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Determining the role of the SDF-1/CXCR4 pathway and its intersection with chronic stress to establish novel precision approaches to head and neck cancer management

Award Number: R21CA279935
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Determining the role of the SDF-1/CXCR4 pathway and its intersection with chronic stress to establish novel precision approaches to head and neck cancer management - PROJECT ABSTRACT/SUMMARY Substantial pre-clinical evidence has demonstrated stress-induced tumor progression in animal models of head and neck cancer (HNC). Clinically, patients with locoregionally advanced Human Papillomavirus (HPV)-negative HNC are exposed to a broad range of chronic stressors. The link between cancer progression and chronic stress may be one contributing explanation for the persistently poor oncologic outcomes of the HPV-negative HNC population. To evaluate mechanism and develop therapeutics, animal models of chronic stress are needed. However, existing models use either immunodeficient mice or syngeneic murine tumors, neither of which recapitulate the human tumor microenvironment (TME). To overcome these limitations, we developed a novel mouse model of chronic stress engineered to have a human immune system and carry human HNC xenografts. In preliminary studies using this model, chronic stress led to increased tumor growth and metastases associated with higher levels of circulating stromal-derived factor 1 (SDF-1) and immune alterations in the TME. Taken together, we hypothesize that chronic stress leads to SDF-1/CXCR4 pathway upregulation which induces an immunotolerant TME and increased tumor growth and metastasis in HNC. To test this hypothesis and determine clinical relevance, we will investigate the mechanisms underlying stress-induced tumor growth in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) humanized models of HNC. We will further evaluate clinical relevance through a prospective observational study in patients undergoing HNC surgery. In Aim 1, humanized CDX mice will be randomized to chronic social isolation stress or control conditions. Three arms will be designed including (1) animals treated with a CXCR4 antagonist, (2) HNC xenografts with a CXCR4 deletion, and (3) a control arm with wild-type HNC xenografts. Tumor growth and lung metastases will be measured. Intra-tumoral immunophenotyping and RNA sequencing will be performed. In Aim 2, we will recruit patients with locoregionally advanced HPV-negative HNC planned for surgical resection, a population with a poor prognosis and significant baseline exposure to chronic stressors. Patients will undergo plasma cytokine assessment and tumor resection specimens will undergo immunophenotyping and RNA sequencing. In a subset of these patients, autologous humanized patient-derived xenograft (PDX) models will be generated, in which the human immune system and tumor are derived from the same patient. This is uniquely feasible for HNC surgery with fibula reconstruction, as a segment of fibula bone is routinely discarded from which hematopoietic stem cells can be harvested for autologous humanization. These autologous PDX models will be randomized to chronic stress and control conditions and treated with a CXCR4 antagonist as compared with control injection. This study will be the first to investigate the mechanism of stress-induced HNC growth in the context of the SDF- 1/CXCR4 axis and the human TME. Results from the humanized pre-clinical models and parallel prospective clinical analyses will lay the foundation for development of precision therapeutics and rational clinical trial design.


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 = $0 )
2025	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	2	7/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $173,208 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	2	2/27/2024	NON-COMPETING CONTINUATION	$164,093
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$9,115
														Subtotal = $173,208

Issue Date FY: 2023 ( Subtotal = $218,790 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Biology Research	000	1	3/1/2023	NEW	$218,790
														Subtotal = $218,790

Grand Total All Awards = $391,998

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Determining the role of the SDF-1/CXCR4 pathway and its intersection with chronic stress to establish novel precision approaches to head and neck cancer management

Award Number: R21CA279935

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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