# The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $413,844

## Abstract

PROJECT SUMMARY/ABSTRACT
The relative scarcity of recurrent somatic mutations in neuroblastoma, a tumor of the developing sympathetic
nervous system, has challenged efforts to devise effective targeted therapies for this devastating childhood
cancer. One exception to this otherwise disappointing picture is the mutated ALK receptor tyrosine kinase,
which appears at a relatively high frequency in neuroblastoma, and has been highlighted as an important
player in the pathogenesis of this tumor and a key target for drug development. Research progress over the
past 5 years in the principal investigator’s (PI’s) laboratory (under 1R01CA148688) and recently acquired
preliminary data indicate that targeted therapies combining improved ALK inhibitors (ALKi) with novel
synergistic inhibitory compounds are needed to induce durable remissions in neuroblastoma patients with
activating ALK mutations. This projected advance will need to be coupled with greater knowledge of the origins
of resistance to such treatment, as well as strategies to extend ALK-directed therapy to larger numbers of
patients. To address these challenges, the PI will pursue three pivotal questions that are intended to propel
targeted therapy research in neuroblastoma into the next era – the long-term goal of this research. Aim 1:
Can the cytotoxicity of ALKi be improved and resistance delayed by combining these agents with
transcriptional CDK inhibitors (CDKi)? Hypothesis – The combination of CDKi with ALKi in ALK-mutated,
MYCN nonamplified neuroblastoma cells produces synergistic activity by disrupting transcriptional regulation
through enhanced inhibition of ALK signaling. Aim 2: What are the mechanisms by which ALK-mutated,
MYCN-amplified neuroblastoma cells develop resistance to ALK inhibitors? Hypothesis – The acquisition of
resistance to ALKi is associated with global redistribution of super-enhancers to BRD4 enhancer sites, leading
to novel molecular vulnerabilities that could be exploited for therapeutic gain. Aim 3: Can wild-type ALK
cleavage be leveraged as a therapeutic target in high-risk neuroblastoma? Hypothesis – Proteolytic cleavage
of the extracellular domain of ALK could be therapeutically targeted through MMP9 inhibition to impede NB cell
migration. Positive results in this renewal proposal would clearly benefit children with high-risk neuroblastoma
and may also benefit patients with different cancers that express aberrant ALK, from non-small cell lung cancer
to anaplastic large-cell lymphoma.

## Key facts

- **NIH application ID:** 9868896
- **Project number:** 5R01CA148688-09
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Rani E. George
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,844
- **Award type:** 5
- **Project period:** 2011-01-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868896

## Citation

> US National Institutes of Health, RePORTER application 9868896, The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma (5R01CA148688-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868896. Licensed CC0.

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