# Targeting Oncogenic ALK Signaling in Neuroblastoma

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $401,600

## Abstract

SUMMARY/ABSTRACT
Neuroblastoma (NB) remains a leading cause of childhood cancer morbidity and mortality. We discovered
heritable activating mutations in the ALK oncogene, and that these same mutations are frequently somatically
acquired during high-risk NB tumorigenesis . Our work established ALK as a tractable molecular target in NB
and provided the rationale for the clinical development of ALK inhibition therapy. This second competitive renewal
builds on six major discoveries over the last decade: 1) we showed that the majority of activating ALK mutations
are not sensitive to first generation drugs such as crizotinib; 2) we demonstrated that chemotherapy could
sensitize ALK mutant NBs to crizotinib, leading to an ongoing Phase 3 trial; 3) we identified lorlatinib as the only
ALK inhibitor that is effective against all activating mutations and rapidly opened a phase 1 clinical trial that is
showing significant anti-tumor activity while still in dose escalation; 4) we developed and implemented a clinical
trial matching genomic aberrations in tumor cells at the time of relapse to rationally designed combinations of
molecularly targeted agents (e.g. ceritinib + ribociclib for patients with ALK-driven NB) that have shown
synergistic activity in our lab; 5) we showed that the superior activity of lorlatinib is mediated through inhibition
of G2/M kinases; and 6) we showed that ALK is abundantly expressed on the cell surface of the vast majority of
NBs and other pediatric malignancies, and have developed immunotherapeutic strategies since ALK is not
expressed on normal tissues. Thus, the long-term goal of this new research proposal is to improve outcomes for
children with NB by leveraging the momentum above into rational new combinatorial and immunotherapeutic
treatment strategies. The objective here is to identify mechanisms regulating adaptive responses to targeted
ALK inhibition with lorlatinib and to develop therapeutic strategies aimed at targeting ALK in the plasma
membrane. Our central hypotheses are that i) ALK-driven NBs adapt to and survive therapy with lorlatinib via
mechanisms that can be therapeutically targeted; and ii) immunotherapeutic targeting of native ALK is of biologic
relevance to the majority of patients with NB and to identifiable subsets of other childhood tumors. We will test
our central hypothesis in two specific aims: 1) Elucidate mechanisms of adaptive resistance to ALK-kinase
inhibition with lorlatinib to identify optimal combination strategies that will result in improved and sustained
therapeutic efficacy; 2) Develop highly specific antibody-based approaches to target cell surface ALK on NBs
and other ALK-expressing pediatric cancers. We consider this proposal significant because it will result in a new
mechanism-based therapeutic strategy that will address the major unmet need that, despite unprecedented
discoveries in defining the basic mechanisms of NB tumorigenesis, this knowledge has not yet translated into
signific...

## Key facts

- **NIH application ID:** 9968053
- **Project number:** 5R01CA140198-12
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Yael P Mosse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,600
- **Award type:** 5
- **Project period:** 2009-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968053

## Citation

> US National Institutes of Health, RePORTER application 9968053, Targeting Oncogenic ALK Signaling in Neuroblastoma (5R01CA140198-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9968053. Licensed CC0.

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