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：
10619565
负责人：
LALI K MEDINA-KAUWE
金额：
$ 37.44万
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/10619565
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 Survival Cell surface Cells Cephalic Clinic Clinical Clinical Treatment Clinical Trials Clonal Expansion Combined Modality Therapy Diagnosis Dimerization Down-Regulation EGF gene EGFR inhibition ERBB2 gene Endosomes 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 Immune Evasion Immunocompetent Implant In Vitro Intervention Intracranial Neoplasms Ligands Liver Mammary Neoplasms Mediating Membrane Metastatic malignant neoplasm to brain Modeling Molecular Mus Nanostructures 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 Testing Therapeutic Tissues Toxic effect Trastuzumab Treatment Efficacy Treatment Protocols Tumor Cell Invasion Tumor Escape Tumor Tissue Tyrosine Kinase Inhibitor Up-Regulation Viral blood-brain barrier crossing chemotherapy density docetaxel effective intervention human model human tissue improved individual response inhibitor lapatinib malignant breast neoplasm mouse model nano nanobiologic neoplastic cell particle pressure receptor receptor mediated endocytosis response self assembly 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.

使用 HER3 归巢纳米衣壳靶向抑制剂耐药性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与对多种信号阻断乳腺癌治疗方法具有耐药性，包括 EGF-R 抑制剂（拉帕替尼）， HER2（拉帕替尼、曲妥珠单抗、T-DM1）、HER2-3（帕妥珠单抗）以及联合疗法 HER3。已在“不可靶向”肿瘤（例如三阴性乳腺癌（TNBC））中发现了升高。目前，此类难治性肿瘤的治疗选择有限且预后不良。 70% 的病例对信号阻断疗法产生耐药性或产生耐药性，这是解决这一问题的另一种方法重要的临床问题具有重大临床影响的潜力我们开发了一种自组装方法。相比之下，纳米生物颗粒 HerDox 使用 HER3 作为有毒分子靶向进入的门户。针对目前临床上使用的受体靶向抗体和酪氨酸激酶抑制剂，HerDox 进行了规避调节信号传导的需要，并可以通过受体诱导有毒分子快速进入肿瘤细胞我们之前已经证明 HerDox 可以引发靶向作用。由于这些细胞上 HER3 水平的增加，对曲妥珠单抗耐药 HER2+ 肿瘤产生毒性与抵抗力相关，同时保护心脏和肝脏组织。 HER2+ 肿瘤细胞表面上的异二聚体可以实现 HerDox 的靶向，暴露幼稚的 HER2+ 肿瘤曲妥珠单抗经历急性转变为 HER3+ 表型并获得对 HerDox 的增强敏感性 EGFR 抑制剂对 HER2+ 和三阴性乳腺癌也具有相同的效果。这些发现表明原发性肿瘤的新辅助治疗具有临床意义。 HER2 或 EGF-R 抑制剂可以对异质肿瘤施加选择性压力，驱动存活细胞具有 HER3 增强表型，从而将这些耐药肿瘤逼入 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一现象。目前在临床或临床试验中使用的针对 HER2 和 EGF 的靶向疗法的治疗我们最近的研究也分别表明，HER3在血脑屏障（BBB）上表达并且可以促进全身性 HerDox 穿过 BBB 并进入大脑局部 HER3+ TNBC 肿瘤。是 TNBC 和耐药 HER2+ 乳腺肿瘤的主要转移部位，但最具针对性颅外有效的疗法对颅内肿瘤和脑转移缺乏显着影响 HER2+ 和 TNBC 肿瘤逃避干预和转移仍然是一个重要的临床问题。因此，我们还将评估 HerDox 对大脑表达高水平的 HER3 的治疗效果。 HER2+ 和 TNBC 肿瘤定位于大脑，作为脑转移后耐药乳腺癌的模型，用于目前尚无针对性的治疗或有效的干预措施。