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

用HER 3归巢纳米衣壳靶向耐药乳腺肿瘤 人表皮生长因子受体亚单位3（HER 3）的细胞表面水平升高与 对许多信号阻断乳腺癌治疗，包括EGF-R抑制剂（拉帕替尼）， HER 2（拉帕替尼、曲妥珠单抗、T-DM 1）、HER 2 -3（帕妥珠单抗）和联合治疗。此外，HER 3 在“非靶向”肿瘤如三阴性乳腺癌（TNBC）上已经鉴定出升高。患者 这种难治性肿瘤目前具有有限的治疗选择和不良的预后。此外，截至 70%的病例对信号阻断疗法产生抵抗或获得抵抗，这是解决这一问题的替代方法。 重要的临床问题可能会产生重大的临床影响。我们开发了一种自我组装的 纳米生物颗粒HerDox，其使用HER 3作为毒性分子靶向进入的门户。相比之下 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规避了 调节信号传导的需要，并可诱导毒性分子通过受体- 介导的内吞作用和膜渗透。我们之前已经证明HerDox可以引起靶向的 对曲妥珠单抗耐药HER 2+肿瘤的毒性，因为这些细胞上的HER 3水平增加， 与抵抗力相关，同时保留心脏和肝脏组织。而HER 2 -3的患病率 HER 2+肿瘤细胞表面上的异二聚体可以使HerDox靶向，暴露的幼稚HER 2+肿瘤 曲妥珠单抗急性转变为HER 3+表型，并获得对HerDox增强的致敏性 针对性和效力。EGFR抑制剂对HER 2+和三阴性乳腺癌也有相同的作用。 肿瘤实验模型这些发现表明，原发性肿瘤的新辅助治疗与临床 HER 2或EGF-R的抑制剂可以对异质性肿瘤施加选择性压力， 存活的细胞转化为HER 3增强的表型，从而使这些耐药肿瘤陷入HerDox攻击。 本研究将在HER 2+和三阴性肿瘤的临床前模型中测试这种现象， 目前在临床或针对HER 2和EGF的临床试验中使用的靶向疗法治疗- R，分别。我们最近的研究还表明，HER 3在血脑屏障（BBB）上表达， 促进全身性HerDox穿过BBB并进入脑定位的HER 3 + TNBC肿瘤。大脑 是TNBC和耐药HER 2+乳腺肿瘤转移的主要部位，但最靶向的是 有效的颅外治疗对颅内肿瘤和脑转移缺乏显著影响 仍然是一个重要的临床问题。逃避干预和转移的HER 2+和TNBC肿瘤 表达高水平的HER 3。因此，我们还将评估HerDox在以下方面的治疗效果： HER 2+和TNBC肿瘤定位于脑中作为脑转移后耐药乳腺癌的模型， 目前还没有针对性的治疗或有效的干预。

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.