Ian F. Pollack, MD

The Role of QPRT and NAD Pathways in DIPG Treatment Resistance

Dr. Pollack’s group has continued to build on their recent studies designed to define the mechanisms underlying resistance in childhood and adult malignant gliomas. For these efforts, they have developed a series of “drug-resistance” tumor model systems, paired with treatment naïve counterparts. They have leveraged this unique resource to built a strong collaboration with the Drug Discovery Institute and the Systems Biology Program, through which they have characterized the NAD metabolic pathway as a key intermediate through which multiple cell lines achieve treatment resistance. Using RNA sequencing studies and pathway analysis they have identified several common molecular drivers of this process as well as downstream signaling pathways that are hijacked to promote a resistance phenotype. These observations have provided a basis for additional studies that examine pharmacological and RNA interference-based strategies for reversing resistance as well as metabolic manipulations that may provide novel approaches for promoting tumor cell killing. Planned studies will also examine whether the resistance phenotype reflects clonal selection or an epitranscriptomic phenomenon, which will have implications for how best to counteract this common process to achieve durable responses.

This project has been supported by The Cure Starts Now Foundation, The Cure Starts Now Australia, Brooke Healey Foundation, Aidan's Avengers, Aubreigh’s Army Foundation 328, Cure Brain Cancer, Jeffrey Thomas Hayden Foundation, Laurie’s Love Foundation, Melina Michelle Edenfield Foundation, Musella Foundation, Pray Hope Believe, Reflections Of Grace, RUN DIPG, Storm the Heavens Fund, Wayland Villars Foundation, Whitley’s Wishes, The Gold Hope Project, Love Chloe Foundation, The Isabella and Marcus Foundation, Lauren's Fight for Cure, Robert Connor Dawes Foundation, American Childhood Cancer Organization, Lily Larue Foundation, Marlee’s Mission, Ryan's Hope, The DIPG Collaborative, and Snapgrant.com.

Preliminary data for this work has also been funded by a grant from the Children’s Neuroscience Institute of the University of Pittsburgh, the Connor’s Cure Fund of the V Foundation, the Translational Brain Tumor Research Fund and the DIPG Research Fund of the Children’s Hospital of Pittsburgh Foundation.

NIH-Funded Brain Tumor Vaccine Studies

Dr. Pollack’s group has also continued their NIH-funded activities that focus on immunotherapy for pediatric brain tumors. They have applied RNA sequencing of peripheral blood mononuclear cells in their low-grade glioma cohort to characterize gene expression patterns associated with favorable response to vaccine therapy, and those associated with resistance to therapy. They are working to counteract the latter in preclinical therapeutic studies. Accrual continues on their ongoing clinical trials for recurrent low-grade gliomas and ependymomas.