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HER2-targeting transformable nanotherapeutic platform against HER2+ cancers

针对 HER2 癌症的可转化纳米治疗平台

基本信息

批准号：
10737741
负责人：
KIT S LAM
金额：
$ 11.35万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737741
关键词：
4T1 Abscopal effect Biodistribution Blood Tests Body Weight decreased Breast Cancer Model Breast Cancer cell line Cell Death Cells Colorectal Cancer Derivation procedure Development Dimerization Disease remission Dose Epidermal Growth Factor Receptor Esters Future Galectin 1 Hispanic Homing Human Imiquimod Immune Immune response Immunocompetent Immunologic Adjuvants Immunologic Stimulation Immunotherapeutic agent Implant In Situ Integrin alpha4beta1 Integrins Ligand Binding Ligands Light Lighting Macrophage Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of urinary bladder Mediating Memory Micelles Modeling Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Nanodelivery Pathway interactions Patient-derived xenograft models of breast cancer Patients Peptides Permeability Pertuzumab Phototherapy Porphyrins Positron-Emission Tomography Proliferating Regimen Reporting Signal Transduction Site T-Lymphocyte Therapeutic Studies Time Transgenic Mice Trastuzumab Treatment Efficacy Xenograft Model Xenograft procedure anti-PD1 antibodies anti-cancer anti-tumor immune response aqueous cancer type chelation chemotherapy design esterase hormone therapy imaging modality imaging system immune stimulatory agent improved in vivo monitoring inhibitor innovation intravital imaging malignant breast neoplasm malignant phenotype malignant stomach neoplasm nano nanofibrillar nanotechnology platform nanotherapeutic nanotherapy neoplastic cell novel optical imaging overexpression patient derived xenograft model receptor resiquimod response self assembly side effect targeted treatment translational potential tumor

项目摘要

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.

摘要