Corrole nanobiologics for targeting resistant and metastatic tumors

 产品说明：目前临床上使用的大多数肿瘤靶向疗法由旨在阻断生长信号传导的抗体或小分子抑制剂组成。然而，由于在靶向治疗中维持信号传导的机制，信号阻断疗法在大多数情况下是无效的，这突出了对不依赖于信号调节的替代策略的需求。 在我们以前资助的项目中，我们 开发了自组装蛋白质-可咯构建体，其通过使用肿瘤细胞表面生物标志物作为可咯分子靶向进入的门户来规避调节信号传导的需要。磺化可咯是水溶性大环化合物，其可以被金属化，自发地与蛋白质组装，并且可以是细胞毒性的，以及具有用于成像和诊断的各种生物物理性质。我们已经表明，磺化corroles是膜不可渗透的，但需要细胞质进入引起细胞毒性，而其余排除从核。我们的靶向细胞穿透蛋白HerPBK 10通过与HER 2二聚化伴侣HER 3的特异性相互作用，使人表皮生长因子受体亚基-2阳性（HER 2+）肿瘤能够摄取corrole，HER 3在这些细胞中特别存在。受体结合触发快速内吞作用，随后通过HerPBK 10上的膜裂解结构域进行内体逃逸，使咔咯进入细胞质。通过HerPBK 10和镓金属化的可咯（S2 Ga或Ga-可咯）的组装形成的肿瘤归巢纳米颗粒HerGa可以以与常规化疗相比低> 10倍的剂量靶向和消融小鼠中的HER 2+肿瘤，同时保留心脏和肝脏组织，并且没有可检测的免疫原性。近年来的研究现已发现，细胞表面HER 3水平升高与对许多信号阻断乳腺癌治疗的耐药性有关，包括EGF-R或HER 1（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）和联合治疗的抑制剂。此外，已经在转移性乳腺肿瘤（包括扩散到脑的那些）和“不可靶向”肿瘤（诸如三阴性乳腺癌（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。HerPBK 10的HER 3特异性预测，抵抗这些信号阻断治疗的肿瘤细胞是HerPBK 10定向纳米生物制剂的主要靶点。本研究将在耐药和转移性乳腺癌模型上探索这一点，特别是那些转移到大脑的乳腺癌。将评估使用EGFR和HER 2抑制剂作为佐剂以使肿瘤对咔咯纳米生物制剂敏感的方案。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1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.