Tuesday, July 1, 2025 7/1/2025

Enhancing chemotherapeutic efficacy in triple-negative breast cancer via DSTYK silence

Award Number: R01CA272760
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Enhancing chemotherapeutic efficacy in triple-negative breast cancer via DSTYK silence - Project Abstract Breast cancer, the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple- negative breast cancer (TNBC), a type of breast cancer considered to be more aggressive and have a poorer prognosis than other types of breast cancer. Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of TNBC patients. Preliminary data demonstrate that TNBC cells surviving from the chronic treatment of chemotherapeutic drugs show significantly higher expression of a special protein kinase, dual serine/threonine and tyrosine protein kinase (DSTYK), than parental cells without treatment. Additionally, from both in vitro and in vivo results, we found that both the knockout of DSTYK and exosome-mediated DSTYK silence can lead to the apoptosis of chemoresistant cells upon drug treatment. This novel finding suggests that DSTYK exerts a previously unknown and important role in promoting chemoresistance. The objective of this proposal is to elucidate the novel role and the underpinning mechanism of DSTYK in regulating chemoresistance in TNBC cells and further explore the potential of exosome-mediated DSTYK silence in TNBC chemotherapy with preclinical models. We hypothesize that DSTYK is a novel target for chemotherapy to induce TNBC cell death. We will test our hypothesis with three specific aims. In Aim 1, we will investigate the mechanism by which DSTYK promotes chemoresistance in TNBC cells. In Aim 2, we will establish DSTYK as a prognostic biomarker in clinical TNBC. In Aim 3, we will evaluate the therapeutic benefit of DSTYK-siRNA-exosomes in chemotherapy. We engineered exosomes containing siRNA against DSTYK that can specifically target TNBC cells. We found these engineered exosomes can significantly promote tumor regression and inhibit metastasis in both cellular and orthotopic models treated with drugs. Successful completion of the proposed studies will provide fundamental insights into the role of DSTYK in chemoresistance in TNBC cells and will lay the essential foundation for the development of an exosome-mediated strategy targeting DSTYK to significantly improve clinical TNBC chemotherapy.


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 = $336,458 )
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Treatment Research	004	3	5/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$119,133
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Treatment Research	002	3	4/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$118,756
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Treatment Research	001	3	3/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$217,702
2025	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Treatment Research	003	2	5/19/2025	NON-COMPETING CONTINUATION	-$119,133
2025	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Treatment Research	000	2	3/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,458

Issue Date FY: 2024 ( Subtotal = $326,143 )
2024	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Treatment Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$17,165
2024	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Treatment Research	000	2	3/15/2024	NON-COMPETING CONTINUATION	$308,978
														Subtotal = $326,143

Issue Date FY: 2023 ( Subtotal = $355,046 )
2023	2023	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Treatment Research	000	1	4/7/2023	NEW	$355,046
														Subtotal = $355,046

Grand Total All Awards = $1,017,647

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Enhancing chemotherapeutic efficacy in triple-negative breast cancer via DSTYK silence

Award Number: R01CA272760

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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