Thanks to a number of grants and private donations, in July and August the CBTP lab team was joined by several young researchers working on specific projects to advance the field of pediatric neuro-oncology. This “summer sprint” was an unprecedented effort that produced some excellent results.
Umberto Tosi, funded by a POST grant from the Alex’s Lemonade Stand Foundation, worked on a project to improve the measurement of drug delivery to the brain via “theranostic” (therapeutic and diagnostic) agents.
The usual method of determining whether a drug has been successfully delivered is to wait for a clinical response, a “wait-and-see” approach that is neither timely nor precise. If researchers could modify a drug to make it fluorescent—and therefore visible on PET or MRI imaging—they would be able to see in real time whether that drug has reached its target. The key is to make delivery of the drug visible and measurable without reducing its effectiveness.
Working with collaborators at Weill Cornell Medicine’s Molecular Imaging Innovations Institute (MI3), Umberto tested several modified versions of the drug dasatinib both in vitro (in petri dishes) and in vivo (in animal models). Several of them acquired their new imaging potential while retaining their therapeutic properties, and they will advance to further rounds of testing on several different malignancies.
The modification technique was then performed on panobinostat, a drug that has already shown significant promise in the treatment of DIPG. As we had hoped, the modified panobinostat was successfully imaged with PET/CT and its therapeutic properties were not altered. We hope this new compound will allow for a more precise treatment of DIPG.
Raymond Chang tested ways to combine drugs to defeat DIPG, which has defense mechanisms that allow it to evade otherwise effective drugs. Research has identified certain molecular signaling pathways that could be promising targets for drug therapy, but the tumor has alternative pathways that allow it to grow despite use of a single drug.
Raymond tested several drugs, individually and in combination, on DIPG cell lines grown in our lab and discovered one potent inhibitor of DIPG growth in vitro. After combining that drug with several other classes of drugs, he found a MEK-inhibitor that showed substantial synergistic effects. Raymond will continue his work in the lab, where he is now using xenograft mouse models of DIPG to demonstrate that this drug combination will be more effective in reducing tumors than either drug individually. Raymond’s summer assignment was funded by the American Brain Tumor Association.
Emilie George established in vitro cell models of gliomatosis cerebri (GC). Together with the Greenfield lab team, Emilie initiated a drug screening protocol to begin testing chemotherapeutic agents on this newly developed cell model. This project is ongoing and promises to add important information to our understanding of the best ways to treat this disease.
Emilie also analyzed and interpreted data on all reported cases of gliomatosis cerebri in the peer-reviewed literature to better understand the incidence and outcomes of GC in the past. Emilie’s research was made possible by a grant from the St. Baldrick’s Foundation.
Christopher Marnell, funded by the AANS/NREF, joined our collaboration with MI3 in which we are exploring the use of peptide-based nanofibers (NFP) to extend the length of time a drug is effective when delivered by CED. A big question is whether a drug would retain its anti-cancer effects after being modified and coupled to the nanofiber. Using in vitro techniques, Christopher showed that dasatinib, which is currently used to treat certain types of leukemias and has been explored for use against DIPG, could still block the growth of DIPG cells when added onto the nanofiber. This is an important finding that will enable the nanofiber project to continue.
Christopher also tested 114 drugs that are FDA
approved for other cancers with the hope of repurposing some of them to treat DIPG. This was the first time many of these drugs (which were provided by the NCI/NIH) were tested against DIPG patient cells, and the results are very promising. Four drugs commonly used to treat breast and prostate cancer (and that target genes with roles previously unrecognized in DIPG) were found to strongly block the growth of DIPG cells in vitro. Testing in mouse models will soon follow to better characterize these drugs’ potential for use against DIPG.
Tina Bharani, a medical student from Qatar Weill Cornell Medical School, joined staffer Rachel Yanowitch to study immunoglobulin
superfamily member 3 (IgSF3) and its role in glioma invasiveness. IgSF3 is a novel gene candidate identified by the Greenfield lab and thought to play a role in how tumors spread throughout the brain. High school student Jared Bassett assisted. The IgSf3 project is still in its earliest stages and results will be ongoing.
Matthew Bernstein, a high school junior whose work was supported by the Samuel Jeffers Foundation, identified several partner institutions willing to share tissue samples of thalamic glioma. He also conducted a literature search and compiled an overview of the data on thalamic glioma, providing an invaluable resource for our researchers.
Benjamin Shtaynberger helped evaluate data that will form the basis for a new academic paper on gliomatosis cerebri (GC) to be published by Dr. Greenfield’s team. Kunal Garg assisted Dr. Greenfield in studying how low-grade gliomas transform into deadly malignancies.
We are grateful not only to the foundations whose grants supported these researchers but also to the private donors, especially those from the Cristian Rivera Foundation, whose generosity provided the drugs, equipment, and supplies they needed to complete their work.