1. NF1 Low-Grade Glioma Synodos
Target Identification and Modeling of NF1-Associated Low-Grade Glioma (LGG)
Michael J. Fisher, MD (CHOP), co-PI
David H. Gutmann, MD, PhD (Washington University), co-PI
Adam Resnick, MD, PhD (CHOP)
Angela J. Waanders, MD (CHOP)
Joanna Phillips, MD, PhD (UCSF)
William A. Weiss, MD, PhD (UCSF)
Stefan Pfister, MD, PhD (German Cancer Research Center)
David Jones, PhD (German Cancer Research Center)
Olaf Witt, MD (German Cancer Research Center)

2. Gliomas in Neurofibromatosis Type 1
15-20% of those with NF1 develop low-grade glioma
Typically young children (< 7 years of age)
Commonly involve the optic pathway and brainstem (90% of tumors)
Impaired visual acuity is observed in 30-50% of children with NF1-OPG

3. The problem Most NF1-LGG do not need treatment
Limited understanding of which tumors are likely to require intervention
Identification of prognostic factors is crucial to minimizing the morbidity of these tumors as well as to limit treatment to only at-risk tumors.
Standard therapies for symptomatic NF1-LGG are limited and have a higher risk of morbidity in NF1
Identification of new potential targets for treatment of NF1-LGGs is crucial

4. Barriers to the design of effective treatments for NF1-LGG
NF1-LGG are rarely biopsied; thus our understanding of the cooperating molecular events beyond NF1 gene inactivation is minimal
Paucity of targetable microenvironmental factors that enable stroma-directed therapeutic development
Limited number of tractable in vitro and in vivo cellular models to evaluate potential promising treatments

5. NF1 Low-Grade Glioma Synodos
Target Identification and Modeling of NF1-Associated Low-Grade Glioma (LGG)
Goal: Identify molecular risk factors and treatments targeted to the cellular and molecular properties unique to NF1-LGG

6. Identify the spectrum of molecular changes in NF1-LGG
tumor microenvironment
signaling pathway growth control
multi-scale genomic analyses
clinical management of NF1 and sporadic LGG
low-grade glioma modeling
Identify the spectrum of molecular changes in NF1-LGG
(What other genetic and genomic changes might drive LGG growth and lead to new therapies?)
Define the adaptive signaling pathway alterations to improve treatment
(What mechanisms do LGG tumor cells develop to escape targeted therapies?)
Determine the contribution of tumor microenvironment contributions to LGG growth
(How do non-cancerous cells in the tumor control LGG growth?)

7. future preclinical applicationsD
NF1-LGGs
genomic
epigenomic
RNA-seq
comparisons to sporadic LGGs
Aim 1
Aim 2
Aim 3
in vitro modeling of genetic events
mouse glia/NSCs
human glia
human iPSC-NPCs
cell growth
targetable signaling pathways
escape mechanisms
in vivo modeling of genetic & stromal determinants
GEM strains
mNSC explants
human iPSC-gliomas
Pfister / Jones
Gutmann
Fisher / Witt
Phillips / Weiss
Resnick / Waanders
a) whole tumor
b) TAMs
a) cell autonomous
b) non-cell autonomous
collection of distinct murine LGG models that capture the genetic and stromal diversity of human LGGs
future preclinical applications
Aim 1) Identify candidate molecular targets beyond NF1 gene inactivation in human NF1-LGG
Aim 2) Evaluate the biological consequence of the cooperating molecular changes identified in Aim 1 in cell models
Aim 3) Evaluate the biological consequence of the most promising molecular changes from Aim 2 in mouse models

8. Aim 1: Specimens 26 specimens with matched germline DNA
6 from CBTTC
18 specimens without matched germline DNA
9 from CBTTC
WGS, RNAseq, methylation array
44 total samples, 26 with matched blood

9. Potential Impact
Revolutionize our understanding of the landscape of molecular changes of NF1-LGGs
Identification of molecular risk factors for NF1-LGG
Identification of new potential targets for treatment of NF1-LGGs
Development of new models of NF1-LGG for preclinical drug testing