Corrole nanobiologics for targeting resistant and metastatic tumors

 描述：目前临床上使用的大多数肿瘤靶向治疗方法都是由抗体或小分子抑制剂组成，目的是阻断生长信号。然而，信号阻断疗法在大多数情况下都是无效的，因为面对靶向治疗时维持信号的机制，突出了不依赖信号调制的替代策略的必要性。在我们之前资助的项目中，我们 通过使用肿瘤细胞表面生物标记物作为靶向进入Corole分子的门户，开发的自组装蛋白-Corole结构绕过了调节信号的需要。磺化腐蚀剂是一种水溶性的大环化合物，可以金属化，与蛋白质自发组装，具有细胞毒性，并具有各种成像和诊断用的光物理性质。我们已经证明，磺化腐蚀剂是不透膜的，但需要进入细胞质以引起细胞毒性，同时保持排除在细胞核之外。我们的靶向细胞穿透蛋白HerPBK10通过与人表皮生长因子受体亚单位-2阳性(HER2+)肿瘤细胞上特异表达的HER2二聚化伙伴HER3相互作用，使Corole能够摄取这些细胞。受体结合触发迅速的内吞作用，随后通过HerPBK10上的膜裂解结构域逃逸，使corole进入细胞质。由HerPBK10和金属化镓(S2Ga或Ga-Corole)组装形成的肿瘤导向纳米颗粒HerGa，与传统化疗相比，可以靶向和消融HER2+肿瘤，剂量比传统化疗低10倍，同时节省心脏和肝脏组织，并且没有检测到免疫原性。近年来的研究发现，细胞表面HER3水平的升高与许多信号阻断乳腺癌治疗方法的耐药有关，包括EGF-R或HER1(拉帕替尼)、HER2(拉帕替尼、曲妥珠单抗、T-DM1)的抑制剂、HER2-3(Pertuzumab)和联合治疗。此外，在转移性乳腺肿瘤，包括那些扩散到大脑的肿瘤，以及诸如三阴性乳腺癌(TNBC)等“不能靶向”的肿瘤上，已经发现HER3的上调，包括对EGF-R抑制具有获得性耐药性的TNBC。HerPBK10的HER3特异性表明，抵抗这些信号阻断治疗的肿瘤细胞是HerPBK10导向的纳米生物的主要靶点。目前的研究将在耐药和转移性乳腺癌的模型上探索这一点，特别是那些转移到大脑的乳腺癌。将评估一种使用EGFR和HER2抑制剂作为佐剂以使肿瘤对科罗尔纳米生物增敏的方案。由于转移性乳腺癌患者的中位生存期为3年，而乳腺癌脑转移患者的平均生存期不到一年，因此迫切需要改进的替代方案。

 DESCRIPTION: The majority of tumor-targeted therapies currently used in the clinic are comprised of antibodies or small molecule inhibitors aimed at blocking growth signaling. However, signal-blocking therapies have been ineffective in a majority of cases due to mechanisms that sustain signaling in the face of targeted treatment, highlighting a need for alternative strategies that do not rely on signal-modulation. In our previously funded project, we developed self-assembling protein-corrole constructs that circumvent the need to modulate signaling by using tumor cell surface biomarkers as portals for the targeted entry of corrole molecules. Sulfonated corroles are water soluble, macrocyclic compounds that may be metallated, spontaneously assemble with proteins, and can be cytotoxic as well as bear various photophysical properties for both imaging and diagnostics. We have shown that sulfonated corroles are membrane-impermeable yet require cytoplasmic entry to elicit cytotoxicity while remaining excluded from the nucleus. Our targeted cell penetration protein, HerPBK10, enables corrole uptake into human epidermal growth factor receptor subunit- 2 positive (HER2+) tumors via specific interaction with the HER2 dimerization partner, HER3, which is particularly represented on these cells. Receptor-binding triggers rapid endocytosis followed by endosomal escape via a membrane-lytic domain on HerPBK10, enabling corrole entry into the cytoplasm. The tumor- homing nanoparticle, HerGa, formed by assembly of HerPBK10 and a gallium metallated corrole (S2Ga or Ga- corrole), can target and ablate HER2+ tumors in mice at >10x lower dose compared to conventional chemotherapy while sparing heart and liver tissue, and with no detectable immunogenicity. Studies in recent years have now discovered that elevated cell surface levels of HER3 is associated with resistance to a number of signal-blocking breast cancer treatments, including inhibitors of EGF-R or HER1 (lapatinib), HER2 (lapatinib, trastuzumab, T-DM1), HER2-3 (pertuzumab), and combination therapy. Moreover, HER3 elevation has been identified on metastatic breast tumors, including those that spread to the brain, and on "untarget-able" tumors such as triple-negative breast cancer (TNBC), including TNBC with acquired resistance to EGF-R inhibition. The HER3 specificity of HerPBK10 predicts that tumor cells resisting these signal-blocking treatments are prime targets for HerPBK10-directed nanobiologics. The present study will explore this on models of resistant and metastatic breast cancer, especially those that metastasize to the brain. A regimen of using EGFR and HER2 inhibitors as adjuvants to sensitize tumors to corrole nanobiologics will be evaluated. As the median survival of patients with metastatic breast cancer is 3 years, and patients with breast cancer metastases to the brain on average survive less than one year, improved alternatives are urgently needed.