Heidi Phillips on the Discovery of Molecularly Distinct GBM Subsets
Emerging Research Front Commentary, August 2010
Article: Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis
Authors: Phillips, HS, et
Heidi Phillips talks with ScienceWatch.com and answers a few questions about this month's Emerging Research Front paper in the field of Biology & Biochemistry.
Why do you think your paper is highly cited?
I think this paper is highly cited since it offers a way to describe meaningful subsets of glioblastoma (GBM), the most common and deadly form of brain cancer occurring in adults. Due in part to interest generated from The Cancer Genome Atlas Project, GBM is now intensively studied by a sizeable number of investigators, many of whom are discovering variations on the basic findings we describe in this publication.
Does it describe a new discovery, methodology, or synthesis of knowledge?
It's really a bit of all three. We describe the discovery of molecularly distinct GBM subsets that are prognostically significant, develop a method for classifying tumors based on gene expression, and then compare the tumor subtypes in several different contexts, including chromosomal alterations, patient demographics, and similarities of gene expression to normal tissues.
Would you summarize the significance of your paper in layman's terms?
"I view our research as one small part of the trend towards personalized medicines. The ability to match therapeutic agents to patients that will derive benefit from them would, of course, represent a major advance in health care."
Our work demonstrates that brain tumors that are indistinguishable by standard microscopic examination can be classified by molecular signatures into major subsets that differ in aggressiveness of the tumor. The work provides a scheme by which a patient's outcome may be better predicted by the addition of molecular analysis to standard diagnostic techniques.
In addition, the findings show that that there are two identifiable groups of more aggressive GBM: one in which tumor cells divide very rapidly and a second in which the tumors can effectively cause the growth of new blood vessels to support tumor growth. Further, the work reveals parallels between the subsets of GBM and cell types in normal brain development, providing potential insights into the cell types-of-origin for GBM.
How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?
My lab initially began work in GBM looking for markers that distinguish tumor from normal brain with a goal of identifying novel drug targets. A major frustration for me was the difficulty in obtaining tissue of adequate quality for investigation. We have an excellent microarray facility here at Genentech, but as a newcomer to neuro-oncology who was working at a pharmaceutical company, I was able to obtain only a limited number of tumor samples suitable for study.
Just as I began to generate data showing that there were distinct classes of tumors with sets of mutually exclusive markers, I met Ken Aldape, a neuropathologist from MD Anderson Cancer Center, who had been studying expression of markers that correlate with outcome in GBM. Ken and I decided to team up to see if we could better define patterns of gene expression in GBM and their relationship to outcome.
This collaboration was mutually beneficial and allowed us to move forward on a set of overlapping goals much more productively than either of us could have done alone. Together with our colleagues at the University of California, San Francisco, the combination of resources and skills available to us at the academic and industry sites propelled the work forward very effectively.
Where do you see your research leading in the future?
My colleagues and I all have a goal of using molecular markers to facilitate the development of new therapies for GBM. Research in my lab now is predominantly aimed at conducting studies that enable new drugs to enter clinical trials for GBM. As we do this, we'll of course, be eager to see whether the molecular sets of tumors we've defined will respond differently to particular therapeutic agents.
I'm very fortunate to work at a company that encourages strong basic science and greater understanding of human disease as well as drug development efforts. Some of our most recent work is yielding interesting insights into the cellular origin and evolution of subtypes of GBM. It's exciting to me to be able to move forward in parallel to extend both the basic and applied science findings from the 2006 paper.
Do you foresee any social or political implications for your research?
I view our research as one small part of the trend towards personalized medicines. The ability to match therapeutic agents to patients that will derive benefit from them would, of course, represent a major advance in health care.
Heidi Phillips, Ph.D.
South San Francisco, CA, USA
KEYWORDS: GLIOBLASTOMA MULTIFORME, MOLECULAR SUBCLASSES, PROGNOSIS, DISEASE PROGRESSION PATTERN, NEUROGENESIS STAGES, NEURAL STEM CELLS, ENDOTHELIAL GROWTH FACTOR, COMPARATIVE GENOMIC HYBRIDIZATION, CENTRAL NERVOUS SYTEM, GENE EXPRESSION, FACTOR RECEPTOR, ANAPLASTIC ASTROCYTOMA, BRAIN TUMORS, IN VITRO.