the work in our laboratory is to explore the role that human cytomegalovirus (HCMV) plays in human cancer. We discovered and first published that HCMV infection is present in nearly 100% of human glioblastomas (GBM), and these findings have been confirmed by others. The focus of our work now is to elucidate patterns of HCMV gene expression in GBM and to determine how the expression of HCMV gene products can promote oncogenesis in tumors that are infected. Our work has led to clinical trials of antiviral therapies for GBM at Duke University and Karolinska Institute, which appear to increase survival in glioblastoma patients. Our efforts thus far indicate that HCMV may drive initial signaling events in gliomagenesis through activation of key growth factor receptors (PDGFRα) and then promote downstream oncogenic events through activation of the PI3-K/AKT signaling pathway and through disruption of the p53 and Rb tumor suppressor signaling pathways. Most recently, we have determined that HCMV infection in GBM occurs preferentially in subsets of cells within the tumor microenvironment, specifically glioma stem cells (GSC) and tumor associated microglia/macrophages (TAMs). Our preliminary experiments with primary GBM cells indicate that HCMV is a key regulator of the self-renewal, angiogenic and invasive phenotypes of GSCs in human GBM. We have determined that several HCMV gene products (including IE1, US28, pp71 and gB) are participating in these oncogenic events in gliomas.
University of Alabama School of Medicine
University of California, San Francisco Medical Center
University of California, San Francisco Medical Center
Areas of expertise:
Neurosurgery: Artificial Cervical Or Lumbar Disc Replacement, Brachial Plexus Injuries, Brain Mapping, Brain Tumors, Cerebrovascular Anomalies, Cervical Spine Disorders, Craniofacial Abnormalities, Epilepsy Surgery, Gamma Knife, Hydrocephalus, Microvascular Surgery, Minimally Invasive Spine Surgery, Neuro-Oncology, Neurocutaneous Syndromes, Parkinson's Disease, Peripheral Nerve Surgery, Scoliosis, Spinal Deformities, Spinal Stenosis, pondylolisthesis, Stereotactic Biopsy, Stereotactic Surgery
Brain tumors & cancer biology with possible role of viral agents in cancer, pituitary tumors, spinal instrumentation.
California Pacific Medical Center
45 Castro St., Suite 421
San Francisco, California
Practice phone number:
There are multiple factors that determine whether or not WBRT is recommended to treat metastatic brain tumors. One of the most critical factors is the status of the patient’s current health and the status of the patient’s primary cancer at the time of the diagnosis. For instance, if a patient has widely metastatic breast cancer and has multiple brain metastases and is thought to have only a couple of months life expectancy, then surgery or stereotactic radiation treatment for multiple brain metastases would be not considered appropriate. In this case whole brain radiation treatment would probably be the recommended therapy. However, as mentioned above, if the patient seems to be doing very well with respect to their primary cancer or has no evidence of significant disease with their primary cancer and they only have one or 2 or 3 metastatic brain tumors, then this patient would be much more likely to get either surgical resection or stereotactic radiosurgery instead of WBRT. Even in cases of surgical resection of one or more metastatic brain tumors, and/or stereotactic radiation therapy of metastatic brain tumors, WBRT is often used as an adjuvant treatment. The current medical literature is somewhat controversial when it comes to the risks vs. benefits of adding WBRT on top of surgery or stereotactic radiation therapy. While WBRT can decrease the occurrence of future brain metastases in many cases, the side effects of WBRT may outweigh the benefits of preventing future potential metastases. This debate continues amongst radiation oncologists.
Primary brain tumors are tumors that arise from cells within the brain. The vast majority of these tumors arise from glial cells. The most common type of glial cell is called be astrocytoma, and this cell is a supporting cell within the brain. The current thinking in terms of the development of astrocytic or glial tumors (of which GBM is the most aggresssive), is that these tumors arise through the malignant transformation of progenitor cells, which are daughter cells of the stem cells that reside in the brain throughout life. These progenitor cells possess the ability to turn into normal glial cells, but in cancer, they are thought to become arrested in their premature state while simulataneously undergoing tumor transformation. Therefore, primary brain tumors are most likely derived from precursor stem like cells that originated in the brain itself.
In contrast, metastatic brain tumors are derived from malignant cells that originated in another organ system. For instance, some of the most common metastatic types of brain tumors are derived from breast cancer or melanomas. These tumors get into the brain after breaking off from the original site of the tumor and circulating through the blood stream. Tumors such as melanoma, breast cancer, and lung cancer seem to have a predilection for metastasizing to the brain. These cancers typically grow as distinct tumor spheres in the brain tissue. In contrast primary brain tumors typically grow by infiltrating into the normal brain tissue and metastasizing widely throughout the normal brain, and do not typically have a clear margin.
