We started with Core 1, or the “Discovery Core,” which is led by the Dr. Frank Furnari of Ludwig Cancer Research, San Diego. Today, we examine Core 2, the “Drug Development Core,” which is being led by a team of researchers including Drs. John de Groot and Erik Sulman from MD Anderson Cancer Center and Dr. Roel Verhaak of the Jackson Laboratory, along with related projects led by Dr. Ingo Mellinghoff of Memorial Sloan Kettering Cancer Center.
Before a potential new medicine can be tried in human patients, it needs to successfully show signs of effectiveness in preclinicallaboratory studies. In the lab, researchers primarily use two types of model systems to study how a medicine could interact with a specific disease – in this case glioblastoma. First, researchers use actual glioblastoma cells taken from patients and grown in lab dishes (think the petri dishes from your middle school or high school biology classes) to study what happens to these cells when a potential medicine or experimental agent being tested is applied. These are “cellular models” and this type of testing is referred to as “in vitro” (in glass) testing. The second step is typically to see how the drug will potentially work in a living animal. These are called “animal models” and “in vivo” (in a living thing) testing. Typically, in cancer research in vivo testing is done in mouse animal models, and consists of various techniques to generate a close copy of the actual human tumor in the mice, so that the effects seen when the drug is provided can best mimic what might happen when tried in humans.
Unfortunately, the traditional model systems used for preclinical testing in glioblastoma have been poorly predictive of actual clinical experience – meaning often the results seen in actual patients, do not mimic what researchers had previously experienced when using lab models. Thus, there is a desperate need for better preclinical testing models which more closely simulate the human disease, so that researchers have a better idea of whether drugs being tested in the laboratory will ultimately succeed in effectively treating human glioblastoma patients.
The overarching goal is to create or identify medicines that can selectively modify key biological targets, successfully kill cancerous cells with targeted mutations, have minimal side effects, and for which anticipated mechanisms of resistance are understood and could be addressed using drug combinations. Ultimately, screening drugs and demonstrating robust effects on tumor cells in preclinical models well enough, will provide reasonable leads for testing in clinical trials.
AIM 1 – Model Development: Progress
The Drug Development team has created, characterized, and analyzed a number of new models using state-of-the-art science to more accurately represent human glioblastoma tumors and how they behave. These type of models are called “Glioma Stem Cell (GSCs) lines.” Currently, the program has characterized more than 70 such GSC lines which are now being used to screen drugs for potential use for patients with glioblastoma. Additionally, the lines have been shared with multiple Defeat GBM researchers in other cores, for use in their studies.
AIM 2 – Drug Discovery: Progress
Once the team had new, better models created, they began in earnest to screen large numbers of compounds and chemical agents (the building blocks of drugs and medicines) as well as existing FDA approved drugs (and combinations thereof) across the new GSC lines in rapid succession.
Over 1,000 drugs have been screened over the last 3 years (and 75,000 combinations of these drugs), and subsequently the team chose 21 of the most potent compounds from the initial screen for further analysis (which it has since culled down further to a more prioritized list – see below).
Using highly stringent criteria, the team also identified and validated multiple drugs that may be potentially efficacious in specific subgroups of patients with glioblastoma that harbor distinct mutations. The use of the validated GSC model allowed the team to identify these potential patient selection biomarkers because of the wealth of genomic data amassed on these lines during their creation and characterization.
In addition to identifying drug candidates through their own screening efforts, the Drug Development group works closely with the other research core groups within the Defeat GBM effort. New agents or combinations that have been discovered within these other Defeat GBM projects are also being tested in the preclinical models and screening system available in Core 2 to confirm and validate results. These included the FGFR targeted drugs noted in the first blog of this series on the Discovery Core team’s work, as well as other drug combinations based on the findings from the Biomarker Core team (more on that in the next blog).
AIM 3 – Targeting Treatment Resistance: Progress
In addition to creating better preclinical drug discovery models to identify promising clinical candidates, the Drug Development team also sought to use their drug screening efforts to identify previously unknown mechanisms that glioblastoma cells use to overcome the effects of medicines. Through these efforts the team found that a protein called “WEE1” may be critical to resistance developed by glioblastoma tumors containing a mutated gene known as p53 when treated with a class of drugs known as “PI3K/Akt inhibitors.” Additionally, they found that a certain type of alteration to the EGFR gene, called an amplification, could be an indication that drugs called “PARP inhibitors” could work in patients with EGFR amplification in their tumor. Finally, the Drug Development team identified four target genes that may indicate which glioblastoma patients will respond best to chemotherapy.
