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Dihydroceramide desaturase (DES1) as a mediator of receptor tyrosine kinase-driven metastasis in breast cancer

Award Number: R01CA248014
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/03/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Dihydroceramide desaturase (DES1) as a mediator of receptor tyrosine kinase-driven metastasis in breast cancer - ABSTRACT Despite improvements in treatment, clinical outcomes for late stage breast cancer (BC) remain poor and there is a critical need for new therapies for metastatic disease. Hyperactivation of receptor tyrosine kinase (RTK) signaling in BC is associated with poor prognosis yet direct RTK inhibitors have had mixed results in clinical trials. RTK signaling drives anoikis resistance, a key metastasis-enabling biology. Thus, defining the underlying mechanisms of this process could identify new druggable targets to treat metastasis. Sphingolipids (SL) are a family of bioactive lipids, classically implicated in cell death, and whose metabolism is altered in cancer. Ongoing studies from the PI’s group, using HER2 amplification as a model system of RTK signaling have identified the SL enzyme dihydroceramide desaturase 1 (DES1) as a key HER2-regulated node in the SL network that was required for anoikis resistance of HER2+ BC cells. In clinical data, high DES1 levels were associated with worse outcomes in HER2+ BC. Moreover, increasing DES1 levels was sufficient to drive in vitro tumorigenicity of HER2+ BC cells whereas DES1 KO reduced in vivo metastasis. Taken together, these novel data have led us to the central hypothesis that DES1 is necessary and sufficient to promote RTK- driven anoikis resistance and metastasis which will be tested by pursuing three specific aims. The first aim will define the role of DES1 in RTK-driven anoikis resistance in vitro and in vivo using Crispr/Cas9 technology to knockout DES1 in RTK-driven BC cells and defining biological effects on in vitro tumorigenicity and in vivo cell survival in the circulation. The second aim will define the mechanism(s) by which RTKs regulate and maintains DES1 activity following ECM detachment using gain of function and loss of function approaches to directly connect DES1 with oncogenic activation of PI3K signaling and the pentose phosphate pathway. The third aim will establish DES1 as a driver of in vivo metastasis and chemoresistance in BC harboring RTK hyperactivation using gain of function approaches to show that increased DES1 is sufficient to promote an aggressive phenotype in RTK-activated BC and can mediate resistance to the targeted HER2 therapy lapatinib. Collectively, these studies will establish DES1 as a key effector of oncogenic RTK signaling and as a novel druggable target, effective at overcoming anoikis resistance and useful for treatment of metastatic BC.


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 = $361,779 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	000	5	2/28/2025	NON-COMPETING CONTINUATION	$325,601
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	001	5	5/21/2025	NON-COMPETING CONTINUATION	$36,178
														Subtotal = $361,779

Issue Date FY: 2024 ( Subtotal = $343,690 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	000	4	4/4/2024	NON-COMPETING CONTINUATION	$343,690
														Subtotal = $343,690

Issue Date FY: 2023 ( Subtotal = $354,543 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	000	3	2/15/2023	NON-COMPETING CONTINUATION	$354,543
														Subtotal = $354,543

Issue Date FY: 2022 ( Subtotal = $354,543 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	001	2	5/3/2022	NON-COMPETING CONTINUATION	$28,942
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	000	2	2/18/2022	NON-COMPETING CONTINUATION	$325,601
														Subtotal = $354,543

Issue Date FY: 2021 ( Subtotal = $361,779 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Cancer Biology Research	000	1	3/3/2021	NEW	$361,779
														Subtotal = $361,779

Grand Total All Awards = $1,776,334

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Dihydroceramide desaturase (DES1) as a mediator of receptor tyrosine kinase-driven metastasis in breast cancer

Award Number: R01CA248014

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/03/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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