# Diversity Supplement to Targeted Therapy in Ex Vivo Medulloblastoma/PNET

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $69,886

## Abstract

PROJECT SUMMARY/ABSTRACT
I lead the Children’s Oncology Group Phase III clinical trial, ACNS0332, which evaluates treatment options for
children with high-risk medulloblastoma (the most common pediatric brain tumor) and supratentorial primitive
neuroectodermal tumors (sPNETs). The study opened in 2007 and underwent a major amendment in 2014,
when emerging data revealed biological disparity between medulloblastomas and sPNETs, as well as
heterogeneity in sPNET patients. We discontinued sPNET patient enrollment when genomic analyses funded
by the prior cycle of this grant revealed that 71% of the non-pineal sPNET patients were actually high grade
glioma, ependymoma, or atypical teratoid rhabdoid tumors, despite sPNET appearance by histopathology. This
reveals the limitations of traditional histopathology and shows that contemporary genomic analyses could
spare many children from receiving craniospinal irradiation that is not necessary and not helpful.
In Aim 1 of this renewal application, we extend the genomic studies to the 300 medulloblastoma patients in the
study. We collected research tissue from more than 95% of these patients and anticipate that the studies will
reveal: 1) patient groups who are likely to die from their disease despite the intense therapy on ACNS0332;
and 2) patient groups who were placed on ACNS0332 because of clinical or histopathologic observations and
who may include a mixture of good prognosis patients (e.g., those who would fare well with much less radiation
than provided on ACNS0332), as well as patients with genomically-predicted poor prognosis, who should be
stratified differently in the future.
In Aim 2 we address the radiation resistance phenotype of the worst prognosis patients, particularly those with
amplified MYC or MYCN. We will collect pre- and post-radiation specimens from patient-derived orthotopic
xenograft (PDOX) models (14 MYC/MYCN amplified) that we generated and characterized in the prior cycle of
this grant, other PDOX models that we receive from four collaborators, and matching cell lines that we
generated and characterized. We will use the cell lines to screen FDA approved drugs for those that overcome
radiation resistance and to conduct functional genomic screens to identify pathways that, when inhibited,
convert radiation resistant cells into radiation sensitive cells. In vivo efficacy studies on PDOX mouse models
representing dozens of patients will follow.
In the Diversity Supplement, we remain focused on MYC/MYCN-amplified medulloblastoma and use the
same PDOX lines to assess whether a multispecific antibody that we engineered to overcome radiation
resistance is sufficient to induce macrophage-mediated cancer cell killing when locally administered.
The significance is that this work will likely reduce unnecessary radiation exposure to patients who do not
warrant high-dose craniospinal irradiation, identify patients who would best be served by alternative therapies,
and generate pre-clinical dat...

## Key facts

- **NIH application ID:** 10380520
- **Project number:** 3R01CA114567-13S1
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** JAMES M OLSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $69,886
- **Award type:** 3
- **Project period:** 2021-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380520

## Citation

> US National Institutes of Health, RePORTER application 10380520, Diversity Supplement to Targeted Therapy in Ex Vivo Medulloblastoma/PNET (3R01CA114567-13S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10380520. Licensed CC0.

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