Summary and Moving Forward
Defeat GBM’s Drug Development Core has successfully identified potential new drug candidates for further evaluation and testing as possible future treatments for glioblastoma patients. In total, the team is now working on further testing for 16 encouraging drug (some in combinations with other drugs) candidates – with 8 prioritized for evaluation, and 4 further categorized as “clinical candidates.” Importantly, these tests were conducted in new and improved laboratory models that better predict how a new potential medicine will do when it enters human clinical trials, creating higher odds for success in possible future trials. Additionally, the team has been able to identify potential subgroups of patients that will respond better to certain potential new treatment than others, setting-up the possibility to deliver more precision, personalized therapies to glioblastoma patients. Finally, by testing drugs in well-characterized models, the team was able to identify additional insights into how glioblastoma cells evade treatment, as well as new ways to study resistance.
Moving forward this team will continue to focus on testing drugs and validating discoveries from other Cores, as well as creating new laboratory models that now can mimic what a glioblastoma cell that has acquired resistance looks and acts like. These could be used for testing of more combination approaches that use several drugs to target different mechanisms of resistance at the same time to block all of a glioblastoma tumor’s escape routes.
Drug Development – Systems Biology: Progress
Because glioblastoma tumors are so complex and difficult to treat, it is important to try and understand how the tumor cells respond to drugs in the context of the entire cellular system. As such, from the beginning of the initiative, Defeat GBM’s Drug Development Core has housed a related “systems biology” project that complements the MD Anderson team and Dr. Verhaak, by screening potential new medicines for resistance that occurs at the “systems level.” This will help identify rational combinations of drugs to overcome the litany of tricks glioblastoma cells seem to be able to use to evade treatment. This effort is being led by Dr. Ingo Mellighoff and his lab at Memorial Sloan Kettering Cancer Center.
Within cells, different components performing all the cell’s various functions communicate with each other via a complex set of “signaling pathways” which use different molecules to interact and pass instructions along to other elements of the cell. When a mutation or alteration occurs to a gene that controls a critical signaling pathway, that pathway can begin sending wrong/incorrect instructions which tell the cell to do something it shouldn’t do and, thus, cause the cell to become cancerous. Most targeted treatment approaches seek to identify key molecules (proteins, enzymes, etc.) that make-up an abnormal signaling pathway and block them. But glioblastoma cells have proven to be able to essentially re-route their messages by activating other molecules, or even whole new pathways, to get their erroneous message delivered.
Dr. Mellinghoff’s theory is that the activation of these “compensatory” signaling networks are major contributors to drug resistance in glioblastoma. To that end, his team is working on characterizing the response of glioma cells to disruptions of key signaling pathways, as well as developing methods to evaluate these changes in tissue samples obtained directly from patients during biopsy or surgery. Specifically, his team is focusing on preclinical testing of drug combinations that have emerged from our understanding of the systems response (again what happens across key signaling pathways and networks when prodded) to drugs that target EGFR mutations in glioblastoma cells. This will help develop a deeper understanding of EGFR regulation and its relationship to other signaling pathways.
Thus far, the team has studied different pathways and signaling molecules that are activated, or triggered, by EGFR mutations. They have discovered a new protein that EGFR interacts with. Further study of this protein’s function found that it actually works with other molecules in EGFR’s signaling network to negatively regulate EGFR – meaning essentially turn EGFR off – and as a result impair tumor growth. If this is confirmed it would mean that the protein may function as a novel tumorsuppressor in GBM tumors and may influence the response to EGFR inhibitors. Dr. Mellinghoff’s team is studying this further.
Other Work and Results
In addition to studying signaling pathways and networks related to EGFR, and how these pathways are altered by drugs that block EGFR signaling, Dr. Mellinghoff is:
Studying a new generation of EGFR targeting drugs to see if they could be more effective than current versions in treating glioblastoma patients.
Studying drugs that target another common mutation found in different types of gliomas, called IDH1, to see if they are effective in certain patients.
Developing a non-invasive imaging method to monitor how patients are responding to treatments that target IDH mutations.
Developing a less-invasive way (than tumor tissue biopsy), to monitor tumor growth (or shrinkage) during treatment using a patients’ cerebrospinal fluid (CSF).
Dr. Mellinghoff and his team’s future research priorities include: (1) the testing of a new generation of EGFR drugs, and combinations; (2) further exploration of the newly discovered protein as a target for blocking glioblastoma growth and treatment resistance; (3) further validation of the use of CSF as a way to study tumors response to treatment.in brain tumor patients.