Corrole nanobiologics for targeting resistant and metastatic tumors

Corrole 纳米生物制剂用于靶向耐药性和转移性肿瘤

基本信息

  • 批准号:
    10241418
  • 负责人:
  • 金额:
    $ 41.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

 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.
 描述:目前临床上使用的大多数肿瘤靶向疗法均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,由于在面对靶向治疗时维持信号传导的机制,信号阻断疗法在大多数情况下都是无效的,这突出表明需要不依赖于信号调节的替代策略。 在我们之前资助的项目中,我们 开发了自组装蛋白-corrole结构,通过使用肿瘤细胞表面生物标志物作为corrole分子靶向进入的门户,避免了调节信号传导的需要。磺化咔咯是水溶性大环化合物,可金属化,与蛋白质自发组装,具有细胞毒性,并具有用于成像和诊断的各种光物理特性。我们已经证明,磺化咔咯是不可渗透膜的,但需要进入细胞质才能引起细胞毒性,同时仍被排除在细胞核之外。我们的靶向细胞渗透蛋白 HerPBK10 通过与 HER2 二聚化伙伴 HER3(特别是在这些细胞上出现)的特异性相互作用,使 Corrole 摄取到人表皮生长因子受体亚基 2 阳性 (HER2+) 肿瘤中。受体结合触发快速内吞作用,然后通过 HerPBK10 上的膜溶解结构域逃逸内体,从而使 Corrole 进入细胞质。肿瘤归巢纳米颗粒 HerGa 由 HerPBK10 和镓金属化 Corrole(S2Ga 或 Ga-corrole)组装而成,可以以比传统化疗低 10 倍以上的剂量靶向并消融小鼠中的 HER2+ 肿瘤,同时保留心脏和肝脏组织,并且没有可检测到的免疫原性。近年来的研究发现,细胞表面 HER3 水平升高与多种信号阻断乳腺癌治疗的耐药性相关,包括 EGF-R 或 HER1 抑制剂(拉帕替尼)、HER2 抑制剂(拉帕替尼、曲妥珠单抗、T-DM1)、HER2-3(帕妥珠单抗)和联合疗法。此外,已在转移性乳腺肿瘤(包括扩散至大脑的肿瘤)和“不可靶向”肿瘤(如三阴性乳腺癌 (TNBC))(包括对 EGF-R 抑制获得性耐药的 TNBC)中发现 HER3 升高。 HerPBK10 的 HER3 特异性预测,抵抗这些信号阻断治疗的肿瘤细胞是 HerPBK10 导向的纳米生物制剂的主要目标。本研究将在耐药性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 HER2 抑制剂作为佐剂使肿瘤对 Corrole 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一年,因此迫切需要改进的替代方案。

项目成果

期刊论文数量(23)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth.
A multimode optical imaging system for preclinical applications in vivo: technology development, multiscale imaging, and chemotherapy assessment.
  • DOI:
    10.1007/s11307-011-0517-z
  • 发表时间:
    2012-08
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Hwang, Jae Youn;Wachsmann-Hogiu, Sebastian;Ramanujan, V. Krishnan;Ljubimova, Julia;Gross, Zeev;Gray, Harry B.;Medina-Kauwe, Lali K.;Farkas, Daniel L.
  • 通讯作者:
    Farkas, Daniel L.
Basal Protein Expression Is Associated With Worse Outcome and Trastuzamab Resistance in HER2+ Invasive Breast Cancer.
  • DOI:
    10.1016/j.clbc.2015.06.001
  • 发表时间:
    2015-12
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Chung A;Choi M;Han BC;Bose S;Zhang X;Medina-Kauwe L;Sims J;Murali R;Taguiam M;Varda M;Schiff R;Giuliano A;Cui X
  • 通讯作者:
    Cui X
Analysis of targeted viral protein nanoparticles delivered to HER2+ tumors.
分析递送至 HER2 肿瘤的靶向病毒蛋白纳米颗粒。
Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.
  • DOI:
    10.1371/journal.pone.0034463
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Hwang JY;Park J;Kang BJ;Lubow DJ;Chu D;Farkas DL;Shung KK;Medina-Kauwe LK
  • 通讯作者:
    Medina-Kauwe LK
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LALI K MEDINA-KAUWE其他文献

LALI K MEDINA-KAUWE的其他文献

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{{ truncateString('LALI K MEDINA-KAUWE', 18)}}的其他基金

Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids
使用 HER3 归巢纳米衣壳靶向抑制剂耐药性乳腺肿瘤
  • 批准号:
    10367490
  • 财政年份:
    2022
  • 资助金额:
    $ 41.56万
  • 项目类别:
Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids
使用 HER3 归巢纳米衣壳靶向抑制剂耐药性乳腺肿瘤
  • 批准号:
    10619565
  • 财政年份:
    2022
  • 资助金额:
    $ 41.56万
  • 项目类别:
Nucleocapsid bioparticles eliciting multi-pronged attack on tumor metastases
核衣壳生物颗粒引发对肿瘤转移的多管齐下攻击
  • 批准号:
    10610443
  • 财政年份:
    2022
  • 资助金额:
    $ 41.56万
  • 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
  • 批准号:
    8599443
  • 财政年份:
    2010
  • 资助金额:
    $ 41.56万
  • 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
  • 批准号:
    8403815
  • 财政年份:
    2010
  • 资助金额:
    $ 41.56万
  • 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
  • 批准号:
    7889775
  • 财政年份:
    2010
  • 资助金额:
    $ 41.56万
  • 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
  • 批准号:
    8021832
  • 财政年份:
    2010
  • 资助金额:
    $ 41.56万
  • 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
  • 批准号:
    8206856
  • 财政年份:
    2010
  • 资助金额:
    $ 41.56万
  • 项目类别:
Corrole nanobiologics for targeting resistant and metastatic tumors
Corrole 纳米生物制剂用于靶向耐药性和转移性肿瘤
  • 批准号:
    9769633
  • 财政年份:
    2009
  • 资助金额:
    $ 41.56万
  • 项目类别:
Corrole nanobiologics for targeting resistant and metastatic tumors
Corrole 纳米生物制剂用于靶向耐药性和转移性肿瘤
  • 批准号:
    10017161
  • 财政年份:
    2009
  • 资助金额:
    $ 41.56万
  • 项目类别:

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