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The Immunomodulatory Effects of Nrf2 Activation on Macrophages in the Lung Tumor Microenvironment

Award Number: F31CA275239
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/16/2023
PERIOD OF PERFORMANCE END DATE: 03/02/2025

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The Immunomodulatory Effects of Nrf2 Activation on Macrophages in the Lung Tumor Microenvironment - Project Summary There is a critical need for the development of new therapies for lung cancer, as current treatments are ineffective and the five-year survival rate remains below 20%. The immune infiltrate in the lung tumor microenvironment is a promising target for anti-cancer therapy. Macrophages make up the majority of this immune population and exist on a dynamic spectrum which can either be anti-cancer or cancer-promoting. In developed tumors, a pro- inflammatory phenotype in macrophages is beneficial for an anti-tumor immune response. To survive in this inflammatory environment, macrophages rely on cytoprotective mechanisms regulated by the Nrf2 pathway. This pathway serves as a defense mechanism against oxidative stress and protects normal, healthy cells from malignant transformation. While constitutive Nrf2 activation in tumor cells can aid tumor cell survival, the effect that Nrf2 activation has on immune cells in the tumor microenvironment is surprisingly underexplored. Synthetic derivatives of oleanane triterpenoids are the most potent known pharmacological activators of the Nrf2 pathway, and the triterpenoid CDDO-Methyl ester (CDDO-Me) has potent anti-tumor activity in a preclinical mouse model of lung cancer. Tumor-educated bone marrow-derived macrophages (BMDMs) increase pro-inflammatory markers associated with an anti-tumor immune response and decrease pro-tumor chemotactic and angiogenic factors when treated with CDDO-Me. Therefore, I hypothesize that by inducing an anti-tumor macrophage phenotype within the tumor microenvironment, Nrf2 activation will decrease lung tumor burden. Aim 1 of this proposal will determine if Nrf2 activation in macrophages increases their anti-tumor function. Aim 2 will evaluate whether Nrf2 activation in tumor cells polarizes tumor-associated macrophages to promote tumor growth and if pharmacological Nrf2 activation in the microenvironment can overcome the effect of Nrf2 activation in mutated tumor cells to reduce tumor burden. This proposal includes a comprehensive training plan including didactic and experimental learning in both in vitro and in vivo model systems, transcriptomics, genome editing, and novel in vivo imaging techniques. Completion of the proposed studies will provide me with the necessary skills and rigorous training needed for success as an independent and collaborative investigator in cancer biology.


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 = -$12,936 )
2025	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Research Manpower	000	2	3/12/2025	NON-COMPETING CONTINUATION	-$12,936
														Subtotal = -$12,936

Issue Date FY: 2024 ( Subtotal = $39,060 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Research Manpower	000	2	7/24/2024	NON-COMPETING CONTINUATION	$39,060
														Subtotal = $39,060

Issue Date FY: 2023 ( Subtotal = $41,833 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Research Manpower	002	1	3/7/2023	NEW	$0
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Research Manpower	001	1	3/7/2023	NEW	$0
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Research Manpower	000	1	3/7/2023	NEW	$41,833
														Subtotal = $41,833

Grand Total All Awards = $67,957

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The Immunomodulatory Effects of Nrf2 Activation on Macrophages in the Lung Tumor Microenvironment

Award Number: F31CA275239

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/16/2023

PERIOD OF PERFORMANCE END DATE: 03/02/2025

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