Protein-DNA Drug Carriers for Targeting Drug-Resistant Tumors

 描述(申请人提供)：人表皮生长因子受体亚单位3(HER3)的细胞表面水平升高与对许多信号阻断乳腺癌治疗方法的耐药性有关，包括EGF-R(拉帕替尼)、HER2(拉帕替尼、曲妥珠单抗、T-DM1)、HER2-3(Pertuzumab)和联合治疗的抑制剂。此外，HER3的上调也被发现存在于“不能靶向的”肿瘤中，例如三阴性乳腺癌(TNBC)，包括对EGF-R抑制产生获得性耐药的TNBC。目前，患有这种难治性肿瘤的患者治疗选择有限，预后也很差。此外，由于多达70%的病例抵抗或对信号阻断疗法产生耐药性，解决这一重要临床问题的替代方法具有重大临床影响的潜力。我们已经开发出一种自组装的纳米生物粒子Herdox，它使用HER3作为靶向进入有毒分子的门户。与目前临床使用的受体靶向抗体和酪氨酸激酶抑制剂不同，Herdox避开了调节信号的需要，并可以通过受体介导的内吞和膜穿透诱导有毒分子快速进入肿瘤细胞。我们之前已经证明，由于HER2-3异源二聚体在肿瘤细胞表面的普遍存在，HerDox可以对HER2+肿瘤产生靶向毒性，同时保留心脏和肝脏组织。我们目前正在探索HerDox针对抵抗HER2抑制剂的肿瘤的靶向毒性的能力。我们的初步研究表明，HerDox在对HER2抑制剂获得性耐药的肿瘤细胞株上表现出比亲本肿瘤细胞更好的治疗效果，部分原因是与HER2+耐药性相关的HER3表达增加。在这里，我们将评估HerDox在几个体外和体内模型中的机制和疗效，这些模型代表了不同的耐药谱。我们将探索导致HerDox对获得性耐药肿瘤高效的其他因素，因为这些细胞显示出适度高水平的HER3。我们将评估使用信号抑制剂作为HerDox治疗初治和内在耐药肿瘤的辅助药物的有效性，因为初步发现，在体外用曲妥珠玛预处理亲本乳腺癌细胞株会诱导HER3的升高。我们还将评估HerDox在免疫激活的播散性乳腺癌模型中对TNBC的疗效，并评估EGF-R抑制是否通过HER3上调进一步增加这些肿瘤对HerDox的敏感性。在这项研究的所有目标中，HerDox将与曲妥珠单抗、拉帕替尼、pertuzumab、T-DM1和联合治疗进行比较。在我们的初步研究中看到的相对于信号阻断抑制剂的优势表明，HerDox可能会提供一种有效的方法来解决抵抗目前临床使用的靶向治疗的肿瘤。

 DESCRIPTION (provided by applicant): 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), including TNBC with acquired resistance to EGF-R inhibition. 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 HER2+ tumors due to the prevalence of HER2-3 heterodimers on the tumor cell surface, while sparing heart and liver tissue. We are currently exploring the capacity for HerDox to target toxicity to tumors that resist HER2 inhibitors. Our preliminary studies show that HerDox exhibits improved therapeutic efficacy on tumor cell lines with acquired resistance to HER2 inhibitors over parental tumor cells, due in part to the elevated HER3 expression associated with the HER2+ drug resistance. Here we will evaluate the mechanism and efficacy of HerDox in several in vitro and in vivo models representing distinct scenarios along the spectrum of resistance. We will probe the additional factors contributing to the high efficacy of HerDox on tumors with acquired resistance, as these cells exhibit moderately elevated levels of HER3. We will evaluate the efficacy of using signal-inhibitors as adjuvants for HerDox treatment on both naïve and inherently-resistant tumors, given the preliminary finding that pretreatment of parental breast cancer cell lines in vitro with trastuzuma induced elevation of HER3. We will also evaluate the efficacy of HerDox on TNBC in an immunocompetent model of disseminated breast cancer and assess whether EGF-R inhibition further sensitizes these tumors to HerDox via HER3 elevation. In all aims of this study, HerDox will be evaluated in comparison to trastuzumab, lapatinib, pertuzumab, T-DM1, and combination treatments. The advantages over signal-blocking inhibitors seen in our preliminary studies suggest that HerDox is likely to present an effective approach in addressing tumors that resist current targeted treatments used in the clinic.