Scientists at the Houston Methodist Research Institute (HMRI) have been successful in better understanding the inverse relationship between Alzheimer’s Disease (AD) and a form of brain cancer, Glioblastoma Multiforme (GBM). The team of investigators led by Stephen Wong, a medical researcher and bioengineer with HMRI, along with co-authors, Hong Zhao and Xiaoping Zhu, also from HMRI, used a systems biology approach driven by the data crunching power of supercomputers for deep data analysis (analyzing quadrillions of data in split seconds). Systems biology focuses on analyzing a condition on the basis of an entire system (a biochemical pathway, signaling pathways, etc.) instead of the conventional methods used by scientists, focusing on one particular gene or molecule.
The notion that an inverse relationship between AD and GBM has already been established earlier through a series of public health studies in Taiwan (2012) and Northern Italy (2013), but no conclusive evidence was drawn against the rare co-existence of these two conditions. “This is the first time people have found that at the molecular mechanism level there are linkages between the two diseases,” Wong said. “No one understands why this link is there, in a biological sense. And that’s the reason we did this study. I think we are among the first to study it this way.”
The study focused on targeting the molecular signaling pathways involved in both diseases. The cells signal inwards from their receptors towards the nucleus, which houses the genetic material. On receiving these signals, the genes become activated and release specific products, which help in growth and proliferation of the cells and hence in progression of the disease, in this case.
Wong and his team executed the study following a systematic approach of first zeroing in on the genes, active and inactive, in both AD- and GBM-affected brain tissue samples, validating the data in cell cultures and live mice models in the laboratory, and then analyzing the results using the Lonestar and Stampede supercomputers from the Texas Advanced Computing Center (TACC) at the University of Texas in Austin. Information about genes were obtained by DNA microarray analysis, followed by sequencing using data from The Cancer Genome Atlas at NIH (for GBM) and Alzheimer’s Disease Neuroimaging Initiative (for AD). The results were then analyzed by supercomputers, which yielded a 1000-fold improved performance as compared to microarray analysis.
The study showed that the ERK/MAPK pathway was unregulated in brain cancer, whereas the Angiopoietin pathway was upregulated in AD. Further validation tests in mice and cell cultures showed that the tumor cells in AD affected mice were suppressed by ERK-AKT-p21 cell pathway and the anti-angiogenesis pathway.
In this regard, it should also be noted that the MAPK (mitogen activated protein kinase) pathway, being a very common and important pathway associated with cancer, has been the topic of research for therapeutic intervention in terms of treating AD.
Speaking on the therapeutic potential of these molecular signaling pathways, co-author Xiaoping Zhu said that, ” If some important molecules are discovered which caused GBM, maybe they could be developed into some drugs and used for the Alzheimer’s disease treatment, which inspire new drugs development.The drug developing process could be shortened compared with the de novo drug discovery.” However, this is just the initial phase of research, with much deeper insights into the molecular pathways still being necessary for complete knowledge. As fellow co-author, Hong Zhao, correctly pointed out, “Reversely, some drugs were developed for targeting Alzheimer’s, but the clinical trials showed unexpected results that in rare cases the drugs induced the cancer occurrence in the patients. Still, there is sharing of some signaling pathways between these two diseases, and thus the studies to reveal the relationship of these two diseases at the transcriptional molecular level are important.”
Commenting on the uniqueness of this study, Wong said,”Conventionally, scientific research focuses on one particular protein or one gene. Such a strategy does not scale up for complex diseases like cancer and neurodegeneration. We’re at the tip of the iceberg. Leveraging the availability of big biomedical data and supercomputing, we’re going to dig deeper to delineate crosstalk between different pathways to identify the promising druggable targets to cure either of these two devastating diseases, or both. It is a fresh, cost-effective strategy, a big data analytic approach to enable us to find this mechanism. We are witnessing a new era of digital biology.”
The National Institutes of Health (NIH) being one of the principal funding bodies for this studies, along with the T.T and W.F. Chao foundation, Dan Gallahan, the NIH program officer for the grant and deputy director of the Division of Cancer Biology with the National Cancer Institute, was impressed by this line of work and was quoted as saying, “This work of Dr. Wong’s is quite exciting in that it shows connections between two of the most intractable diseases in modern society. And while our focus is on cancer, the great hope is that as we make these connections we can leverage that knowledge to find new targets and opportunities that can provide meaningful intervention for either disease.”