# MYC activation in tumor progression of neuroblastoma

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2020 · $394,841

## Abstract

Post-consolidation maintenance therapy with 13-cis retinoic acid (13-cisRA) and the chimeric anti-GD2
antibody dinutuximab (Unituxin®) improves the survival of high-risk neuroblastoma (NB) patients.
Despite currently available optimal therapy > 40% of children still develop recurrent disease, which is
fatal for most. In the current proposal we seek to identify molecular mechanisms of progressive disease
in NB patients. Although MYC genomic amplification is seen in 1% of NB patients, c-MYC protein is
overexpressed in 11% of patients at diagnosis. Our preliminary data show that high c-MYC protein
expression is far more frequent in progressive disease relative to diagnosis using patient-derived cell
lines established from clinical samples at progressive disease and at diagnosis. In searching the
mechanisms of MYC transcriptional activation, we demonstrated that transcription factors, OCT4 and
TCF 3 were elevated in a cell line model selected to express high c-MYC in replicating the clinical
treatment schedule of maintenance therapy (13-cisRA) in high-risk neuroblastoma. When OCT4 was
knocked-down, the expression of c-MYC was decreased and the sensitivity to 13-cisRA was restored.
Subsequently, we identified two kinases, MAPKAPK2 (MK2) and DNAPK, which are predicted to bind
and phosphorylate OCT4. The MK2-OCT4-c-MYC axis was confirmed in another progressive disease
model of neuroblastoma with high c-MYC expression. Based on our preliminary data, we hypothesize
1) that kinase(s) phosphorylate OCT4 and the phosphorylated OCT4-induces transcriptional activation of
c-MYC and that those kinases can be targeted to inhibit the activation of OCT4-induced c-MYC
overexpression, and thus the expression of the kinase(s) could be biomarkers and therapeutic targets for
patients with progressive disease with high c-MYC. Our goals are: 1) to employ our extensive panel of
NB cell lines and patient-derived xenografts (PDXs) to define the specific roles of OCT4 and its
phosphorylation regulation by MK2 and DNA-PKcs kinases in a c-MYC overexpression state that
causes resistance to one of the maintenance therapy in NB, 2) to validate them as potential markers of
poor outcome in collaboration with the Children's Oncology Group (COG) in patient tumor samples, and
3) to demonstrate the feasibility of inhibiting key kinase(s) to modulate OCT4/c-MYC axis to enhance
activity of chemotherapy in NB cell lines and patient-derived xenografts (PDXs). The ultimate goal of
the proposed study is to validate regulation of c-MYC as a novel mechanism of tumor progression in
neuroblastoma and to identify a druggable target(s) for drug-resistant recurrent neuroblastoma.

## Key facts

- **NIH application ID:** 9843647
- **Project number:** 5R01CA232591-02
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** Min Hee Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,841
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843647

## Citation

> US National Institutes of Health, RePORTER application 9843647, MYC activation in tumor progression of neuroblastoma (5R01CA232591-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843647. Licensed CC0.

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