Developing novel ALK targeting therapies through the expansion of targeted protein degradation
About This Grant
PROJECT SUMMARY/ABSTRACT: This proposal aims to address a critical challenge in treating anaplastic lymphoma kinase (ALK)-driven neuroblastoma (NB) and other cancers: namely the development of resistance to targeted therapies, particularly tyrosine kinase inhibitors (TKIs). ALK is a receptor-tyrosine kinase that plays a crucial role in the development of the central and peripheral nervous systems, and its dysregulation, through mutations, fusions, and overexpression, has been implicated in several cancers, most notably NB. Despite the success of TKIs in treating ALK-driven cancers, resistance mutations in ALK often emerge, leading to disease relapse and limited long-term efficacy. One promising alternative approach to bypass resistance is targeted protein degradation through PROteolysis TArgeting Chimeras (PROTACs), small molecules that harness the ubiquitin-proteasome system to degrade specific target proteins. However, the current landscape of protein degradation therapies is limited to the near-exclusive use of two E3 ubiquitin ligases – CRBN and VHL – for PROTAC development. These ligases, while effective for certain targets, may not be optimal for all targets, and the emergence of resistance to these degrader-based therapies highlights an overlap in limitations between TKIs and PROTACs that necessitates recruitment of more diverse and effective degraders. Additionally, while at least a third of the proteome transits the endoplasmic reticulum (ER) through its membrane or lumen, almost all current degraders target cytosolic proteins leaving a large swathe of the proteome unexplored. Given ALK mutant proteins in NB often mislocalize to the ER, where they become constitutively activated and contribute to oncogenic signaling, the ER presents an untapped resource for therapeutic development through targeted protein degradation. This project intends to leverage ER-associated degradation (ERAD), a posttranslational quality control system within the ER that aids in protein homeostasis by degrading misfolded and immature proteins, to target mutant ALK. The ERAD system, which consists of membrane-embedded E3 ligases and their associated cofactors, provides a unique platform and specificity to target a previously under-explored pool of disease- related proteins, including ALK mutants. The research strategy will focus on several key innovations: (1) identifying selective protein degraders that can efficiently target ALK mutants and overcome resistance mutations, (2) expanding the therapeutic landscape of targeted protein degradation through ORFeome-based screening approaches in search novel target-degrader pairs, (3) developing genetic proof-of-principle tools to rapidly test and validate these novel degradation strategies, and (4) leveraging the specificity of organellar- based degradation to selectively degrade disease-relevant proteins localized to the ER. Ultimately, this research seeks to develop a more diverse set of tools for targeted degradation therapies, offering promising new strategies for overcoming drug resistance in ALK-driven NB and improving clinical outcomes in cancer treatment as a whole.
Grant Summary
Developing novel ALK targeting therapies through the expansion of targeted protein degradation is a NCI - National Cancer Institute grant providing up to $78K for university, nonprofit, healthcare org. Applications are due 2028-12-31 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $78K
2028-12-31
- 1Confirm your organization is eligible for Developing novel ALK targeting therapies through the expansion of targeted protein degradation from NCI - National Cancer Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NCI - National Cancer Institute before the deadline.
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Developing novel ALK targeting therapies through the expansion of targeted protein degradation: Frequently Asked Questions
Who is eligible for the Developing novel ALK targeting therapies through the expansion of targeted protein degradation?
Developing novel ALK targeting therapies through the expansion of targeted protein degradation is offered by NCI - National Cancer Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Developing novel ALK targeting therapies through the expansion of targeted protein degradation provide?
Developing novel ALK targeting therapies through the expansion of targeted protein degradation provides up to $78K per award from NCI - National Cancer Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Developing novel ALK targeting therapies through the expansion of targeted protein degradation deadline?
Applications for Developing novel ALK targeting therapies through the expansion of targeted protein degradation are due 2028-12-31 (open). Because deadlines can change, verify the date with the funder, NCI - National Cancer Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Developing novel ALK targeting therapies through the expansion of targeted protein degradation?
To apply for Developing novel ALK targeting therapies through the expansion of targeted protein degradation, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NCI - National Cancer Institute.