# Isolation, characterization and translational development of glioma stem cells

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $1,077,600

## Abstract

Project Summary/Abstract
Solid tumors arise as the consequence of accumulation of oncogene and/or tumor suppressor mutations.
How these mutations arise and accumulate in one cell over a lifetime remains a mystery. It is likely that an
improved understanding of the early events that form a pre-tumorigenic cell could have implications for
analysis of mature tumor cells and insights into improved therapy development. We have developed fully
penetrant genetically engineered mouse models of glioblastoma multiforme (GBM) by mutation of three
tumor suppressors commonly found mutated in human GBM (P53, PTEN, & NF1). Using our combined
background in developmental biology and neuroscience, we have traced the origin of these tumors to the
adult stem/progenitor cell population. We have developed tools to uncover functional GBM subtypes that are
predicated on the tumor cell of origin rather than on specific driver mutations (Alcantara, Cancer Cell, 2015).
These studies will be extended to identify cell of origin and relationship to genotype and phenotype.
Moreover, using gene expression signatures from the novel mouse GBM subtypes, we have identified
human GBM counterpart signatures that suggest similar biological origins and a novel strategy for human
GBM molecular stratification. Our data provide evidence for additional human GBM subtypes that may also
relate to novel cells of origin. The mouse models demonstrate an endogenous GBM tumor cell hierarchy
placing a cancer stem cell at the apex. Our ongoing studies suggest that each of the new stratified GBM
subtypes are governed by a cancer stem cell pattern of growth. We will expand and confirm these
observations. Using a phenotypic high throughput small chemical compound screen we have identified small
molecules that have nanomolar toxicity on primary low passage GBM derived cells but not on primary
normally dividing cells such as mouse embryo fibroblasts or neonatal astrocytes. In addition, lead
compounds including a benzimidazolium compound and its derivatives demonstrate toxicity on primary
human GBM derived tumor spheres. These compounds hold promise for in vivo studies and identifying novel
key GBM dependency pathways for therapeutic development. We are developing a comprehensive GBM
patient derived xenograft program that will be employed to further validate our mouse model finding and to
identify, isolate and neutralize human GBM cancer stem cells.

## Key facts

- **NIH application ID:** 9933829
- **Project number:** 5R35CA210100-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Luis Fernando Parada
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,077,600
- **Award type:** 5
- **Project period:** 2017-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933829

## Citation

> US National Institutes of Health, RePORTER application 9933829, Isolation, characterization and translational development of glioma stem cells (5R35CA210100-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9933829. Licensed CC0.

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