Molecular signatures predict disease progression and prognosis of high grade brain tumors

Scientists have gained valuable new insight into the biology of aggressive, incurable brain tumors. A research study published in the March issue of Cancer Cell uses gene expression profiling to identify molecular profiles and signaling pathways associated with tumor aggressiveness and disease progression. This work provides clues about what drives tumor formation and progression and will guide researchers in new directions for development of more effective therapies for this devastating disease.

High-grade gliomas (HGGs) are the most common intrinsic brain tumors in adults and are known for being fast growing, difficult to treat, and for most patients, ultimately fatal. A group of scientists from Genentech, Inc., the Brain Tumor Research Center at the University of California, San Francisco and the M.D. Anderson Cancer Center in Houston, Texas used a sophisticated genetic screening technique to perform an extensive examination of samples from multiple HGGs. The researchers were able to identify molecular subclasses of tumors that were based on perturbation of specific signaling pathways and distinct clinical characteristics.

Activation of different signaling pathways among tumors could be correlated to disease progression and prognosis. Specifically, signaling in two pathways that are critical for controlling normal brain development, the Notch and Akt pathways, was correlated with outcome in tumor patients. Information was also obtained about the physical progression of the different tumor subtypes. Of the two subtypes that had a poor prognosis, one was associated with a high rate of tumor cell proliferation, while the other was characterized by increased blood vessel formation. Identification of a tumor's molecular profile, signaling pathways, and characteristic features may substantially increase the effectiveness of treatment, as therapies can be targeted more specifically to each tumor subtype.

Interestingly, the subtypes of HGGs identified in this study closely resembled key stages seen in the process of neurogenesis, with some tumors presenting characteristics of neural stem cells and others displaying elements distinctive for intermediate stages of development or even immature neurons. The authors suggest that the aggressiveness of tumor growth might be regulated by mechanisms that regulate cell fate decisions during brain development. According to study author Dr. Heidi S. Phillip of Genentech, Inc., "Similarities between stem cell biology and glioma aggressiveness suggest that greater understanding of normal brain development may lead to novel insights for therapeutic intervention in glial malignancies."

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The researchers include Heidi S. Phillips, Samir Kharbanda, Ruihuan Chen, Liliana Soroceanu, William F. Forrest, Robert H. Soriano, Thomas D. Wu, P. Mickey Williams, and Zora Modrusan of Genentech, Inc. in South San Francisco, CA; Anjan Misra, Janice M. Nigro, and Burt G. Feuerstein of the University of California, San Francisco in San Francisco, CA; Howard Colman and Ken Aldape of the M.D. Anderson Cancer Center in Houston, TX. H.S.P., S.K., R.C., W.F.F., R.H.S., T.D.W., L.S., and Z.M. are full-time employees of Genentech, Inc. K.A. was supported by an institutional research grant from MDACC.

Phillips et al.: "Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis." Publishing in Cancer Cell 9, 157173, March 2006. DOI 10.1016/j.ccr.2006.02.019 www.cancercell.org


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