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

定位于HER3的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(HER3)细胞表面水平升高与 由于对包括EGF-R(拉帕替尼)抑制剂在内的多种信号阻断乳腺癌治疗方法耐药， HER2(拉帕替尼、曲妥珠单抗、T-DM1)、HER2-3(Pertuzumab)和联合治疗。此外，HER3 三阴性乳腺癌(TNBC)等“不能靶向”肿瘤的升高已被确定。病人 对于这种难治性肿瘤，目前的治疗选择有限，预后也很差。此外，由于高达 70%的病例抵抗或获得对信号阻断疗法的抵抗力，这是解决这一问题的替代方法 重要的临床问题有可能产生重大的临床影响。我们已经开发出一种自组装的 纳米生物粒子HerDox，它使用HER3作为定向进入有毒分子的门户。相比之下， 对于目前临床上使用的受体靶向抗体和酪氨酸激酶抑制剂，Herdox绕过了 需要调节信号，并可以通过受体诱导有毒分子快速进入肿瘤细胞- 介导的内吞作用和膜穿透作用。我们之前已经证明HerDox可以诱导靶向 HER3对曲妥珠单抗耐药HER2+肿瘤细胞的毒性作用 与抵抗力相关，同时保留心脏和肝脏组织。鉴于HER2-3的流行 HER2+肿瘤细胞表面的异源二聚体可使Herdox、未暴露的HER2+肿瘤靶向 曲妥珠单抗急性转变为HER3+表型并获得对HerDox的增敏作用 目标和效力。EGFR抑制剂对HER2+和三阴性乳房也有相同的效果 实验模型中的肿瘤。这些发现表明，新辅助治疗原发性肿瘤具有临床意义。 HER2或EGF-R的抑制剂可以对异质肿瘤施加选择性压力，推动 存活的细胞转变为HER3增强表型，从而使这些耐药肿瘤转向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。 目前在临床或针对HER2和EGF的临床试验中使用的靶向治疗- R，分别为。我们最近的研究还表明，HER3表达在血脑屏障(BBB)上，并且可以 促进全身性Herdox穿过血脑屏障，进入大脑局部的HER3+TNBC肿瘤。大脑 是TNBC和耐药HER2+乳腺肿瘤的主要转移部位，但最具靶向性 颅外有效的治疗方法对颅内肿瘤和脑转移没有显著影响。 仍然是一个重大的临床问题。逃脱介入和转移的HER2+和TNBC肿瘤 向大脑表达高水平的HER3。因此，我们还将评估Herdox对 HER2+和TNBC肿瘤定位于脑内，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措施。

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.