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p27pTpT drives cancer-promoting inflammation and shapes the tumor microenvironment (TME) toward a more tumor-permissive state in vivo

Award Number: F99CA284295
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/19/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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p27pTpT drives cancer-promoting inflammation and shapes the tumor microenvironment (TME) toward a more tumor-permissive state in vivo - Breast Cancer (BC) is the leading cause of cancer-related death in women. Therapy resistance is a major limiting factor. Therefore, the long-term goal of this grant is to elucidate novel molecular mechanisms underlying therapy resistance. BC stem cells (CSCs) may mediate treatment resistance in part by altering the tumor microenvironment (TME) to promote immune evasion. p27 plays a dual role: as a tumor suppressor, it inhibits cell cycle; and as an oncogene, it promotes metastasis when phosphorylated by PI3K activated kinases on its C-terminal at T157 and T198 (p27pTpT). p27pTpT acts as a transcriptional regulator of cJun, driving EMT/pro-metastatic gene profiles. My thesis work showed it also coactivates STAT3 to upregulate CSCs and cancer promoting-inflammation. My overarching hypothesis is that p27pTpT co-activates STAT3 gene profiles to expand cancer stem cells and promote immune evasion. My thesis work in AIM1.1 made the novel observation that p27pTpT upregulates stem cell properties including sphere formation and embryonic stem cell transcription factors (ES-TFs, MYC, OCT4, NANOG, and KLF4), by co-activating STAT3. My ChIP- seq/RNA-seq showed p27 recruits STAT3 to gene promoters to induce broad profiles of p27/STAT3 co-targets, including MYC and JAG1, to increase tumor-initiating stem cells (TISC) in vivo. I showed p27pTpT-driven CSC expansion is in part mediated through the novel p27/STAT3 co-target gene, ANGPTL4. In the F99, AIM1.2, pursues the hypothesis that p27pTpT/STAT3 promotes tumor immune evasion by re-shaping the TME. I will expand my research into cancer immunology which provides me with an outstanding training opportunity. My ATAC-seq showed p27pTpT increases chromatin accessibility to co-recruit p27/STAT3 at promoters of oncogenic, proinflammatory genes (IL-6, NF-κB (RELA), VEGFA) and the mediator of immune evasion, PDL1. p27pTpT also increased NF-κB (p65), IL6 proteins and secreted CCL2. Next, I will test if p27pTpT drives cancer-promoting inflammation and shapes the TME toward a more tumor-permissive state in vivo. First, I will identify how p27pTpT modulates both tumor cell and immune cell signatures and cytokine expression by single cell RNA-seq of BC and Luminex assays of cytokines in peripheral blood of tumor bearing mice in vivo. I will also test how p27pTpT might drive immune evasion by modulating CD4, CD8 T cell and NK cell infiltration in TME and test if p27pTpT recruits MDSCs, Tregs and increases the M2/M1 macrophage ratio in the TME by IHC and by flow cytometry. In AIM2, my K00 addresses mechanisms underlying the greater prevalence and mortality of breast cancer in obese women. My K00 will investigate if p27pTpT promotes the chronic inflammation of obesity by cooperating with the estrogen receptor (ER) to activated NFB/STAT3 to promote immune evasion and endocrine therapy resistance. I will further investigate if dual therapy with ER blockade and checkpoint inhibitors can reverse endocrine resistance in breast cancers in obese hosts. The F99/K00 will help my transition from predoctoral to postdoctoral research and, ultimately, into an independent investigator.


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 = -$10,184 )
2026	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Cause and Prevention Research	001	2	5/27/2026	SUPPLEMENT FOR EXPANSION	-$3,000
2026	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	2	5/27/2026	NON-COMPETING CONTINUATION	-$7,184
														Subtotal = -$10,184

Issue Date FY: 2025 ( Subtotal = $3,000 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Cause and Prevention Research	001	2	2/12/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Cause and Prevention Research	000	2	12/6/2024	SUPPLEMENT FOR EXPANSION	$3,000
														Subtotal = $3,000

Issue Date FY: 2024 ( Subtotal = $36,274 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	2	7/10/2024	NON-COMPETING CONTINUATION	$36,274
														Subtotal = $36,274

Issue Date FY: 2023 ( Subtotal = $36,494 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	1	8/17/2023	NEW	$36,494
														Subtotal = $36,494

Grand Total All Awards = $65,584

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p27pTpT drives cancer-promoting inflammation and shapes the tumor microenvironment (TME) toward a more tumor-permissive state in vivo

Award Number: F99CA284295

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/19/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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