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Dual function of HSP70 in cytoprotection of tumor cells and generation of permissive microenvironment

Award Number: R01CA251676
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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Dual function of HSP70 in cytoprotection of tumor cells and generation of permissive microenvironment - It has been widely accepted that distinct epithelial to mesenchymal transition (EMT) phenotype and cancer stem cell (CSC) properties as well as the immunosuppressive tumor microenvironment (TME) in triple negative breast cancer (TNBC) subtype account for the aggressive behavior of this disease. Although increased levels of tumor- infiltrating lymphocytes (TILs) in TNBC predicted better clinical outcome, the majority of these patients display progressive disease due to the immunosuppressive TME. Although the clinical relevance of TME/pre-metastatic niche in disease progression has been well recognized, the molecular mechanisms that regulate these processes remain elusive. Preclinical and clinical data provide compelling evidence that immune cells of myeloid origin (macrophages, neutrophils, MDSCs) are major components of the TME and predictive of poor prognosis as well as therapeutic resistance. Therefore, further research is required to understand the underlying molecular mechanism of formation of immunosuppressive TME/pre-metastatic niche and its role in disease progression and therapeutic resistance. Our primary objectives in this application are; to determine how stress-induced HSP70 regulates two fundamental processes; i) protecting tumor cells from cytotoxic cell death by inducing an epithelial mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype and ii) generating a permissive microenvironment via the modulation of immunosuppressive myeloid cells. Our central hypothesis is that A20 induced HSP70 in TNBCs protects tumor cells from cytotoxic cell death while inducing an EMT phenotype and inflammatory cytokines which in turn promote the accumulation of immunosuppressive MDSCs. Therefore, targeting HSP70 will have a dual activity on tumors and MDSCs. Our rationale is that the identification of molecular mechanism(s) that sensitize tumor cells to cytotoxic agents while reversing immunosuppression will improve the effectiveness of currently available therapeutics. We previously demonstrated that growth of tumors at metastatic sites is dependent of granulocytic MDSCs and suppression of anti-tumor responses and thus blocking HSP70 in combination with standard of care and/or checkpoint inhibitors could have significant clinical benefit. Based on these concepts we propose to test our hypothesis by investigating the following specific aims: Aim 1 will test the hypothesis that a reciprocal A20/HSP70 signaling axis provides cytoprotection to tumor cells by inducing EMT/CSC phenotype in TNBC subtype. Aim 2 will test the hypothesis that HSP70 regulates immunosuppressive MDSC induction and acitivity. Aim 3 will determine the molecular mechanism and functional importance of HSP70 in generation of TME and pre-metastatic niche. At the completion of our proposal, we expect to elucidate the molecular mechanism by which HSP70 cytoprotects tumor cells from cytotoxic agents by inducing EMT/CSC phenotype while regulating the immunosuppressive MDSCs in response tumor secreted cytokines facilitating the tumor progression. It will also determine whether blocking HSP70 potentiates the efficacy of the chemotherapies and/or immunotherapy in syngeneic mouse models representing TNBC subtype.


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 = $352,275 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	002	6	4/25/2025	NON-COMPETING CONTINUATION	$317,049
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	004	6	6/9/2025	NON-COMPETING CONTINUATION	$35,226
2025	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	003	5	5/27/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	3	1/27/2025	NON-COMPETING CONTINUATION	-$113,762
2025	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	001	4	1/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$113,762
														Subtotal = $352,275

Issue Date FY: 2024 ( Subtotal = $402,108 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	002	5	7/30/2024	SUPPLEMENT FOR EXPANSION	$67,446
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	000	5	6/24/2024	NON-COMPETING CONTINUATION	$334,662
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	001	5	7/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,108

Issue Date FY: 2023 ( Subtotal = $345,230 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	3	4/24/2023	NON-COMPETING CONTINUATION	$345,230
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	001	3	9/19/2023	NON-COMPETING CONTINUATION	-$230,387
2023	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Biology Research	002	4	9/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$230,387
														Subtotal = $345,230

Issue Date FY: 2022 ( Subtotal = $345,230 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$345,230
														Subtotal = $345,230

Issue Date FY: 2021 ( Subtotal = $352,275 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	1	4/26/2021	NEW	$352,275
														Subtotal = $352,275

Grand Total All Awards = $1,797,118

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Dual function of HSP70 in cytoprotection of tumor cells and generation of permissive microenvironment

Award Number: R01CA251676

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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