Surgical resection of metastatic brain tumors can be controversial. There is clear evidence based on prospective randomized controlled studies that in patients with one metastatic brain tumor, they do better with surgical resection followed by radiation versus radiation alone. Therefore, in cases where there is a single metastatic tumor that is easily accessible surgically, surgical resection may be the best choice-especially the tumor is causing pressure on the adjacent brain. However, if there is a single metastatic tumor that is not causing significant mass effect and is deep in the brain or is in an area of brain that is critical such as the motor area or the speech area, then this type of tumor may be better treated by focused stereotactic radiation therapy. Often there is no clear right or wrong answer in terms of whether or not surgery for a single metastatic lesion should be done. In cases where there are more than one or two metastatic lesions, the role of surgery is considered to be much less appropriate unless one of these metastatic tumors is causing a huge amount of mass effect and needs to be removed in order to decompress the brain.
Most of the time when the patient with brain cancer first meets the neurosurgeon, they have been sent from a referring neurologist or from an emergency room after having presented with some type of neurological symptoms such as a headache or seizure. Usually there is an MRI scan or CT scan that shows a tumor, and most of the time the patient has not even seen the scan itself. The best way a patient can prepare for their first meeting with a neurosurgeon is to be prepared to ask questions about the type of tumor, the cause of the tumor, how long the tumor has been there, and what type of progression of the tumor is to be expected. Many patients are seen after getting a brain CT scan or an MRI for a headache for instance and are found to have an incidental tumor such as a small meningioma or pituitary tumor. More often than not, these tumors are totally benign and can often be followed by just getting serial MRI scans to track the size of the tumor. In contrast, if the tumor is thought to be a malignant tumor, either metastatic or primary such as GBM, the patient is likely to need to make certain decisions about proceeding towards surgery, radiation treatment, et cetera. Many of these life decisions need to be based on the current health situation of the patient. For instance, in very elderly patients who are disabled, undergoing any therapy for an aggressive malignant brain tumor may not be suitable. The role of the neurosurgeon in this setting is to provide as much information as possible to the patient to get them the appropriate knowledge and expectations as to what to be gained by surgery, what can be gained by holding off on surgery, and what other interventions might be involved after surgery. The patient should also be prepared to ask about the surgeon's experience in this particular type of surgery, and the risks involved.
As mentioned, GBM is the most common malignant primary brain tumor, with a mean survival of only 13 months. These tumors are typically treated by maximal surgical resection whenever feasible. In certain cases, if the tumor is in an area of critical brain tissue such as the motor area or language area, the tumor cannot be maximally resected. After resection, malignant glioma tumors such as GBM are typically treated with external beam radiation treatment. This type of radiation is performed by treating the patient on 30 separate days with small doses of radiation to the area of the tumor plus a surrounding area of a couple of centimeters. At the same time these patients typically take a chemotherapy drug called temozolomide or Temodar. Temodar is given for the first month 5 days a week, and then subsequent months for only the first few days of the month.
In contrast, metastatic brain tumors are treated in multiple different ways. When metastatic tumors arise as a solitary mass with significant pressure on the brain, especially when located in a superficial and safe area, they can be completely resected. Often however they will arise as multiple metastatic tumors dispersed throughout the brain. In this case, if there are only a few metastatic tumors, they may be treated by radiating each individual tumor with focal stereotactic radiation treatment (also called stereotactic radiosurgery or SRS). Stereotactic radiation therapy involves using a computer assisted high-dose approach to deliver maximal radiation to a focal area such as a small metastatic tumor while delivering very low dose radiation to the adjacent normal brain. The Gamma Knife and the Cyber Knife are two such well-known computer assisted SRS devices. More and more, metastatic brain tumors are treated with stereotactic radiation. However, if the tumor is disseminated widely throughout the brain and the patient is very ill, another type of radiation called whole brain radiation treatment (WBRT) is commonly utilized. This is essentially treatment to the entire brain over 10 different days with radiation. The side effects of WBRT can be quite disabling if the patient survives more than a year or so. Some of the side effects of WBRT include rapidly progressive dementia from the direct damaging effects of the radiation on the normal brain. In general, chemotherapy has very limited role in the treatment of metastatic brain tumors.
