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Targeting actionable liabilities in Merlin-deficient breast cancer

Award Number: R21CA277267
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/27/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Targeting actionable liabilities in Merlin-deficient breast cancer - ABSTRACT During tumor progression, loss of cell:cell adhesion and detachment from the extracellular matrix induces dynamic reorganization of the cytoskeleton, formation of invadopodia by the tumor cells, and activation of epithelial-to-mesenchymal transition. This is enabled by tuning molecular programs in order to adapt to loss of attachment. Merlin, encoded by the NF2 gene, is a member of the ezrin-radixin-moesin protein family that links membrane proteins to the cortical actin cytoskeleton and regulates adhesion, migration, cell-cell contact, proliferation, and signal transduction. Merlin is critically involved in contact-dependent inhibition of growth. We found that Merlin protein levels are reduced in the majority of cases of infiltrating ductal carcinoma and metastatic breast cancer tissues. Decreased Merlin protein expression was also seen with advanced nodal involvement in breast cancer. In order to ascribe clinical relevance, we re-capitulated the loss of Merlin in breast cancer cells. Merlin deficiency elicited a markedly invasive phenotype, morphologically and programmatically evident as epithelial-to-mesenchymal transition. In order to overcome the challenge of embryonic lethality of a total Nf2-knockout, we generated a unique mammary-specific Nf2-knockout mouse mammary tumor model. These mice show remarkably accelerated development of tumors. In this R21 application, our objective is to target potential liabilities in Merlin-deficient mammary tumors to mitigate their metastasis-conducive tumor portfolio. Using multiple Merlin-deficient mammary tumor systems and tumor- derived organoids, we will investigate (i) targeting aberrantly activated Hh signaling in Merlin-deficient tumors, and (ii) the potential to target deregulated tryptophan metabolism in Merlin-deficient tumors. Our approaches are non-overlapping and complementary. Outcomes from our work will present two unprecedented strategies to target possible liabilities in Merlin-deficient breast cancer; these findings can be expanded and/or translated to other tumor types that harbor Merlin deficiency.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $208,271 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	2	11/18/2024	NON-COMPETING CONTINUATION	$187,444
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	001	2	6/9/2025	NON-COMPETING CONTINUATION	$20,827
														Subtotal = $208,271

Issue Date FY: 2024 ( Subtotal = $173,559 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	1	12/27/2023	NEW	$173,559
														Subtotal = $173,559

Grand Total All Awards = $381,830

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Targeting actionable liabilities in Merlin-deficient breast cancer

Award Number: R21CA277267

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/27/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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