# Incorporation of Novel MADR-GESTALT Technology into UCLA SPORE in Brain Cancer

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $214,029

## Abstract

ABSTRACT (Overall)
Glioblastoma, the most common primary brain tumor in adults, is one of the most lethal of all human cancers.
This disease requires innovative approaches and more effective treatments. Treatment resistance presents a
fundamental barrier, and given the heterogeneous nature of malignant gliomas, a combination of diverse
approaches will likely be needed to overcome it. To achieve this, we need a better understanding of the genetic
diversity and heterogeneity of the disease, as well as better pre-clinical animal models that recapitulate human
glioma heterogeneity. A state-of-the-art methodology—mosaic analysis with dual recombinases (MADR) and
genome editing of synthetic target arrays for lineage tracing (GESTALT)—addresses this need. MADR provides
a flexible means for single-copy somatic transgenesis (or mutation with CRISPR/Cas9). MADR-GESTALT
provides a suite of tools to study the emergent heterogeneity in cancer formation and recurrence by providing a
consistent, single-copy, genetic framework for the expression of multiple “personalized” patient driver genes.
Perinatal electroporation is used to deliver genes to brain stem and progenitor cells, and to avoid multiple copy
insertion, a new technique for single-copy transgene insertion in vivo was developed. Mosaic Analysis with Dual
Recombinases (MADR) employs dual recombinase-mediated cassette exchange for high efficiency insertion of
transgenes to a single genetic locus. To model loss-of-function mutations, CRISPR/Cas9-mediated gene editing
is also incorporated into the MADR-GESTALT system. Several areas of MADR can be expanded and leveraged
to enhance specific projects within the UCLA Brain Cancer SPORE, which, in addition, will independently validate
the utility of MADR-GESTALT for the wider cancer research community. This proposal utilizes an IMAT-funded
technology that enhances three ongoing projects within our SPORE program: 1) Active immunotherapy
combined with checkpoint modulation for glioblastoma. MADR will be used to develop syngeneic
immunocompetent mice with gliomas and GESTALT will be used to evaluate barcode diversity with and without
treatment to further understand tumor evolution under immunotherapeutic pressure. 2) Genetic susceptibility in
pediatric glioma development. MADR-GESTALT will be used to establish a moderate-throughput, high-fidelity,
patient-specific in vivo modeling platform to understand pathogenicity of novel germline variants, their effects on
gene expression, and their contribution to pediatric high-grade glioma susceptibility. 3) Adaptive immunotherapy
to target the H3.3G34 mutation in glioblastoma. MADR-GESTALT models will be used to examine mechanisms
by which particular histone mutations affect oncogenesis and immunotherapy for G34R mutant glioblastoma.

## Key facts

- **NIH application ID:** 10271986
- **Project number:** 3P50CA211015-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Linda M Liau
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $214,029
- **Award type:** 3
- **Project period:** 2017-08-11 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271986

## Citation

> US National Institutes of Health, RePORTER application 10271986, Incorporation of Novel MADR-GESTALT Technology into UCLA SPORE in Brain Cancer (3P50CA211015-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271986. Licensed CC0.

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