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Crosslinking-based targeted therapy for triple-negative breast cancer

Award Number: R21CA280458
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/13/2023
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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Crosslinking-based targeted therapy for triple-negative breast cancer - Abstract The HER1 and/or HER3 receptors are overexpressed in most triple-negative breast cancers (TNBCs), a subtype of breast cancer that lacks estrogen receptor, progesterone, and HER2 expression and is associated with poor prognosis and a high lung and brain metastasis rate. Chemotherapy is the mainstay of TNBC treatment. Our long-term goal is to develop more effective therapy for this aggressive subtype of breast cancer. In this proposal, we aim to develop a novel crosslinking-based targeted therapy. For this purpose, we will create a series of multi-functional DNA-affibody-drug nanoparticles containing multiple copies of HER1 and/or HER3 specific affibody molecules covalently coupled to a DNA nanostructure, of which the latter binds to tens of small molecule drugs such as THZ1. In the presence of these nanoparticles, HER1+ and/or HER3+ TNBC cells will be tightly bound together, thus preventing metastasis in its initial stage. In the cross-linked TNBC cell clusters, the small molecule anticancer agent THZ1 reversibly bound to the nanoparticles will be released slowly, resulting in killing of crosslinked TNBC cells. These nanoparticles can bind to HER1+ and/or HER3+ TNBC cells in primary tumors, metastatic sites, and circulation. In our preliminary study, cultured HER1+ TNBC cells were crosslinked together to form cell clusters with a 96% crosslinking efficiency, 99% migration inhibition, and 90% invasion inhibition by a DNA-4ZHER1-THZ1 nanoparticle (drug-to-cargo ratio is 50). To enhance the efficiency and overcome the resistance to HER1 inhibitors, a novel DNA-2ZHER1-2ZHER3-THZ1 nanoparticle that targets dual HER1 and HER3 will be synthesized and tested in this study. Our design and hypothesis will be tested with the following specific aims: In specific aim 1, we will prepare a DNA-2ZHER1-2ZHER3- drug nanoparticle for targeting HER1- and/or HER3-overexpressing TNBC. In specific aim 2, we will evaluate the inhibition of HER1- and HER3-overexpressing TNBC cell growth and metastasis by the DNA-2ZHER1-2ZHER3- drug nanoparticle in vitro. In specific aim 3, we will study distribution and pharmacokinetics of selected DNA- 2ZHER1-2ZHER3-drug nanoparticle in healthy mice, and to evaluate its suppression of mammary tumor growth and metastasis in TNBC xenograft models. If successful, this innovative approach will open a new avenue for developing new therapy for treatment of TNBC. The pilot study will lay a foundation for further studies to investigate the utilities and mechanisms of the new class of anticancer agents for targeted therapy.


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 = -$1,537 )
2026	2024	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Cancer Treatment Research	000	2	1/16/2026	NON-COMPETING CONTINUATION	-$1,537
														Subtotal = -$1,537

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Treatment Research	000	2	3/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $215,376 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Treatment Research	000	2	3/14/2024	NON-COMPETING CONTINUATION	$204,040
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Treatment Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$11,336
														Subtotal = $215,376

Issue Date FY: 2023 ( Subtotal = $202,921 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Cancer Treatment Research	000	1	4/13/2023	NEW	$202,921
														Subtotal = $202,921

Grand Total All Awards = $416,760

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Crosslinking-based targeted therapy for triple-negative breast cancer

Award Number: R21CA280458

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/13/2023

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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