Several of the important CMV gene products that we believe can promote oncogenesis in tumors have been described by our group and other groups. One of the best ways to conceptualize the ways CMV gene product can promote tumors is to focus on the canonical hallmarks of cancer as originally described by Hanahan and Weinberg. For each of these key cancer pathways, at least one or more CMV gene products are known to facilitate them (CMV gene products shown in italics). These include: 1) sustaining proliferative signaling (IE1, IE2, pp71, UL97), 2) evading tumor suppressors (IE1, mtr2), 3) activating invasion and metastasis (US28), 4) enabling replicative immortality (IE1), 5) inducing angiogenesis (IE1, US28), 6) resisting cell death (IE2, vMIA, vICA), and 7) avoiding immune destruction (cmvIL-10, US2, UL16). Many others are still yet to be recognized in terms of their contribution to cancer pathways.
All viruses have genes just like human cells. The genes that viruses express can lead to the production of proteins that can manipulate and alter the host cell function. In some cases, the viruses are “smarter” than the cells and the virus’ genes can completely sabotage normal cellular functions and lead to cancers. For instance, viruses likely HPV have genes that encode for proteins that block cellular process involved in preventing tumor formation. In the case of HPV, these viral proteins can directly cause cancer to form in normal cells. In the case of CMV however, we did not see clear-cut evidence of any viral related proteins that directly cause cancer under normal circumstances. However, we have identified multiple viral proteins from this virus that can drive pathways that are very important in the progression of cancer. We believe that these CMV genes may become cancer-promoting genes in the setting of a prior “first hit” mutation in cells with stem cell properties. For instance, some of the CMV genes that are immediately produced after infection can drive the cell into a proliferative state, and can cause tumor formation when combined with other oncogenic proteins. Other CMV genes produced later on in the viral life cycle can prevent the cell from shutting down in the setting of imminent tumor formation. These are called anti-apoptotic genes. Another category of viral gene products can prevent the normal host immune response from eradicating the infected cells by blocking many of the human normal immune response mechanisms.
With respect to the question of whether or CMV produces or alter genes, the answer is both. CMV actually does produce genes of its own that are encoded by the DNA of the virus. It also encodes for viral proteins that can cause alterations in human genes by either directly causing mutations in them or by modifying them through a mechanism called epigenetics. Some of the genes that have been reported to become mutated or modified by CMV gene products, such as the P53 and Rb genes, are critical for preventing tumor development, and thus CMV might promote cancer formation by disabling these key tumor suppressor genes. This is a major area of interest currently in the cancer research community.
Human cytomegalovirus (or HCMV or CMV) is a human DNA virus and a member of the herpesvirus family. Other members of the herpes virus family including herpes simplex type I, which causes cold sores, the chickenpox virus, Epstein-Barr virus, and the virus that causes Kaposi's sarcoma. All of these viruses share the property that they cause chronic infection and cannot be eradicated from the host once the initial infection occurs. CMV is the most common cause of congenital human brain infection and it can cause severe congenital defects including brain injury and deafness. About 70% of adult humans are infected with CMV. In people who become immunosuppressed, including patients with AIDS and transplant patients, CMV can cause severe and even fatal infections.
I began studying the possible link between CMV and malignant brain tumors because I was interested in the possibility that a chronic infection could participate in the development of the most malignant of brain tumors, called glioblastoma multiforme, or GBM. It is well-known that many infectious agents, especially those causing chronic infections, can give rise to and promote cancer. However, there was no known link between CMV and human tumors. I hypothesized that since CMV could infect fetal brain, and stem cells in the normal brain, the virus might also have a predisposition to infection of brain tumor cells. My reasoning was that cancers have many properties consistent with fetal cells and stem cells, and normal stem cells in the brain are thought to be the cells of origin of GBM. Since CMV was such a common infection of the developing brain, it seemed possible that this virus might persistently infect brain stem cells, and reactivation of this virus might occur in early stages of brain tumors. Since it was known that CMV reactivation was associated with chronic inflammation, and that CMV could even promote pathways that are known to be involved in tumor progression, it made sense to look for this virus. In 2002, we published the first report of CMV in GBM in over 95% of cases. Since then, other groups have confirmed our findings. Furthermore there has been increasing evidence that some of the CMV gene products and proteins can drive pathways that are known to accelerate cancer progression. Some of these pathways are involved in suppressing the local immune response against the tumor, and some are involved in promoting cell proliferation, inducing stem cell growth, blocking tumor cell death, and promoting the development of new cancer blood vessels. Currently we're not sure whether the virus infection causes the tumor itself or whether it arises within a developing tumor. In either case however, it seems that the chronic inflammation and production of viral proteins in the setting of these tumors is likely to make them more aggressive. This concept is supported by a mouse model of GBM formation in the setting of CMV infection, in which the mice develop GBMs more rapidly and die earlier when the mice are infected with CMV at birth.