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Functional analysis of a novelintegrin-dependent metastasis pathway in melanoma

Award Number: R01CA247957
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Functional analysis of a novelintegrin-dependent metastasis pathway in melanoma - Human malignant melanoma is an aggressive cancer with high propensity for metastatic dissemination. Despite recent advances in melanoma therapy, most patients with metastatic disease do not experience durable benefit from current treatment options. Indeed, existing targeted and cancer immunotherapeutic modalities do not directly inhibit tumor metastasis, which accounts for most cancer-related deaths. Accordingly, the development of new agents that specifically target pro-metastatic pathways intrinsic to melanoma cells could greatly improve treatment outcomes and reduce off-target toxicities. The trafficking processes observed in disseminating metastatic cancers resemble, at least in part, the leukocyte homing paradigm, a sequential multistep adhesive cascade involving cell tethering and rolling on microvascular endothelium, followed by integrin-mediated arrest and transendothelial migration into secondary tissues. Leukocyte homing is dependent on specialized integrin heterodimers and their cognate ligands on endothelial cells. To date, however, expression of these distinct leukocytic homing integrin subsets has not been described in melanoma. Our preliminary studies demonstrate, for the first time, aberrant expression of integrin heterodimers, conventionally thought to be restricted to leukocytes, by melanoma cell subsets with high metastatic capacity. In patient primary melanomas, cancer cell-intrinsic integrin positivity correlated with sentinel lymph node metastases. Melanoma-specific inhibition of these integrin heterodimers suppressed endothelial adhesion and significantly blocked growth and metastasis formation in preclinical mouse models of human melanoma. These paradigm- shifting findings identify leukocytic homing integrins as novel mediators of tumor cell dissemination. While hematopoietic integrin targeting approaches, including humanized antibodies, have already been developed for the treatment of patients with inflammatory and autoimmune leukocyte trafficking disorders, they have never been examined in the context of cancer. In this proposal, we newly investigate the therapeutic utility of these validated and readily available integrin inhibitors in blocking metastatic dissemination in preclinical melanoma models. Our specific aims are to 1) dissect mechanisms of melanoma cell-intrinsic homing integrin induction and functional activation, and define integrin glycosylation states and heterodimer composition in patient tumor biospecimens at various stages of progression, and 2) examine the therapeutic efficacy of CRISPR/Cas-9-mediated leukocytic integrin knockout or clinical-grade integrin inhibitors originally formulated for the treatment of immune trafficking disorders, in preclinical melanoma models. We have assembled a team of experts in the melanoma metastasis, leukocyte homing, gene editing, dermatopathology, and glycobiology fields, to bring to fruition the translationally relevant aims of this proposal. Results from our studies could establish melanoma cell-expressed leukocytic integrins and their glycostructural determinants as novel therapeutic targets for selective inhibition of metastatic dissemination.


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 = $511,820 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	12/20/2024	NON-COMPETING CONTINUATION	$460,639
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	5	7/11/2025	NON-COMPETING CONTINUATION	$51,181
														Subtotal = $511,820

Issue Date FY: 2024 ( Subtotal = $486,230 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$25,591
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	11/15/2023	NON-COMPETING CONTINUATION	$460,639
														Subtotal = $486,230

Issue Date FY: 2023 ( Subtotal = $501,583 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	3	3/15/2023	NON-COMPETING CONTINUATION	$40,944
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	11/29/2022	NON-COMPETING CONTINUATION	$460,639
														Subtotal = $501,583

Issue Date FY: 2022 ( Subtotal = $508,408 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	2	5/17/2022	NON-COMPETING CONTINUATION	$41,503
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	12/1/2021	NON-COMPETING CONTINUATION	$466,905
														Subtotal = $508,408

Issue Date FY: 2021 ( Subtotal = $524,606 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	11/27/2020	NEW	$524,606
														Subtotal = $524,606

Grand Total All Awards = $2,532,647

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Functional analysis of a novelintegrin-dependent metastasis pathway in melanoma

Award Number: R01CA247957

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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