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Targeting RAGE in tumor and TME to oppose inflammation and drug resistance in obesity associated ER+ breast cancer

Award Number: R01CA276587
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Targeting RAGE in tumor and TME to oppose inflammation and drug resistance in obesity associated ER+ breast cancer - PROJECT SUMMARY/ABSTRACT Obesity is associated with increased postmenopausal estrogen receptor-positive (ER+) breast cancer (BC) risk and a 2-4 fold increase in mortality from all BC subtypes. Mechanisms of increased resistance to therapy and ensuing fatal BC metastasis in obesity remain unclear. Here, we study how the inflammatory state of obesity drives ER+ BC. We study how postmenopausal estrogen, estrone (E1), which is 3-fold higher in obesity, co- operates with NFκB and the Receptor for Advanced Glycation End-products (RAGE) to upregulate metastasis. Our data indicate that BC cell:adipocyte contact activates NFκB and E1:ERα to induce pro-inflammatory cytokine genes in both cell types, stimulating greater cancer stem cell expansion, and rapid ER+ BC growth and metastasis. Preliminary data show NFκB and E1:ER co-stimulate genes encoding RAGE-ligands (S100A8/A9). RAGE is a major NFκB activator in other cell types (including immune and endothelial cells), but little is known of RAGE/NFκB signaling in BC. We showed that RAGE acts in both tumor cells and the host microenvironment (stroma and fat) to upregulate cytokines that recruit myeloid-derived suppressor cells (MDSC) to promote metastasis. In obese mice, E1 increases BC growth, in part by stimulating immune evasion. New data show antiestrogen-resistant ER+BC lines, including those bearing ESR1 mutations, show increased NFκB activity and RAGE levels. Moreover, the investigational RAGE inhibitor, TTP488, cooperates with the ER-blocker, fulvestrant, to arrest antiestrogen-resistant ER+ BC cell growth in multiple resistant lines. Here, we test if E1-bound ER, NFκB, and RAGE interact in ER+ BC, adipocytes and immune cells to drive gene programs of endocrine therapy resistance and if RAGE inhibitors reverse this. We hypothesize that E1:ER and NFκB cooperate to induce RAGE, and RAGE activates NFκB in ER+ BC tumor cells and peritumoral fat to drive pro-inflammatory, pro-metastatic gene expression programs of tumor progression and acquired drug resistance. Aim 1 will identify tumor cell-intrinsic feed-forward mechanisms mediating RAGE/ NFκB activation in an E1-rich breast cancer environment, testing if E1 and NFκB induce RAGE to activate Rac1, and TLR4 driving feed-forward oncogenic NFκB activation in ER+ BC. Aim 2 will test if RAGE mediates pro-oncogenic, pro-inflammatory target gene activation by E1/ER and NFκB in breast cancer cells. We will identify E1/ER and NFκB cistromes and transcriptomes and test if these require RAGE. The relevance of RAGE-dependent ER/κB co-target genes activation in obesity will be validated by comparing ScRNAseq in human ER+ breast cancers from obese and lean donors. Aim 3 will identify tumor cell-extrinsic mechanisms whereby peritumoral fat in obese hosts promotes acquired antiestrogen resistance and immune evasion in ER+ cancers. Aim 4 will test if RAGE inhibitors restore endocrine therapy responses in organoid and PDX models derived from ER+ breast cancers. This work could identify new approaches to treating acquired endocrine resistance in metastatic ER+BC, particularly in obese patients.


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 = $532,533 )
2026	2026	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	4	7/6/2026	NON-COMPETING CONTINUATION	$532,533
														Subtotal = $532,533

Issue Date FY: 2025 ( Subtotal = $529,962 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	3	7/1/2025	NON-COMPETING CONTINUATION	$529,962
														Subtotal = $529,962

Issue Date FY: 2024 ( Subtotal = $494,656 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	2	7/1/2024	NON-COMPETING CONTINUATION	$494,656
														Subtotal = $494,656

Issue Date FY: 2023 ( Subtotal = $516,548 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	1	7/7/2023	NEW	$516,548
														Subtotal = $516,548

Grand Total All Awards = $2,073,699

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Targeting RAGE in tumor and TME to oppose inflammation and drug resistance in obesity associated ER+ breast cancer

Award Number: R01CA276587

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/07/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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