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Defeat GBM-Funded Research Helps Reveal Another Astonishing Trick Brain Tumors Play

Summary: A surprising, counter-intuitive discovery by Defeat GBM Research Collaborative-funded researchers opens up a potential new approach to slowing glioblastoma (GBM) growth

We all learn during grade school math that when doing multiplication, “a negative times (x) a negative equals a positive.”

Could this be true for glioblastoma tumor biology, too? A new study from Defeat GBM-funded researcher, Dr. Frank Furnari of Ludwig Institute for Cancer Research, San Diego, suggests it might.

Dr. Frank Furnari at the NBTS 2016 Scientific Summit

First some basics: As most are familiar with, cancerous tumors – like glioblastoma – grow as the result of cells replicating/dividing out-of-control. What causes cells to do so is the subject of much research and many hypotheses. Further, for different tumors the causes may differ. What is generally understood, however, is that tumor growth is generally (or broadly) due to normal cellular mechanisms – which usually keep things running like a fine-tuned machine – going awry because one or more genes have picked-up errors at some point during cell division.

One of the prime suspects in the breakdown of normal cellular processes is the deletion or loss of function of what are known as “tumor suppressor genes.”

With billions of cells in our bodies dividing constantly over our lifetimes, there are bound to be errors in the process occasionally. However, our genomes possess these “tumor suppressor genes” which help keep the division/replication process in check; so, usually, potential cancer-causing mistakes during cell division are no big deal. That is to say, if something goes wrong during normal cell division – say a piece of DNA gets copied wrong as its being passed down to daughter cells – tumor suppressor genes are there to produce proteins that effectively swoop in to nip the problem in the bud before it gets out of control. But when the mistake during cell division is to a tumor suppressor gene that is key to protecting that particular cell type, tumors like GBM can grow. Thus, the deletion or loss of normal function of a tumor suppressor gene that is important to the regulatory mechanisms of glial cells (the cells that make up GBM tumors) is a negative.

Dr. Furnari (left) with Defeat GBM Scientific Director, Dr. Al Yung (center), at the 2016 NBTS Scientific Summit

The loss of one such tumor suppressor gene, known as PTEN, has widely been linked to the growth and treatment-resistant nature of GBM tumors. Normally, PTEN regulates a broad spectrum of biological functions in cells including cell proliferation and survival and has been shown to maintain the integrity of DNA. Yet, what Dr. Furnari and colleagues found in this study – published today in the leading scientific and medical journal, Nature Communications – is that under circumstances where PTEN is deleted, and no longer able to regulate cell growth, blocking another tumor suppressor gene known as DAXX actually helps slow the growth of GBM tumors in mice.

The reason this finding is so astounding is that, previously, it stood-to-reason that if losing the function of one tumor suppressor gene was bad, losing a second would presumably make things even worse. But, unexpectedly, Dr. Furnari and his team have found that the loss of these two normally-important genes (two negatives) actually might equal a positive.

This apparent paradox however, can be explained by the discovery of a previously unknown interaction between PTEN and DAXX proteins by Dr. Furnari and a postdoctoral researcher in his lab, Dr. Jorge Benitez.

The DAXX gene produces a protein by the same name, whose job it is to help guide – or chaperone – another protein called H3.3 to a specific spot on structures called “chromatin,” which help package DNA to be able to fit into the nucleolus of cells. H3.3 is a type of protein called a histone. Histones usually help in the packing process for chromatin. But H3.3 appears to have a special role in which, instead of helping pack DNA, it actually attaches to a spot on chromatin that typically contains stretches of DNA that include a number of “oncogenes” – or cancer-causing genes. This suggests that H3.3 plays a key role in helping to keep these cancer-causing oncogenes suppressed.

Therefore, the discovery that PTEN actually interacts with DAXX indicates that together these two genes can impact how H3.3 binds to chromatin. Specifically, the scientists believe PTEN helps suppress oncogenes by working with DAXX to transport and deposit more H3.3 molecules onto the location of the oncogenes in chromatin to regulate their expression (or block them). But if PTEN gets deleted or loses its function, not enough H3.3 gets to the right spots on chromatin to block the activity of the oncogenes (because, strangely, under these circumstances chromatin and DAXX compete to bind with H3.3). But if both genes are deleted, H3.3 is free to bind to chromatin and slow tumor growth.

Dr. Furnari and his team validated this through experiments using lab mice, where they demonstrated that if either PTEN or DAXX was eliminated in GBM cells, then tumor growth occurred. But, if both were eliminated, then tumor growth slowed.

In these experiments the researchers used genetic engineering techniques to “knockdown” and inhibit DAXX. But for this approach to ultimately prove successful as a treatment strategy that could help GBM patients, they need to develop a new drug that achieves the same effect. As such, their next step is to identify exactly how DAXX and H3.3 bind together, and then seek to design a chemical molecule (the basis for a drug) that, in the absence of PTEN, can prevent this binding so that, again, H3.3 is free to bind to chromatin and suppress the cancer-causing oncogenes.

“We feel our findings, made possible through the support and network of the Defeat GBM Research Collaborative, provide a new direction for developing a therapeutic for PTEN-mutated glioblastomas,” says Dr. Furnari. “We are energized to embark on this next phase of our research and to make a difference for GBM patients.”

If you want to support more discovery – that can lead to much-needed new treatments for glioblastoma – via the Defeat GBM Research Collaborative, visit here