This, however, does not mean that high-impact science must be resigned to this slow pace. By creating a new model – by changing the way the research enterprise is aligned, incentivized, funded, and managed – the translation of basic discoveries into new treatments can be transformed to a more efficient and effective process.
This is where the Defeat GBM Research Collaborative comes in.The idea is this:
By allowing some of the world’s foremost experts in GBM research – with complementary skill sets – to work together in a structure that allows unprecedented collaboration for the teams to regularly interact; share data, information, and ideas; work on multiple, interrelated projects simultaneously; and push toward a singular goal, we can accelerate the time it takes to produce new and better treatments for GBM patients.
Attribution: Defeat GBM Research Collaborative
Discovery, Progress, and Process Acceleration
To date, the Defeat GBM Research Collaborative’s approach has been validated by successfully accelerating the process from research discovery to drug development by at least 1-2 years. The infrastructure of the Collaborative allowed the immediate translation of pre-published findings from Core 1 (Discovery) to Core 2 (Drug Development).
All told, Defeat GBM has advanced in three key areas:
Utilizing one of the most comprehensive sets of pre-clinical testing models, the Drug Development team, led by researchers at MD Anderson Cancer Center, has screened thousands of compounds (alone and in combinations) obtained from different biopharmaceutical companies.
Over 75,000 combinations have been screened across a range of 12 different GBM lab models. This screening effort has prioritized the most active compounds to advance to further study in mice models.
Additionally, this work is allowing researchers to identify the type of molecular profiles that may predict whether a patient’s tumor is going to be sensitive or resistant to a targeted therapy – which will help all of the other Cores, as well as potential future clinical trials.
Defeat GBM researchers have discovered that levels a critical protein found in healthy cells, known as Bim, decreases when GBMs are treated with drugs that target one of these tumors’ most common mutations (the EGFR mutation). Importantly, researchers found that by using drugs that mimic the activity of Bim, there is an opportunity to restore the critical role Bim plays in keeping cells healthy, and thus overcome EGFR inhibitor resistance.
Defeat GBM researchers discovered that GBM tumors can increase their uptake of the nutrients glucose and acetate. Increased levels of these two nutrients helps tumors continue growing even in the face of treatment. This is leading to a completely new hypothesis that modifying the levels of these nutrients could impact tumor growth and response to treatment.
Another Defeat GBM team has research underway to understand why radiation therapy – a standard cancer treatment – is also not as effective in killing GBM cells as it should be. Their work is focusing on designing so-called “radio-sensitizers,” which would make GBMs less resistant to radiation.
3. Identifying the Role of Tumor Cell Metabolism & Epigenetics in GBM Growth
Cancer has long been recognized as diseases caused by genetic abnormalities. But research is beginning to show that alterations to tumor cell metabolism, as well as changes to the process in which a cell’s DNA sequence is decoded, or read (called transcription), but are NOT linked to changes in actual DNA sequence – so called “epigenetic” changes – can also drive tumor growth:
Defeat GBM’s findings related to glucose and acetate, as well as discoveries regarding a complex of proteins called mTORC2, have revealed the importance of a tumor’s own metabolism in driving its growth. The two nutrients and mTORC2 can “re-wire” a GBM cell’s metabolism – shifting it into overdrive so that it can produce the increased energy needed to grow uncontrollably. This, “suggests that dietary influence might actually have some effect, either in sensitizing [the tumor] to targeted therapies, or in understanding why they escape from these therapies,” said Dr. Webster Cavenee. “We never would have even thought about that before, but now it’s actionable.”
The most common EGFR mutation in GBM tumors is known as EGFRvIII. Defeat GBM researchers have discovered that an EGFRvIII mutation can change the tumor cells’ transcription process to activate a gene that isn’t typically “turned on” in healthy glial cells – BRD4. The BRD4 gene, when turned on, creates a protein that controls the activity of a molecule called cMyc. cMyc plays 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. Defeat GBM Researchers are now interested in exploiting this finding to develop a BET inhibitor to target BRD4 in GBM tumors.
Moving Forward – Translating Science into Survival
These research leads will advance the field from where it has been. Now the Defeat GBM will have to prioritize the most favorable opportunities on its ‘menu’ of research findings for further study and push toward the clinic. The most promising targets and compounds will be further developed, with the intention of preparing them for evaluation in patients.
Defeat GBM can be made even stronger through your support. National Brain Tumor Society invested in the core infrastructure, but Defeat GBM embraces partners and contributors. We would welcome your interest and support to help propel this initiative forward! Together we CAN achieve our goal.