# The Immortality and Evolution of Adult Brain Tumors

> **NIH NIH R50** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $179,819

## Abstract

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...

## Key facts

- **NIH application ID:** 10692793
- **Project number:** 5R50CA274229-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Chibo Hong
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $179,819
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692793

## Citation

> US National Institutes of Health, RePORTER application 10692793, The Immortality and Evolution of Adult Brain Tumors (5R50CA274229-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10692793. Licensed CC0.

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