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

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $235,632

## 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 recombinase-mediated
cassette exchange (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) Targeting immunotherapy-resistance with DC vaccination and PD-1/CSF-1R
inhibition. 2) Overcoming drug-induced resistance to intrinsic apoptosis in 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 and small
molecule inhibitor pressure. 3) Adaptive immunotherapy to target the H3.3G34 mutation in pediatric
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:** 10709378
- **Project number:** 3P50CA211015-07S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Linda M Liau
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $235,632
- **Award type:** 3
- **Project period:** 2017-08-11 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709378

## Citation

> US National Institutes of Health, RePORTER application 10709378, Incorporation of Novel MADR-GESTALT Technology into UCLA SPORE in Brain Cancer (3P50CA211015-07S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10709378. Licensed CC0.

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