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Multifunctional siRNA/antibody nanocarriers to treat metastatic triple-negative breast cancer

Award Number: R01CA211925
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/07/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Multifunctional siRNA/antibody nanocarriers to treat metastatic triple-negative breast cancer - PROJECT SUMMARY/ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive disease that grows quickly and metastasizes early. There are no effective therapies for metastatic TNBC, so new strategies are needed. We will meet this need using nanoparticles (NPs) we developed that interfere with Wnt signaling, the key driving force behind TNBC growth and metastasis. The main effector of Wnt signaling is β-catenin, and it is activated in TNBC cells when wnt ligands bind frizzled7 (FZD7) receptors that are overexpressed on TNBC cells relative to normal cells. Active β-catenin promotes TNBC growth and metastasis by amplifying the expression of genes that support cell survival, proliferation, stem-like behavior, migration, and invasion. Our central hypothesis is that suppressing Wnt signaling at two levels will reduce TNBC cells’ metastatic potential, so we have created Wnt inhibitory NPs coated with both FZD7 antibodies and β-catenin small interfering RNAs (siRNAs) to accomplish this task. The FZD7 antibodies enable TNBC cell binding and prevent Wnt signaling from being activated by blocking wnt ligands from binding FZD7. The siRNAs further suppress Wnt signaling by directly inhibiting β- catenin through RNA interference. Our preliminary studies indicate that these NPs can enter existing TNBC lung metastases in mouse models to inhibit their growth. In the proposed work we will elucidate the mechanism of action of these NPs in greater detail by studying their interaction with TNBC cells in vitro (Aim 1), validate that they can penetrate existing metastases in mice to halt their growth (Aim 2), and show that they can safely prevent the formation of new metastases in immune competent tumor-bearing mice (Aim 3). All aims will compare NPs that co-deliver FZD7 antibodies and β-catenin siRNAs to NPs that deliver either agent individually in order to reveal if their combined effects are additive or synergistic. In addition to studying the NPs’ impact on TNBC cells, we will also evaluate their effect on non-cancerous cells from breast, lung, and bone tissue in order to confirm they have negligible off-target effects. We will further study their safety in Aim 3 by monitoring animal weight, blood chemistry, and major organ histopathology. We expect to find that these NPs can inhibit Wnt signaling in TNBC cells to reduce their metastatic potential without impacting non- cancerous cells, enabling them to be used as tools to either treat existing metastases or prevent formation of new metastases. We also expect for NPs that co-deliver FZD7 antibodies and β-catenin siRNAs to be more effective than NPs that deliver either agent individually. In summary, this project will evaluate Wnt inhibitory NPs as tools to treat and/or prevent TNBC metastasis. Unlike current therapies, which have unpredictable and insufficient results, our NPs will directly target TNBC cells and reduce their ability to grow and metastasize by suppressing Wnt signaling. If successful, this therapy will improve survival and quality of life for patients with metastatic TNBC, and it may ultimately be expanded to other cancers with different molecular drivers by altering the antibodies and siRNAs that are delivered with the NPs.


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 = -$1,360 )
2026	2023	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Cancer Treatment Research	000	5	11/20/2025	NON-COMPETING CONTINUATION	-$1,360
														Subtotal = -$1,360

Issue Date FY: 2023 ( Subtotal = $342,055 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cancer Treatment Research	000	5	5/9/2023	NON-COMPETING CONTINUATION	$342,055
														Subtotal = $342,055

Issue Date FY: 2022 ( Subtotal = $342,278 )
2022	2022	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cancer Treatment Research	000	4	7/25/2022	NON-COMPETING CONTINUATION	$342,278
														Subtotal = $342,278

Issue Date FY: 2021 ( Subtotal = $349,485 )
2021	2021	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cancer Treatment Research	000	3	5/28/2021	NON-COMPETING CONTINUATION	$349,485
														Subtotal = $349,485

Issue Date FY: 2020 ( Subtotal = $349,699 )
2020	2020	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cancer Treatment Research	000	2	5/20/2020	NON-COMPETING CONTINUATION	$349,699
														Subtotal = $349,699

Issue Date FY: 2019 ( Subtotal = $349,907 )
2019	2019	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cancer Treatment Research	000	1	6/7/2019	NEW	$349,907
														Subtotal = $349,907

Grand Total All Awards = $1,732,064

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Multifunctional siRNA/antibody nanocarriers to treat metastatic triple-negative breast cancer

Award Number: R01CA211925

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/07/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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