Dr. Charles Cobbs, recipient of 2002 Charles B Wilson Award funded by NBTS, talks to ABC News in San Francisco.
The 2002 Charles B Wilson Award, funded by NBTS, supported a study of the connection between human cytomegalovirus (CMV) and Glioblastoma. Drs. Charles Cobbs and Liliana Soroceanu made the startling discovery that CMV was present in the vast majority of brain tumors. On San Francisco’s ABC News affiliate, Dr. Cobbs said, "I don't believe this virus causes brain tumors, but I believe that this virus has the potential to be the promoter.” In other words, it could be the switch that turns on tumor growth and a target for therapies to stop or prevent growth.
NBTS is currently funding a clinical project in this field (Duane Mitchell at Duke University Medical Center, through our SPORE Collaborative funding) and sponsored a CMV/GBM conference in 2008 to promote further discussion in this field.
Dr. Charles Cobbs: Virus could be key to fighting brain tumors (ABC News, San Francisco)
News addendum: 11/16/2009
CMV Workshop Summary - workshop sponsored by NBTS
By Charles Cobbs, MD
In October 2008 a meeting took place in Boston sponsored by the National Brain Tumor Society (NBTS). The meeting was organized by Dr. Charles Cobbs from the California Pacific Medical Center. The theme of the meeting was investigation of the potential role of human cytomegalovirus (CMV) in the pathogenesis and therapy of malignant glioma. The concept of the meeting originated with observations by Dr. Cobbs and others demonstrating that CMV infection is strongly associated with human malignant gliomas. First published by Cobbs et al. in Cancer Research in 2002, these findings had been more recently confirmed by others at Duke University, MD Anderson Cancer Center, Karolinska Institute and UCLA. Subsequently, two groups of investigators at Karolinska Institute and at Duke University had initiated clinical trials to investigate the potential role of anti-CMV strategies in glioblastoma therapies.
The meeting had an excellent representation of leaders in the fields of Neuro-oncology and CMV virology. Drs. Susan Chang from UCSF, Dr. Darell Bigner from Duke, Dr. Nino Chiocca from University of Ohio, and Dr. Melissa Bondy from MD Anderson Cancer Center provided expert neuro-oncological scientific perspective.
The meeting occurred over one and a half days of conferences. The first day was organized first with presentations by the various investigators who had shown evidence for the presence of CMV in malignant gliomas. This included presentations by Dr. Charles Cobbs, Dr. Duane Mitchell from Duke University, Dr. Afsar Rahbar form Karolinska Institute, Dr. Michael Scheurer from MD Anderson Cancer Center, Dr. Dan Streblow from Oregon Health Sciences University, Dr. Robert Prins from UCLA, and Dr. Liliana Soroceanu from California Pacific Medical Center in San Francisco. The consensus from the presentations was that CMV infection and gene expression is highly associated with malignant gliomas in humans.
A second session consisted of presentations by various investigators to explore the role CMV might play in the pathogenesis and progression of gliomas. This session was led off by Dr. Cecilia Soderberg-Naucler from Karolinska Institute in Stockholm, Sweden, who proposed the concept that CMV microinfection in tumors could promote multiple tumor-relevant pathways including inflammation, immunosupression, angiogenesis and growth. Dr. William Britt from the University of Alabama at Birmingham (UAB) then discussed mouse models of persistent CMV brain infection, and their relevance to a hypothetical model for how CMV might cause chronic brain infection, which could potentially promote oncogenesis. Dr. Caposio, from OHSU then discussed mechanisms by which CMV infection could promote chronic inflammatory pathways through NF-kappaB signaling. Dr. Jay Nelson from OHSU then discussed recent work from his lab demonstrating evidence that chronic CMV infection in a model of chronic vascular disease led to the production of high levels of secreted growth factors that could enhance the proliferative and angiogenic environment, should this occur in a chronically infected tumor cell. Dr. Randa El-Zein from MDACC then discussed her work implicating CMV infection in DNA injury and mutagenesis.
A later session then continued along the theme of potential mechanisms of CMV in "oncomodulation". Dr. Rob Kalejta from the University of Wisconsin discussed the potential role of oncogenic CMV gene products and their potential to interfere with normal tumor suppressor pathways, and he highlighted some work that he recently published in Science on this topic. Dr. Tim Kowalik from the University of Massachusetts Medical School then discussed other mechanisms by which CMV gene products could promote tumor signaling pathways and block apoptosis. Dr. Liliana Soroceanu then discussed work she had published in Nature indicating that the PDGF-beta growth factor receptor, an important growth factor implicated in gliomagenesis, was the cellular receptor for CMV and that CMV infection activated this important tumor signaling pathway in a way that could promote tumor growth and angiogenesis. Dr. Cecilia Soderberg-Naucler then summarized the concept again that CMV infection may promote the malignant phenotype of brain tumors.
The final session focused on clinical trials with CMV anti-viral strategies against malignant gliomas. The session started with Dr. Don Diamond from City of Hope Hospital in Duarte, CA, who discussed whether therapeutic vaccination that augments CMV-specific cell mediated immunity could improve glioblastoma outcomes. Dr. Cecilia Soderberg-Naucler then discussed the Karolinska Institute phase II trial based on the administration of the antiviral drug Valcyte to patients in addition to standard therapies for glioblastoma. Dr. Duane Mitchell then discussed the clinical trial at Duke University, which uses a dendritic cell immunotherapy approach to treat glioblastomas in patients. The session ended with a discussion of the status of the clinical trials and the role for further collaborations among investigators present to advance the knowledge in the field and to improve chances of clinical trial success.
The overall consensus of the group with respect to the status of the field of CMV in malignant gliomas and the future of this area of investigation was then discussed. With the exception of one investigator, all agreed that the current evidence demonstrates a strong association between the presence of CMV infection and malignant gliomas. The investigators discussed the likelihood that further research into this area would be accelerated by developing collaborations among the investigators at the meeting, and indeed several collaborations were initiated. Intentions to continue the clinical trials at Karolinska and Duke Universities were discussed. The Duke investigators mentioned that future trials may evolve into adoptive T cell immunotherapy approaches instead of pulsed dendritic cell approaches. Finally, representatives from the NIH including Dr. Jane Fountain and Dr. May Wong discussed strategies that investigators might pursue to develop successful funding for further research into this area. A future meeting of this group was briefly mentioned and will hopefully occur within the next two years to document progress in this field.