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Mechanisms of LY6K-NSC243928 action in anti-tumor immune response in triple negative breast cancer

Award Number: R01CA227694
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Mechanisms of LY6K-NSC243928 action in anti-tumor immune response in triple negative breast cancer - Summary: Triple negative breast cancer (TNBC) is a lethal subtype of breast cancer, which lacks targeted therapies, it affects younger women and has the worst overall survival rate among breast cancer subtypes. Although immune- oncology (IO) has led to a paradigm shift in cancer therapeutics, its effect in TNBC has been modest. There is an urgent need to identify and develop novel, effective and safe approaches to treat TNBC. We and others have shown that the cell surface protein Lymphocyte antigen 6K (LY6K) is heavily expressed in 80% of TNBC clinical samples and that the increased mRNA expression is associated with poor survival outcome in TNBC. LY6K is mostly expressed in testes tissue and LY6K knockout mice remain healthy. R01CA227694, grant allowed us to validate LY6K protein as a therapeutic target in TNBC. We showed that NSC243928 small molecule can bind with LY6K molecule physically and exhibit anti-tumor properties in LY6K-dependent manner. NSC243928 could inhibit tumor progression and offered long-term tumor protection (unpublished). We show that the that the anti-tumor properties of NSC243928 may be associated with anti-tumor immune cell distribution in tumor microenvironment (TME) in vivo and its direct effect on chromatin modulation. The data from R01 resulted in grant of Canadian Patent No. 3082397 and U.S. Patent No. 12,134,601B2, for the use NSC243928 in “LY6K-targetted therapies using small molecules” award. The goal of the revised renewal application is to identify the mode of action underlying NSC24328-LY6K interaction, identify the most effective rationale treatments in combination with NSC243928 for phase 1 clinical trials and Investigational New Drug (IND) filing. The signaling events in cell-extrinsic and cell-intrinsic effects of LY6K and its regulatory mechanisms remains poorly defined. The first knowledge gap is the lack of mechanistic insight in LY6K-NSC243928 induced anti-tumor immune response such as immune cell infiltration, survival and differentiation of anti-tumor immune cells in TME. A second mechanistic gap remains in understanding the direct effect of LY6K-NSC243928 in chromatin remodeling and cell cycle. TGF-β and Aurora B have been known as important oncogenic signaling pathways. LY6K is the first identified cancer cell specific protein which can regulate both TGF-β and Aurora-B kinase, thus LY6K-targeting small-molecule can be powerful anti-cancer agent active only in cancer context due to cell-specific LY6K expression.


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 = $411,575 )
2026	2026	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Treatment Research	001	6	9/17/2026	COMPETING CONTINUATION	$436,022
2026	2022	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	5	1/5/2026	NON-COMPETING CONTINUATION	-$24,447
														Subtotal = $411,575

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	5	7/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $388,498 )
2022	2022	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	5	7/31/2022	NON-COMPETING CONTINUATION	$388,498
														Subtotal = $388,498

Issue Date FY: 2021 ( Subtotal = $399,241 )
2021	2021	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	4	7/19/2021	NON-COMPETING CONTINUATION	$399,241
														Subtotal = $399,241

Issue Date FY: 2020 ( Subtotal = $398,541 )
2020	2020	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	3	8/4/2020	NON-COMPETING CONTINUATION	$398,541
														Subtotal = $398,541

Issue Date FY: 2019 ( Subtotal = $389,208 )
2019	2019	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	001	2	8/2/2019	NON-COMPETING CONTINUATION	$389,208
2019	2018	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	1	11/19/2018	NEW	$0
														Subtotal = $389,208

Issue Date FY: 2018 ( Subtotal = $367,045 )
2018	2018	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Biology Research	000	1	8/3/2018	NEW	$367,045
														Subtotal = $367,045

Grand Total All Awards = $2,354,108

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Mechanisms of LY6K-NSC243928 action in anti-tumor immune response in triple negative breast cancer

Award Number: R01CA227694

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/03/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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