Summary: Defeat GBM-funded research discovers a completely new process whereby EGFR alterations – which occur in the majority of GBMs – fuel tumor growth, and, importantly, identifies a potential way to exploit these changes in tumor cells to treat GBM using a class of anti-cancer drugs already in development.
The majority of cells within the human body are constantly dividing. Our biology provides a number of natural signals that let a cell know when it’s time to grow and divide. In healthy individuals, this process is tightly controlled through the finely-tuned machinery and processes of a human cell.
However, in a disease like cancer, the signals that coordinate critical cellular processes are interfered with by alterations in either the genes and/or proteins that provide the instructions for all of our cells’ functions.
“Growth factors” are one of the aptly named natural substances that tell our cells to grow and divide. Growth factors bind to receptors on the surface of cells (also aptly named as “growth factor receptors”) and activate a chain of biochemical reactions within the cell (called signal transduction or cell signaling) that eventually tells the DNA, housed in the cell’s nucleus, to begin preparing for cell division.
Mutations to growth factor receptors can lead to their constant activation, which can cause uncontrolled cell division – a hallmark of cancer – as the cell keeps receiving signals to grow.
In glioblastoma (GBM), specifically, a growth factor receptor named EGFR (epidermal growth factor receptor) is commonly mutated or amplified. In fact, it is altered in approximately 60% of GBM tumors. The most common EGFR mutation is known as EGFRvIII.
This mutation has been known for a long time, but attempts to apply treatments that counteract it have been unsuccessful to-date. Because of this, one group of researchers within NBTS’ Defeat GBM Research Collaborative has focused their efforts on better understanding the full impact the EGFRvIII mutation has on GBM cells.
These two findings were very important and both provided potential new treatment strategies against GBM. But because GBM is one of the most complex and adaptive cancers, it is important to understand the full “story” of EGFRvIII, so that combination treatments (a cocktail of drugs, so to speak) can be used to block all of the tumor’s escape routes.
Now, a study just published from Defeat GBM’s team at Ludwig provides a completely new insight into how the EGFR mutation causes tumors and helps us get closer to understanding the full “story” of EGFRvIII in GBM. In this new study, the researchers map how EGFRvIII mutations change the processes in which the genetic code, stored in DNA, is transcribed into the instructions that regulate cell functions – as well as, importantly, how these multiple processes converge and might be exploited with new treatments.
“We started our study because we think EGFRvIII causes cancer through an integrated series of events,” said Dr. Paul Mischel of Ludwig Cancer Research and the University of California, San Diego. “EGFRvIII changes the cell’s internal signaling network, its uptake and use of nutrients, key elements of its gene-reading machinery known as transcription factors, and its epigenetic landscape – the distribution of chemical tags that determine which parts of its genome are available for reading. We wanted to find the nodes connecting these processes and see if they could be targeted by a drug.”
Specifically, the researchers found through scientific analysis that an EGFRvIII mutation changes the landscape of “enhancers” that are activated in a GBM tumor cell. Enhancers are regions of DNA that boost the activity of other genes that they are connected with. The altered group of enhancers – activated by EGFRvIII mutations – turn out to be binding sites for a number of different “transcription factors” – proteins that regulate the process whereby a genetic sequence of DNA is read and interpreted to eventually become a protein. Of the transcription factors that recognized the signatures of enhancer regions activated by EGFRvIII, two stood out as being particularly elevated in GBM cells and were identified as SOX9 and FOXG1.
So, while an EGFRvIII mutation changes which enhancers are activated in a GBM cell, it, at the same time, noticeably increases the activity of SOX9 and FOXG1 in the cell. Together, these processes change the mix of genes expressed by GBM cells versus healthy cells.
Dr. Mischel and team took this new finding even farther. They used scientific methods to “silence” the SOX9 and FOXG1 in GBM cells in lab dishes and mice. When they did this, tumor growth remarkably stopped. So the team determined it might be possible to use a drug to create this therapeutic affect, as well.
To do so they would have to identify what genes, specifically, have their expression regulated by the two transcription factors (SOX9 and FOXG1). One of the genes they found was BRD4. The BRD4 gene, when expressed, creates a protein by the same name and controls the expression and activity of another transcription factor called cMyc, which Dr. Mischel has shown previously to play a central role in reprogramming metabolism and growth of GBM cells.
Importantly, there is already a class of drugs being developed which target BRD4, called BET inhibitors. When the research team tried treating GBM cells and mice with GBM with one of these drugs they saw the cancer cells die in the lab dishes and tumors shrink in the mice.
We think these findings have major implications, including developing a new treatment strategy that is ready to be evaluated in GBM patients, and which can be leveraged to develop additional drugs with even more favorable [effects] that target this pathway.
Attribution: Dr. Mischel
“We are deeply grateful for Defeat [GBM]’s support. You, your colleagues and the generous donors made this possible,” added Dr. Mischel, to NBTS Chief Research Officer Carrie Treadwell, who also serves as president of Cure GBM LLC, the NBTS subsidiary that houses the Defeat GBM Research Collaborative.
The team now plans to explore how these interconnected processes they’ve found are linked in even greater detail. They also want to work on developing newer, improved versions of BET inhibitors specifically for GBM. They point out that there is an added advantage of having a predetermined biomarker – the presence of EGFRvIII – to determine which patients are most likely to benefit from the treatment.