Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids

使用 HER3 归巢纳米衣壳靶向抑制剂耐药性乳腺肿瘤

基本信息

批准号：
10367490
负责人：
LALI K MEDINA-KAUWE
金额：
$ 37.28万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-09 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367490
关键词：
Acute Address Adjuvant Therapy Antibodies Automobile Driving Benchmarking Binding Biological Markers Blood - brain barrier anatomy Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Bypass Capsid Carboplatin Cell Communication Cell Surface Receptors Cell surface Cells Clinic Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Diagnosis Down-Regulation EGF gene EGFR inhibition ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Estrogens Experimental Models Exposure to Growth Growth Factor Receptors HER2 inhibition Heart Homing Human Immune Immunocompetent Implant In Vitro Intervention Intracranial Neoplasms Invaded Lead Ligands Liver Mammary Neoplasms Mediating Membrane Metastatic malignant neoplasm to brain Modeling Molecular Mus Neoadjuvant Therapy Neoplasm Metastasis Patients Penetration Pertuzumab Phenotype Phosphotransferases Pre-Clinical Model Prevalence Primary Neoplasm Progesterone Receptors Prognosis Proteins Recurrence Refractory Reporting Resistance Route Serum Signal Transduction Site Structure Testing Therapeutic Tissues Toxic effect Trastuzumab Treatment Efficacy Treatment Protocols Tumor Escape Tumor Tissue Tyrosine Kinase Inhibitor Up-Regulation Viral chemotherapy density dimer docetaxel effective intervention improved individual response inhibitor lapatinib malignant breast neoplasm mouse model nano nanobiologic nanosized neoplastic cell particle pressure receptor receptor mediated endocytosis response targeted treatment therapeutic target trafficking triple-negative invasive breast carcinoma tumor tumor growth tumor heterogeneity tumor progression tumor xenograft

项目摘要

Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids Elevated cell surface levels of the human epidermal growth factor receptor subunit 3 (HER3) is associated with resistance to a number of signal-blocking breast cancer treatments, including inhibitors of EGF-R (lapatinib), HER2 (lapatinib, trastuzumab, T-DM1), HER2-3 (pertuzumab), and combination therapy. Additionally, HER3 elevation has been identified on “untarget-able” tumors such as triple-negative breast cancer (TNBC). Patients with such refractory tumors currently have limited treatment options and a poor prognosis. Moreover, as up to 70% of cases resist or acquire resistance to signal-blocking therapies, an alternative approach addressing this important clinical problem has the potential for significant clinical impact. We have developed a self-assembling nanobiological particle, HerDox, which uses HER3 as a portal for targeted entry of toxic molecules. In contrast to receptor-targeted antibodies and tyrosine kinase inhibitors currently used in the clinic, HerDox circumvents the need to modulate signaling and can induce rapid entry of toxic molecules into tumor cells by receptor- mediated endocytosis and membrane penetration. We have previously shown that HerDox can elicit targeted toxicity to trastuzumab-resistant HER2+ tumors due to the augmented levels of HER3 on these cells in association with resistance, while sparing heart and liver tissue. Whereas the prevalence of HER2-3 heterodimers on the HER2+ tumor cell surface can enable targeting by HerDox, naïve HER2+ tumors exposed to trastuzumab undergo acute shift to a HER3+ phenotype and acquire augmented sensitization to HerDox targeting and potency. EGFR inhibitors also have the same effect on both HER2+ and triple-negative breast tumors in experimental models. These findings suggest that neoadjuvant treatment of primary tumors with clinical inhibitors of HER2 or EGF-R can impart selective pressure on a heterogeneous tumor, driving expression of surviving cells to a HER3 augmented phenotype and thus cornering these resistant tumors for HerDox attack. This study will test this phenomenon in preclinical models of HER2+ and triple-negative tumors undergoing treatment with targeted therapies currently used in the clinic or in clinical trials that are aimed at HER2 and EGF- R, respectively. Our recent studies also show that HER3 is expressed on the blood-brain barrier (BBB) and can facilitate passage of systemic HerDox across the BBB and into brain-localized HER3+ TNBC tumors. The brain is a predominant site of metastasis for both TNBC and resistant HER2+ breast tumors, but most targeted therapies that are effective extracranially lack significant impact on intracranial tumors and thus brain metastases remain a significant clinical problem. Both HER2+ and TNBC tumors that escape intervention and metastasize to the brain express high levels of HER3. Therefore, we will also evaluate the therapeutic efficacy of HerDox on HER2+ and TNBC tumors localized in the brain as models of post brain-metastatic resistant breast cancer, for which there is currently no targeted treatment or effective intervention.

用Her3-Homing Nano-Capsids靶向抗抑制剂的乳腺肿瘤人表皮生长因子受体亚基3（HER3）的细胞表面水平升高是相关的具有对许多信号阻塞乳腺癌治疗的抗性，包括EGF-R（Lapatinib）的抑制剂， HER2（Lapatinib，Trastuzumab，T-DM1），HER2-3（Pertuzumab）和组合疗法。此外，Her3 在“不可靶”肿瘤（例如三阴性乳腺癌（TNBC））上已经确定了升高。患者由于这种难治性肿瘤目前的治疗选择有限，预后不良。而且， 70％的病例抵抗或获得对信号阻滞疗法的抵抗力，这是一种解决此问题的替代方法重要的临床问题可能会产生重大临床影响。我们已经开发了一个自我组装纳米生物学粒子，Herdox，它使用HER3作为有毒分子靶向进入的门户。相比之下对于目前在诊所中使用的受体靶向抗体和酪氨酸激酶抑制剂，Herdox绕过需要调节信号传导，并可以通过受体诱导毒性分子快速进入肿瘤细胞介导的内吞作用和膜渗透。我们以前已经表明，Herdox可以引起针对性的由于这些细胞上的HER3水平增加，对曲妥珠单抗耐药的HER2+肿瘤的毒性与阻力相关，同时保留心脏和肝组织。而HER2-3的患病率 HER2+肿瘤细胞表面上的异二聚体可以通过暴露于Herdox，幼稚的HER2+肿瘤的靶向靶向曲妥珠单抗会急性转移到Her3+表型，并获得对Herdox的增强敏感性定位和效力。 eGFR抑制剂也对HER2+和三阴性乳房具有相同的作用实验模型中的肿瘤。这些发现表明，新辅助治疗原发性肿瘤 HER2或EGF-R的抑制剂可以在异质肿瘤上施加选择性压力，驱动表达将细胞存活到HER3增强表型，从而将这些抗性肿瘤转化为Herdox攻击。这项研究将在HER2+和三阴性肿瘤的临床前模型中测试这种现象目前在诊所或针对HER2和EGF-的临床试验中使用的有针对性疗法的治疗 R，分别。我们最近的研究还表明，HER3在血脑屏障（BBB）上表达，可以促进系统性Herdox穿越BBB并进入脑部重新定位的HER3+ TNBC肿瘤。大脑是TNBC和抗性HER2+乳腺肿瘤的主要转移部位，但最针对性的有效颅外的疗法对颅内肿瘤和脑转移缺乏显着影响仍然是一个重大的临床问题。逃避干预和转移的HER2+和TNBC肿瘤大脑表达高水平的HER3。因此，我们还将评估Herdox的治疗效率 HER2+和TNBC肿瘤本地位于大脑中，作为大脑后抗性乳腺癌的模型，用于目前尚无目标治疗或有效干预。