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CXCL5/CXCR2 axis as a therapeutic vulnerability of breast cancer metastasis to bone

Award Number: R01CA252878
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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CXCL5/CXCR2 axis as a therapeutic vulnerability of breast cancer metastasis to bone - PROJECT SUMMARY/ABSTRACT The majority of breast cancers express estrogen receptor a (ER+), a molecule that typically promotes cell proliferation when activated by its ligand estrogen. Despite successes seen in treating patients with ER+ breast tumors with endocrine therapies, approximately 33% of these treated patients will develop recurrent metastatic tumors after endocrine treatment. These recurrent tumors primarily metastasize to bone and do not respond to current treatment options. Bone is the most common and one of the most dangerous sites for breast cancer metastatic tumor growth. At death, roughly 73% of women with breast cancer have bone metastasis. The bone architecture and the ubiquity of vascular sinusoids provide accessibility to and easy exit from bone to increase the spread through the body from the metastatic bone tumor. The bone microenvironment releases cytokines, chemokines, and growth factors that inhibit colonization of cancer cells in healthy bone or support colonization in cancer. These factors also can create an immunosuppressive environment that prevents a normal immune response or response to immunotherapy. In the proposed research, we will investigate how the chemokine Cxcl5, its decoy receptor Ackr1, and its receptor Cxcr2 contribute to ER+ breast cancer metastatic colonization of bone. We also will examine CXCR2 inhibitors for their efficacy as single agents and as a combination therapy (with bisphosphonates or immunotherapy) to inhibit breast cancer metastasis to bone. CXCR2 inhibitors are attractive therapeutics against metastatic breast cancer that may have efficacy in treating the formation of metastatic bone tumors that are dependent on the CXCL5:CXCR2 signaling axis and resistant to current therapies. Since patients with these tumors currently have few treatment options and often are incurable, this study could have significant translational potential. Significantly, if targeting or inhibiting these factors can reduce bone metastasis in preclinical animal models, then we will be in a position at the end of the grant period to propose that these compounds be used in a clinical trial in breast cancer patients with ER+ tumors metastasized to bone. Since these recurrent tumors typically do not respond well to current therapies, this treatment strategy would be significantly impactful and bring significant hope for patients with this disease. Future development of additional optimized small molecules or peptide inhibitors of CXCL5/CXCR2 will expand the therapeutic options available to clinicians in the care of breast cancer patients with metastatic disease.


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 = $357,994 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	5	5/12/2025	NON-COMPETING CONTINUATION	$357,994
														Subtotal = $357,994

Issue Date FY: 2024 ( Subtotal = $368,165 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	$340,095
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	001	4	9/11/2024	NON-COMPETING CONTINUATION	$28,070
														Subtotal = $368,165

Issue Date FY: 2023 ( Subtotal = $350,834 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	3	5/4/2023	NON-COMPETING CONTINUATION	$350,834
														Subtotal = $350,834

Issue Date FY: 2022 ( Subtotal = $350,834 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	2	4/26/2022	NON-COMPETING CONTINUATION	$350,834
														Subtotal = $350,834

Issue Date FY: 2021 ( Subtotal = $357,994 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	1	4/28/2021	NEW	$357,994
														Subtotal = $357,994

Grand Total All Awards = $1,785,821

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CXCL5/CXCR2 axis as a therapeutic vulnerability of breast cancer metastasis to bone

Award Number: R01CA252878

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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