Researchers at Northwestern University have determined that a class of drugs known as BET inhibitors may provide an effective treatment for DIPG. These researchers treated mice with BET inhibitors and found that, after ten days of treatment, the mice’s tumors were significantly smaller. The results of these study were recently published in Nature Medicine, and has generated significant media coverage.
We recently had the chance to discuss this paper with the lead researchers: Andrea Piunti, Rishi Lulla, C. David James, and Ali Shilatifard. Here is what we discussed.
Defeat DIPG: Your study shows that drugs known as BET inhibitors appear to be an effective treatment option for DIPG tumors with the H3K27M histone mutation. Can you briefly explain to us what BET inhibitors are and how they work?
Northwestern: BET inhibitors (Bromo and ExtraTerminal domain inhibitors) are a class of drugs that aim to disrupt the binding of bromdomain proteins from chromatin. Chromatin is a mix of proteins and DNA. The most abundant protein in chromatin is the histone. In most DIPG tumors, one of these histones has a mutation which makes a normal H3 into a mutant H3K27M.
In our work we characterized where in the genome (DNA) of DIPG cells, the H3K27M histones containing nucleosomes are localized. We found that those are often present in genes that are highly active in those tumors and create an aberrant gene network that fuels the tumor. The H3K27M containing nucleosomes also bind the bromodomain proteins. We hypothesized that, given the well-known role of these proteins in regulating the gene network, inhibiting the binding of these proteins to H3K27M containing nucleosomes could impair the tumor growth by disrupting the gene network. Indeed, treatment with BET inhibitors results in the disruption of the aberrant gene network and dramatically decreases the tumor proliferation in our model.
Defeat DIPG: As part of your study, you used a mouse model and injected BET inhibitors directly into the mice’s brain tumors, and you found that these injections significantly reduced tumor size. Does this approach suggest that BET inhibitors will need CED to be effective in DIPG patients? Or is there evidence that BET inhibitors can sufficiently cross the blood-brain barrier to be effective in DIPG patients?
Northwestern: We tested two BET inhibitors for activity against human DIPG tumors in the brainstems of mice: JQ1 and I-BET-762. JQ1 was administered by intraperitoneal injection whereas I-BET-762 was administered orally. Each inhibitor-route of administration combination slowed the growth of DIPG xenograft tumors, indicating that systemic administration of either inhibitor had access to tumors engrafted in the brainstem of mice. We did not do CED in this study but it is an interesting possibility, as it would certainly increase the concentration of inhibitor in the tumor, and potentially heighten BET inhibitor anti-tumor activity. The BET inhibitors we are considering for clinical trials do cross the blood-brain-barrier in pre-clinical models.
Defeat DIPG: As we understand it, BET inhibitors are not yet FDA approved for any use, but there are several ongoing clinical trials testing these drugs for use in other cancers. What have we learned about BET inhibitors from those trials? Will the results of those trials have any effect on DIPG children getting access to BET inhibitors?
Northwestern: The BET inhibitors are in Phase I clinical trials in adult patients and we are learning about the safety, best dosing and side effects. The results of these trials will affect our plans for treating pediatric patients – to guarantee that we perform the trial in the safest possible manner.
Defeat DIPG: What are the next steps in your research? Do you plan to test the effectiveness of BET inhibitors in combination with other drugs, such as panobinostat? Is any more lab work necessary before DIPG patients can be treated with BET inhibitors?
Northwestern: The history of targeted small molecule inhibitors in treating cancer indicates that tumors adapt and acquire resistance to sustained small molecule inhibitor when used alone. We are interested in determining if this is the case for treating DIPG with BET inhibitors, and if so, characterizing the molecular changes that occur in tumors that acquire resistance in order to identify additional therapeutic targets that can be targeted. We are also working with combination therapies in the lab to improve effectiveness or prevent tumors from acquiring resistance to BET inhibitors.
Defeat DIPG: What is your best guess for how long it will be before DIPG patients are treated with BET inhibitors? What steps need to occur before this is possible?
Northwestern: It is hard to say for sure, but we are hopeful that as soon as the Phase I clinical trials in adults have been completed, we will be able to open a Phase I clinical trial in pediatric patients. We are working with several drug companies to make this happen as quickly as possible – we hope that it can be sometimes before the end of 2017.
Defeat DIPG: Thank you Drs. Piunti, Lulla, James, and Shilatifard. We appreciate your efforts to find effective treatments for DIPG. We hope that DIPG children will soon benefit from your research and can be treated with BET inhibitors.