The Immortality and Evolution of Adult Brain Tumors

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PROJECT ABSTRACT The Costello lab investigates cellular immortality and evolution in brain tumors with the goal of translating our discoveries into new therapies. I play an essential role in our studies to understand and overcome the genomic and epigenomic intra-tumor heterogeneity, driven by tumor evolution, that underlies therapeutic failures. One translational goal is to identify mutations that produce immunogenic neoantigens that are present throughout the whole tumor, to develop personalized immunotherapies in collaboration with Dr. Okada. Working with an interdisciplinary clinical team, we developed a unique, 3-dimensional whole tumor sampling approach in which we obtain 10 spatially mapped samples per tumor selected by the neurosurgeon to maximally represent the whole tumor. We have begun applying the genomic, transcriptomic and T cell receptor (TCR) sequencing data I produced from these spatially mapped samples to identify immunogenic neoantigens and their cognate TCR present throughout the tumor. I am also a significant contributor to our tumor immortality studies. To proliferate indefinitely, tumor cells must overcome the normal limits on lifespan dictated in large part by telomere shortening, a consequence of cell divisions in the absence of telomerase activity. Eighty percent of glioblastoma and many other cancers overcome this lifespan barrier to achieve cellular immortality by acquiring a mutation in the promoter of Telomerase Reverse Transcriptase (TERT). We discovered that the TERT promoter mutation activates the normally silent TERT gene and telomerase activity through selective recruitment of GABP, a transcription factor which does not normally regulate TERT. Using experimental targeting of GABP, we showed that TERT expression is reduced selectively in cells with the TERT promoter mutation, and when combined with chemotherapy, it dramatically reduces GBM growth in vivo. Currently, I am studying a newly discovered homeostatic control on GABP subunit expression and its relationship to TERT regulation. To translate these mechanistic studies into a new therapy, Dr. Costello co-founded a biotech startup which has discovered small molecules with drug-like properties that reduce TERT in a mutation dependent manner. In addition to performing bench research to address these translational goals, my responsibilities include: (1) management and oversight of the lab’s infrastructure and tumor sample collection; (2) technology and methods development for the group; (3) ensuring that all laboratory research is conducted safely in accordance with regulatory requirements; and (4) training new lab members and individuals throughout the Brain Tumor Center. This R50 application requests salary support for these ongoing activities to advance the scientific goals of the following NCI-funded projects: 3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation (R01 CA244838); The Brain Tumor SPORE P1 – A New Therapeutic Target for TERT Promoter Mutant Glioma (2P50CA097257).