Roger McLendon on Solving the Jigsaw Puzzle of Glioblastoma
Special Topic of Glioblastoma Interview, October 2011
A significant advance in neuro-oncology in the past 10 years has been the establishment of consortia of academic centers that have come together to share ideas on etiology, progression, and treatment of both adult and childhood brain tumors, including glioblastoma. Cooperation and collaboration have resulted in sharing not only of ideas, but also tissues among partner institutions. These consortia could not be possible without significant financial support of both federal government as well as foundations focused on brain tumor research. The result is that it is becoming much rarer these days to see papers with less than 10 authors or coming out of only one institution.
Demands for high-quality tissue have placed increased demands on morphologists, that is neuropathologists, to characterize each block of tissue in great detail and also have the tissue blocks collated with detailed clinical and pathologic data. The problem with glioblastoma is the inherent issue of spontaneous focal tumoral necrosis as well as the propensity of the tumor to infiltrate surrounding brain. Thus it is incumbent upon a neuropathologist to review each tissue block to characterize it with respect to percent of good tumor, percent of tumor that is infiltrating surrounding normal brain, and percent of the block occupied by necrosis. The time is now past that someone lacking morphologic skills can be relied upon to provide quality tissues to these researchers.
Furthermore, most reports today also report the cytologic and histologic localization and distribution of the reported biomarker in tumors, cell cultures, and/or xenografted tissues. Thus, rather than replacing neuropathologists, each advance places higher demands on their training. Neuropathologists, therefore, are the first to translate the discoveries from the bench to bedside by investigating their clinical and prognostic significance in tumor samples.
Another factor that is impacting tissue banking is the number of primary neurosurgical resections that are occurring at non-academic centers. These "virgin" tumors are thus being lost to tissue bankers. The number of patients who are coming to academic medical centers having had prior first-line surgery and therapy is increasing yearly. This is particularly true in much rarer pediatric tumors where we are learning that the molecular bases of disease are much more diverse than their adult counterparts.
"Read a classic (Oct. 1990) interview
with
Bert Vogelstein."
Vogelstein is an HHMI investigator.
Where do you hope to see this research go in the next decade?
I think the next major steps forward will come from the systems biologists.
As Churchill once said, "Now this is not the end. It is not even the beginning of the end, but it is, perhaps, the end of the beginning." This statement perhaps rings most true for the adult glioblastomas, and hopefully, the lessons we learn going forward will help us with the pediatric tumors. When I was a child, I was given a wood block jigsaw puzzle. Cancer is very much like that puzzle, however, not only do we have to put the pieces together, we have to determine the size and shape of each intricately small piece from experiments.
To date, we have begun to understand the sizes and shapes of the individual pieces and found that we are dealing with at least six different puzzles (types of glioblastomas) with some pieces specific for just one of the puzzles. We think we have accumulated most of the pieces. At present we have only a vague understanding of how these pieces fit together and we are running into some significant surprises, such as where does the IDH1/2 mutation piece fit in and how big is its piece? And the glioma stem cell theory has proven to be a significant surprise piece that seems to govern how to put together pieces at the histologic level.
It is clear that every cell in a glioblastoma draws upon its genetics to provide it with a repertoire of malignant capabilities to respond to its local environmental challenges, such as hypoxia, acidosis, growth factors, therapy, etc. If and how these responses are guided by local stem cells is a higher-level problem related to systems biology, an area of research, that, to date, has not made a significant contribution.
The histologic, antigenic, and molecular heterogeneity found within and among glioblastoma is well known. From my neuropathologist's perspective, advances will come from those willing to tease out these complex interactions of cells in a tumor's micro-environment, that is to say, to put the pieces of the puzzle together.
Roger E. McLendon, M.D.
Department of Pathology
Duke University Medical Center
Durham, NC, USA
ROGER E. MCLENDON'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Bao SD, et al., “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response,” Nature 444(7120): 756-60, 7 December 2006 with 693 cites. Source: Essential Science Indicators from Clarivate.
KEYWORDS: GLIOBLASTOMA, BRAIN TUMORS, NEUROPATHOLOGY, EPIDEMIOLOGY, GEORGIA TUMOR REGISTRY, TUMOR CELL TYPES, HETEROGENEITY, GLIOMA STEM CELLS, NEOPLASTIC PROGRESSION, DOUBLE MINUTES, EGFR VARIANT 3, GLI, WHOLE GENOME STUDIES, PIK3CA, OTX2, ISOCITRATE DEHYDROGENASE 1 AND 2 MUTATIONS, ERRFI1, TACC3, ATRX, DAXX, LONG-TERM SURVIVAL, TISSUE BANKS, PRESERVATION, HANDLING TECHNIQUES, ISCHEMIC TIME, PHOSPHORYLATION STATUS, HIGH-THROUGHPUT ANALYSIS, CONSORTIA, ETIOLOGY, PROGRESSION, TREATMENT, ADULTS, CHILDREN, COOPERATION, COLLABORATION, TISSUE BLOCKS, LOCAL ENVIRONMENT, HYPOXIA, ACIDOSIS, GROWTH FACTORS, SYSTEMS BIOLOGY.