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HER2-targeting transformable nanotherapeutic platform against HER2+ cancers

Award Number: R01CA247685
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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HER2-targeting transformable nanotherapeutic platform against HER2+ cancers - Abstract Human epidermal growth factor receptor 2 (HER2) is overexpressed in over 20% breast cancers, and to a lesser degree in gastric cancers, colorectal cancer, ovarian cancers and bladder cancers. In HER2+ tumors, HER2s are massively overexpressed and constitutively dimerized, leading to unrelenting activation of down-stream proliferation and survival pathways and malignant phenotype. Because of the high expression level of HER2, trastuzumab and pertuzumab, the two anti-HER2 monoclonal antibodies are ineffective as monotherapy against these tumors. They need to be given in combinations with other HER2-targeted therapy, chemotherapy or hormonal therapy. Here we will optimize and further improve a novel HER2-mediated, peptide-based, and non-toxic transformable nano-agent that has been proven to be highly efficacious as a monotherapy against HER2+ breast cancer xenograft models. This receptor- mediated transformable nanotherapy is comprised of a peptide with unique domains that allow self- assembly forming micelles under aqueous conditions and transformation into nanofibrils at the tumor site, where HER2 is encountered. The resulting nanofibrillar network effectively suppresses HER2 dimerization, and downstream signaling leading to increased tumor cell death and complete remission of the HER2+ tumors in xenograft models. We recently reported the development of an ICG-derivatized nanoplatform that can deliver potent immuno-stimulant imiquimod to the tumor sites in a 4T1 syngeneic breast cancer model, and we were able to demonstrate that upon local light illumination (800nm) of the tumor, the photo-active micellar nanoplatform was able to elicit a strong systemic anti-tumor immune response, particularly when given in conjunction with anti-PD1 antibody. In addition to potent abscopal effects, this nano-photo-immuno- therapeutic regimen was able to elicit strong immuno-memory against future tumor implants. For this R01-IRCN proposal, we will apply some of the promising features of the two above mentioned nanoplatforms, to generate a novel HER2-targeting transformable cancer targeting nanoplatform (TCTN) that not only can directly suppress HER2 dimerization and signaling leading to tumor cell death, but can also greatly augment systemic anti-tumor immune response. To achieve this, we will modularly incorporate to the transformable nanoplatform HER2 binding ligands, T-cell and macrophage capturing agents (e.g. LLP2A targets activated α4β1 integrin of immune cells), galectin-1 inhibitor (e.g. LLS30) and immunostimulant (e.g. resiquimod). Specific Aims: Aim 1. To design, synthesize, & characterize the novel transformable HER2-targeting TCTN nanoplatform. Aim 2. To use optical and MR imaging methods to determine the biodistribution of the TCTN constructs in xenograft, PDX and syngeneic tumor models. To use the novel in-house developed EyePod intravital imaging system to longitudinally evaluate, in real time, the intra-tumoral distribution and in situ transformation of TCTN, cellular immune response, and tumor response of sub-retinal tumor implant. Aim 3. To evaluate the therapeutic efficacy of TCTN in HER2+ PDX models of breast and gastric cancers. Aim 4. To evaluate the immunotherapeutic efficacy of TCTN in an immunocompetent murine syngeneic breast cancer model comprised of HuHER2-L2-Luc+ murine breast cancer cell lines implanted orthotopically in MMTV.f.HuHER2 transgenic mice.


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: 2024 ( Subtotal = $540,560 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	001	5	4/18/2024	NON-COMPETING CONTINUATION	$28,452
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	5	1/5/2024	NON-COMPETING CONTINUATION	$512,108
														Subtotal = $540,560

Issue Date FY: 2023 ( Subtotal = $673,636 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	001	4	3/22/2023	SUPPLEMENT FOR EXPANSION	$113,453
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	4	3/22/2023	NON-COMPETING CONTINUATION	$560,183
														Subtotal = $673,636

Issue Date FY: 2022 ( Subtotal = $676,191 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	001	3	1/21/2022	SUPPLEMENT FOR EXPANSION	$104,191
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	3	1/20/2022	NON-COMPETING CONTINUATION	$516,799
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	003	3	5/4/2022	SUPPLEMENT FOR EXPANSION	$9,263
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	002	3	5/3/2022	NON-COMPETING CONTINUATION	$45,938
														Subtotal = $676,191

Issue Date FY: 2021 ( Subtotal = $643,553 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	2	2/10/2021	NON-COMPETING CONTINUATION	$572,096
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	001	2	9/17/2021	SUPPLEMENT FOR EXPANSION	$71,457
														Subtotal = $643,553

Issue Date FY: 2020 ( Subtotal = $573,341 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Detection and Diagnosis Research	000	1	2/11/2020	NEW	$573,341
														Subtotal = $573,341

Grand Total All Awards = $3,107,281

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HER2-targeting transformable nanotherapeutic platform against HER2+ cancers

Award Number: R01CA247685

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/11/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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