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Characterization of anti-tumor networks in tumor-associated macrophages

Award Number: K00CA274682
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Characterization of anti-tumor networks in tumor-associated macrophages - PROJECT SUMMARY Cancer continues to be a leading cause of death worldwide. Despite significant efforts devoted towards developing effective treatments, the survival rates remain low in many types of tumors. The long-term goal of both the F99 and K00 phases of this work will be to reveal new strategies that lead to novel anti-cancer therapies. The F99 phase will be focused on a cell-intrinsic aspect of cancer biology, while the K00 phase will focus on an immune cell with great potential to directly inhibit tumor growth and to modulate the efficacy of already approved cancer immunotherapies. The F99 phase: An increasing body of evidence has shown that many cancer cells develop an addiction to the nuclear transport machinery and have increased numbers of Nuclear Pore Complexes (NPCs), the multi- protein structures that regulate the nucleocytoplasmic transport of molecules. Recent work has revealed that inhibition of the assembly of NPCs could represent an effective target for cancer therapeutics. However, the molecular factors that regulate NPC assembly are incompletely understood and a targetable pathway has yet to be identified. A whole genome siRNA screen was performed to find genes that regulate assembly of these structures. Genes were identified that, when knocked down, either increase or decrease the NPC content on the surface of the nucleus. Knockdown of 3 members of the CCR4-NOT complex were found to increase NPCs. The CCR4-NOT is a major deadenylase complex that controls protein levels via regulation of mRNA metabolism in eukaryotes. The work proposed here will characterize the effect of CNOT knockdown on the NPC number/functionality and how these changes alter basic cellular physiology. Additionally, this work will elucidate the molecular mechanism by which the CCR4-NOT complex regulates NPCs. The K00 phase: In recent years immuno-oncology therapies, namely immune checkpoint blockers, have shown remarkable clinical efficacy however only a small proportion of patients respond to treatments. One of the reasons underlying the lack of efficacy stems from the presence of a strong immunosuppressive tumor microenvironment (TME). Until the TME can be modified into a more immuno-activating environment, immune checkpoint blockade therapies will have limited success. The K00 phase of this project will focus on a unique and dynamic leukocyte that strongly contributes to the observed immunosuppression; the Tumor-Associated Macrophage (TAM). TAMs have been shown to compose up to 50% of a tumor’s mass and have both pro- and anti-tumorigenic phenotypes. The need remains to develop more effective strategies to target this cell type and reprogram it. The K00 research will characterize the transcriptional networks that can be harnessed to modulate macrophage repolarization in the TME. Successful completion of the F99 phase will reveal a targetable cell-intrinsic aspect of cancer biology, while completion of the K00 phase will reveal an immuno-oncology targetable pathway.


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: 2026 ( Subtotal = $92,826 )
2026	2026	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	5	3/6/2026	NON-COMPETING CONTINUATION	$92,826
														Subtotal = $92,826

Issue Date FY: 2025 ( Subtotal = $91,546 )
2025	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	001	4	4/1/2025	NON-COMPETING CONTINUATION	$0
2025	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	4	3/19/2025	NON-COMPETING CONTINUATION	$91,546
														Subtotal = $91,546

Issue Date FY: 2024 ( Subtotal = $88,047 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	002	3	7/18/2024	EXTENSION WITH OR WITHOUT FUNDS	$6,399
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	001	3	4/8/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	3	3/20/2024	EXTENSION WITH OR WITHOUT FUNDS	$81,648
														Subtotal = $88,047

Grand Total All Awards = $272,419

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Characterization of anti-tumor networks in tumor-associated macrophages

Award Number: K00CA274682

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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