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：
10553132
负责人：
KIT S LAM
金额：
$ 56.02万
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/10553132
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.

抽象的人表皮生长因子受体 2 (HER2) 在超过 20% 的乳腺癌中过度表达，并且在胃癌、结直肠癌、卵巢癌和膀胱癌中，作用程度较小。在肿瘤中，HER2 大量过度表达并组成型二聚化，导致无情的下游增殖和生存途径的激活以及恶性表型。 HER2、曲妥珠单抗和帕妥珠单抗（两种抗 HER2 单克隆抗体）的高表达水平单一疗法对这些肿瘤无效，需要与其他疗法联合使用。 HER2靶向治疗、化疗或者激素治疗我们会在这里进行优化和进一步完善。一种新型 HER2 介导的、基于肽的、无毒的可转化纳米制剂，已被证明作为针对 HER2+ 乳腺癌异种移植模型的单一疗法非常有效。介导的可转化纳米疗法由具有独特结构域的肽组成，该结构域允许自我在水性条件下组装形成胶束并在肿瘤部位转化为纳米原纤维，遇到 HER2 时产生的纳米纤丝网络可有效抑制 HER2。二聚化和下游信号传导导致肿瘤细胞死亡增加和完全缓解异种移植模型中的 HER2+ 肿瘤。我们最近报道了 ICG 衍生纳米平台的开发，该平台可以提供有效的将免疫刺激剂咪喹莫特注射到 4T1 同基因乳腺癌模型的肿瘤部位，我们能够证明在肿瘤的局部光照射（800nm）下，光活性胶束纳米平台能够引发强烈的全身抗肿瘤免疫反应，特别是当给予与抗 PD1 抗体结合使用，除了有效的远隔效应外，这种纳米光免疫 - 该治疗方案能够引发针对未来肿瘤植入的强烈免疫记忆。对于这个 R01-IRCN 提案，我们将应用上述两个方案的一些有前途的功能纳米平台，生成新型 HER2 靶向可转化癌症靶向纳米平台 (TCTN) 不仅可以直接抑制 HER2 二聚化和导致肿瘤细胞死亡的信号传导，而且可以也极大地增强了全身抗肿瘤免疫反应为了实现这一目标，我们将模块化。将 HER2 结合配体、T 细胞和巨噬细胞捕获纳入可转化纳米平台药物（例如 LLP2A 靶向免疫细胞的激活 α4β1 整合素）、galectin-1 抑制剂（例如 LLS30）和免疫刺激剂（例如瑞喹莫特）。具体目标：目标 1. 设计、合成和表征新型可转化 HER2 靶向 TCTN 纳米平台。目标 2. 使用光学和 MR 成像方法确定 TCTN 构建体的生物分布在异种移植、PDX 和同基因肿瘤模型中使用内部开发的新型 EyePod 活体肿瘤模型。成像系统实时纵向评估肿瘤内分布和原位 TCTN的转化、细胞免疫反应和视网膜下肿瘤植入物的肿瘤反应。目的 3. 评估 TCTN 在乳腺癌和胃癌 HER2+ PDX 模型中的治疗效果。目标 4. 评估 TCTN 在免疫活性小鼠同系小鼠中的免疫治疗效果由植入的HuHER2-L2-Luc+鼠乳腺癌细胞系组成的乳腺癌模型在 MMTV.f.HuHER2 转基因小鼠中进行原位移植。