The fiscal year at Weill Cornell Medicine closes in June, at which time we will provide an updated annual report. In the meantime, some of our greatest accomplishments from 2019 are highlighted here.
EXPANDING THE TEAM: In research, the greatest investments are made in the people doing the work. We can’t make discoveries in the lab without having brain power at the bench, and we can’t bring those discoveries to clinic without a motivated translational team. In 2019, the Children’s Brain Tumor Project welcomed eight talented new researchers with various levels of expertise to help move our research forward. The CBTP lab has become overloaded with activity, and the space is getting crowded. This is certainly a good problem to have when your goal is to increase the speed at which scientific breakthroughs are made!
GROWING THE RECISION MEDICINE INITIATIVE: Dr. Jeffrey Greenfield was awarded $1.08 million in support of his precision medicine initiative. The generous gift from the Patrick Bayly Marsano Foundation is enabling a tremendous increase in defining individualized cancer therapies for children with rare and inoperable pediatric brain tumors. The two-year initiative is funding the expansion of the lab’s cellular and molecular precision medicine approach to pediatric brain tumor therapy, with a goal of establishing safe and curative patient-specific therapies for devastating pediatric brain tumors. Clinicians, computational biologists, neuroscientists, immunologists, biochemists, and stem cell biologists, have begun working together to conduct next-generation sequencing on every pediatric brain tumor resected at the Weill Cornell Medical Center—an anticipated 50 to 80 children. They will identify new mutations specific to the cell population and to the patient, and create cell repositories and mouse models to test different targeted therapeutics. Following a comprehensive review of the genetics, cell biology, and pharmacogenomics of patient-specific tumors, a customized therapeutic regimen will be determined for each patient.
ADVANCING TRANSLATIONAL RESEARCH: Translational research is often referred to as the process of applying findings from the laboratory to practices in a clinical setting. Our team recently finalized an agreement with Macrogenics, a biopharmaceutical company, to provide us with a promising antibody drug conjugate to target an antigen commonly found in pediatric brain tumors. The study will help to evaluate the antitumor efficacy and pharmacokinetics of the drug, informing our design of a possible FDA approved clinical trial for children that uses convection-enhanced delivery. This agreement with Macrogenics demonstrates our reputation in the research community and among industry representatives who want to partner with us.
MAKING CONTINUED INROADS IN COLLABORATIVE EFFORTS: In the December newsletter we share that the Children’s Brain Tumor Project has recently been named a regional “Center of Excellence” by the Gift from a Child initiative. This is a game-changer not only for the CBTP, where it will increase the amount of rare tumor tissue we have access to through rapid autopsy, but also for our collaborating institutions through the Children’s Brain Tumor Tissue Consortium, with whom we will share access to that tissue. Similarly, the DIPG Collaborative has accepted the CBTP protocol for participating in the DIPG registry, another vehicle for sharing detailed information specific to DIPG tumor tissue across a multitude of participating institutions. In addition, Dr. Mark Souweidane and Dr. Jeffrey Greenfield recently received faculty appointments to the pediatric neurosugery team at Columbia Medical Center, which means they are able to bring alternative drug delivery methods including convection-enhanced delivery and intra-arterial delivery to even more patients outside of their pre-existing practices at Weill Cornell Medicine, Memorial Sloan Kettering and New York-Presbyterian.
KEY PEER-REVIEWED PUBLICATIONS:
Immune landscapes associated with different glioblastoma molecular subtypes.
PUBLICATION: Acta Neuopathologia Communications. November 29, 2019 AUTHORS: Martinez-Lage M, Lynch TM, Bi Y, Cocito C, Way GP, Pal S, Haller J, Yan RE, Ziober A, Nguyen A, Kandpal M, O’Rourke DM, Greenfield JP, Greene CS, Davuluri RV, Dahmane N. ABSTRACT: Recent work has highlighted the tumor microenvironment as a central player in cancer. In particular, interactions between tumor and immune cells may help drive the development of brain tumors such as glioblastoma multiforme (GBM). In this study, we use an unbiased, automated immunohistochemistrybased approach to determine the immune phenotype of the four GBM subtypes in a cohort of 98 patients. Tissue Micro Arrays (TMA) were stained for a mulititude of antibodies. Using automated image analysis, the percentage of each immune population was calculated with respect to the total tumor cells. Mesenchymal GBMs displayed the highest percentage of microglia, macrophage, and lymphocyte infiltration. CD68+ and CD163+ cells were the most abundant cell populations in all four GBM subtypes, and a higher percentage of CD163+ cells was associated with a worse prognosis. We also used RNA-seq to compare results with the relative composition of immune cell type infiltration across TCGA GBM tumors and validated our results obtained with immunohistochemistry with an external cohort and a different method. The results of this study offer a comprehensive analysis of the distribution and the infiltration of the immune components across the four commonly described GBM subgroups, setting the basis for a more detailed patient classification and new insights that may be used to better apply or design immunotherapies for GBM.
Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy
PUBLICATION: Neuro-Oncology Advances, Volume 1, Issue 1, May-December 2019. AUTHORS: Raymond Chang, Umberto Tosi, Julia Voronina, Oluwaseyi Adeuyan, Linda Y Wu, Melanie E Schweitzer, David J Pisapia, Oren J Becher, Mark M Souweidane, Uday B Maachani ABSTRACT: The manuscript showed the results of a comprehensive study of midline gliomas including diffuse intrinsic pontine gliomas (DIPG), and the relationship between amplified phos-phatydylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK), and the development of these particular tumor types. Studies have implied that amplifications in the PI3K signaling pathway may result in tumorigenesis, and that the activation of parallel pathways (e.g., mitogenactivated protein kinase [MEK]) may be causing the resistance to PI3K inhibition that has been observed in the clinic. An accurate understanding of this relationship could open doors to potential new treatment options for children with DIPG and other midline gliomas in the future.
Real-Time, in vivo correlation of molecular structure with drug distribution in the brain striatum following convection-enhanced delivery
PUBLICATION: ACS Chemical Neuroscience. May 15, 2019. AUTHORS: Tosi U, Kommidi H, Bellat V, Marnell CS, Guo H, Adeuyan O, Schweitzer ME, Chen N, Su T, Zhang G, Maachani UB, Pisapia DJ, Law B, Souweidane MM, Ting R. ABSTRACT: In this study, researchers modified an existing therapeutic commonly used for Leukemia (dasatinib) to monitor the movement of the drug in real time via PET imaging. The team created a panel of significantly improved dasatinib analogues, which can now be observed as they move across the brain and leave the site of injection over time. In other words, the research team was able to watch the dissemination of the drug in vivo when delivered via CED, and tweak the analogues with the goal of seeing concentrated drug present at the tumor site, extended half-life, and little movement throughout the rest of the body. The findings from this study are of paramount importance as they relate to the team’s parallel work studying and fine-tuning the use of convection-enhanced delivery (CED) to treat DIPG, a technique pioneered by Dr. Souweidane using a cannula to deliver drugs directly into the tumor tissue in order to bypass the blood-brain barrier and reduce systemic toxicity.