# Brain microenviornment-dependent lineage plasticity drives adaptation to targeted therapy in malignant gliomas

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $41,328

## Abstract

PROJECT SUMMARY/ABSTRACT
Malignant gliomas are the most common primary adult brain cancer, affecting over 20,000 Americans each year.
While molecularly targeted therapies have demonstrated tremendous successes in other malignancies, there is
a lack of effective and personalized therapeutic approaches for these deadly brain cancers. The goal of this
study is to investigate the complex phenomena of phenotypic plasticity in glioblastoma (GBM), the most lethal of
all brain tumors in adults, in driving resistance to targeted therapies via non-genetic mechanisms facilitated by
the unique brain microenvironment. Extensive preliminary data, which incorporate a large cohort of genetically
diverse preclinical glioma models and drugs in clinical development for GBM, indicate the oncogene epidermal
growth factor receptor (EGFR) maintains a radial glia (RG)-like cell state in GBM, which drives glioma initiation,
heterogeneity, and plasticity. Moreover, preliminary data demonstrate pharmacologic ablation of EGFR induces
lineage reprogramming from RG-like to neural/oligodendrocyte progenitor (NPC/OPC)-like programs uniquely in
the brain microenvironment, which is hypothesized to drive rapid adaptation and resistance to EGFR-targeted
therapy. Specific Aim 1 utilizes cutting-edge single-cell RNA sequencing (scRNA-seq) combined with an
innovative genetic fluorescent reporter system and high-resolution barcoded lineage tracing to elucidate the
evolutionary mechanisms driving lineage transformations following targeted therapy in GBM. Through the use of
state-of-the-art preclinical models that capture the unique brain microenvironment, this approach is expected to
provide unprecedented insights into the influence of the brain environment in driving cellular dynamics and
lineage transformations during response to therapeutic interventions. Specific Aim 2 focuses on defining the
signaling pathways that facilitate brain microenvironment-dependent lineage transitions that drive resistance to
oncogene ablation in GBM. Using novel, clinical stage molecularly targeted therapeutics and innovative in vitro
models of the brain microenvironment, this aim will uncover the pivotal signaling pathways and brain-derived
factors that drive lineage transitions and contribute to resistance against EGFR-targeted therapies in malignant
gliomas. Overall, this project represents a significant step towards a deeper understanding of the molecular and
cellular mechanisms underpinning tumor heterogeneity and therapy resistance in GBM. By elucidating the
dynamics of cellular state transitions and the role of the brain microenvironment in these processes, this work
has the potential to significantly impact the development of more effective, targeted treatment strategies for
patients suffering from this devastating disease.

## Key facts

- **NIH application ID:** 10997865
- **Project number:** 1F30CA295084-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Dimitri Cadet
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,328
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997865

## Citation

> US National Institutes of Health, RePORTER application 10997865, Brain microenviornment-dependent lineage plasticity drives adaptation to targeted therapy in malignant gliomas (1F30CA295084-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997865. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*