Protein-DNA Drug Carriers for Targeting Drug-Resistant Tumors

 描述（由申请方提供）：人表皮生长因子受体亚基3（HER 3）的细胞表面水平升高与对多种信号阻断乳腺癌治疗的耐药性相关，包括EGF-R（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）抑制剂和联合治疗。此外，已经在“不可靶向”肿瘤如三阴性乳腺癌（TNBC）（包括对EGF-R抑制具有获得性抗性的TNBC）上鉴定出HER 3升高。患有这种难治性肿瘤的患者目前的治疗选择有限，预后不良。此外，由于高达70%的病例对信号阻断疗法产生抵抗或获得抵抗，因此解决这一重要临床问题的替代方法具有显著临床影响的潜力。 我们开发了一种自组装纳米生物颗粒HerDox，它使用HER 3作为有毒分子靶向进入的门户。与目前临床上使用的受体靶向抗体和酪氨酸激酶抑制剂相比，HerDox避免了调节信号传导的需要，并且可以通过受体介导的内吞作用和膜渗透诱导毒性分子快速进入肿瘤细胞。我们之前已经表明，HerDox可以引起靶向毒性HER 2+肿瘤由于HER 2 -3异二聚体的肿瘤细胞表面上的流行，同时保留心脏和肝脏组织。 我们目前正在探索HerDox靶向毒性的能力，以抵抗HER 2抑制剂的肿瘤。我们的初步研究表明，HerDox对具有对HER 2抑制剂的获得性耐药性的肿瘤细胞系的治疗效果优于亲本肿瘤细胞，部分原因是与HER 2+耐药性相关的HER 3表达升高。在这里，我们将评估HerDox在几种体外和体内模型中的机制和疗效，这些模型代表了沿着耐药谱的不同情况。我们将探索导致HerDox对获得性耐药肿瘤的高疗效的其他因素，因为这些细胞表现出适度升高的HER 3水平。我们将评估使用信号抑制剂作为HerDox治疗初治和固有耐药肿瘤的佐剂的疗效，初步发现体外用曲妥珠单抗预处理亲代乳腺癌细胞系可诱导HER 3升高。我们还将在播散性乳腺癌的免疫活性模型中评估HerDox对TNBC的疗效，并评估EGF-R抑制是否通过HER 3升高进一步使这些肿瘤对HerDox敏感。在本研究的所有目的中，将评价HerDox与曲妥珠单抗、拉帕替尼、帕妥珠单抗、T-DM 1和联合治疗的比较。 在我们的初步研究中看到的信号阻断抑制剂的优势表明，HerDox可能是一种有效的方法，可以解决抵抗临床上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.