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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

基本信息

批准号：
10610443
负责人：
LALI K MEDINA-KAUWE
金额：
$ 37.44万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610443
关键词：
Active Sites Affect Antiviral Response Automobile Driving Benchmarking Blood - brain barrier anatomy Brain Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Bypass Capsid Cell Survival Cell surface Cells Chemoresistance Clinical Cytoplasm Distant ERBB3 gene Encapsulated Endocytosis Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epitopes Estrogen Receptors Experimental Models Exposure to FOXC1 gene Gene Targeting Genetic Transcription Genomics Growth Heterogeneity Histologic Human Immune Immune Evasion Immune Targeting Immunologic Deficiency Syndromes Immunologic Stimulation Intervention Invaded Left Ligands Liposomal Doxorubicin Lung Mammary Neoplasms Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Mutation Nanostructures Neoplasm Metastasis Nucleic Acids Nucleocapsid Organ Outcome Patients Penetration Phosphotransferases Progesterone Receptors Proteins RNA Interference Radiation therapy Receptor Inhibition Recombinant Proteins Recurrence Regulator Genes Resistance Response Elements Route Serum Signal Transduction Site Small Interfering RNA Suicide Testing Therapeutic Time Tissues Treatment Efficacy Tumor Cell Invasion Tumor Cell Line Tyrosine Kinase Inhibitor Untranslated RNA Variant Viral Virus Xenograft Model Xenograft procedure blood-brain barrier crossing cancer biomarkers cancer subtypes cell motility chemotherapy density design effective intervention efficacy evaluation endonuclease endosome membrane gene network improved malignant breast neoplasm migration nano neoplastic cell particle patient derived xenograft model patient prognosis penton base prevent receptor receptor binding response self assembly small molecule targeted delivery targeted treatment transcription factor triple-negative invasive breast carcinoma tripolyphosphate tumor tumor progression

项目摘要

ABSTRACT Triple negative breast cancer (TNBC) is among the most aggressive, recurrent and highly metastatic of breast tumors with a worse clinical outcome compared to other breast cancer subtypes. While the median survival for patients with metastatic breast cancer is ~2-5 years depending on the subtype, the prognosis of patients with metastatic TNBC is ~1 year overall survival from the time of treatment with a preponderance of tumor cases showing early metastasis to the lung as well as other distant site organs. TNBC is characterized by low to undetectable levels of estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) and thus cannot be treated with clinical targeted therapies. Worse yet, metastasis to the brain predicts an average survival of less than one year and drastically reduces therapeutic options as most targeted therapies cannot cross the blood-brain barrier (BBB). Chemotherapy is typically the only recourse for TNBC patients but chemoresistance eventually develops thus underscoring the need for improved alternative interventions. A significant subset of TNBC tumors express the human epidermal growth factor receptor 3 (HER3/ErbB3) which associates with resistance, metastasis, and invasion into the brain. HER3 lacks receptor kinase activity and thus cannot be inhibited by tyrosine kinase inhibitors. However, the increased cell surface density of HER3 on metastatic TNBC tumors may attract HER3-targeted carriers delivering tumoricidal agents. We have developed a chimeric, endosomolytic tumor-invading protein, HPK, that uses HER3 to penetrate metastatic and resistant tumors, including TNBC, in experimental models. HPK can self-assemble with small nucleic acids forming serum-stable nano-capsids (NCs) that evade immune-inhibition and bypass tumor barriers by mimicking an essential ligand that enters tumor cells through HER3. Systemic HPK NCs in xenograft breast cancer models show preferential accumulation in secondary tumors due to the increased HER3 associated with metastasis. Systemic HPK NCs can also cross the BBB19 and accumulate in intracranial (IC) TNBC tumors using HER3 to mediate both routes. HPK NCs delivering chemotherapy reduced IC TNBC growth, but chemoresistance could still develop. The current study will test HPK for targeting delivery of siRNA silencing the master transcriptional regulator FOXC1, which drives TNBC growth, metastasis, and chemoresistance. To augment the therapeutic potency of RNAi, we will modify the siRNA with a 5’-triphosphate (5’ppp) tag which can activate a cell-intrinsic anti-viral response causing tumor suicide. Taken altogether we hypothesize that HPK can encapsulate 5’ppp-modified siRNA directed against FOXC1 forming nano- nucleocapsid bioparticles that launch a multi-pronged attack on metastatic tumors through the combination of HER3 targeted tumor penetration, silencing of a master regulator gene target, and epitope-mediated tumor suicide.

摘要三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性、复发性和高转移性的肿瘤之一。与其他乳腺癌亚型相比，乳腺肿瘤的临床结局更差。而中位数转移性乳腺癌患者的生存期约为2-5年，这取决于亚型，转移性TNBC患者从治疗开始的总生存期约为1年，肿瘤病例显示早期转移到肺以及其他远端部位器官。TNBC的特点是雌激素受体（ER）、孕激素受体（PR）和人表皮细胞的低至不可检测水平，生长因子受体2（HER 2），因此不能用临床靶向疗法治疗。更糟糕的是，脑转移预测平均生存期不到一年，由于大多数靶向治疗不能穿过血脑屏障（BBB），因此没有选择。化疗通常是对于TNBC患者来说，这是唯一的求助手段，但最终会产生耐药性，因此强调需要改进替代干预措施。TNBC肿瘤的一个重要亚群表达人表皮生长抑制因子，因子受体3（HER 3/ErbB 3），其与耐药、转移和侵袭脑相关。HER3 缺乏受体激酶活性，因此不能被酪氨酸激酶抑制剂抑制。然而，增加转移性TNBC肿瘤上HER 3的细胞表面密度可能吸引HER 3靶向载体，杀肿瘤剂。我们已经开发了一种嵌合的、内体溶解的肿瘤侵袭蛋白，HPK，它使用HER 3 在实验模型中穿透转移性和耐药性肿瘤，包括TNBC。HPK可以自组装小核酸形成血清稳定的纳米衣壳（NC），逃避免疫抑制和旁路通过模拟通过HER 3进入肿瘤细胞的必需配体来形成肿瘤屏障。全身HPK NC 异种移植乳腺癌模型显示由于HER 3增加而在继发性肿瘤中优先蓄积与转移有关。全身性HPK NC也可穿过BBB 19并在颅内（IC）中蓄积。使用HER 3介导两种途径的TNBC肿瘤。递送化疗的HPK NC降低IC TNBC生长，但耐药性仍可能产生目前的研究将测试HPK靶向递送siRNA 沉默主转录调节因子FOXC 1，其驱动TNBC生长、转移和化学抗性为了增强RNAi的治疗效力，我们将用5 '-三磷酸修饰siRNA，（5 ′ ppp）标签，其可以激活引起肿瘤自杀的细胞内在抗病毒应答。总之，我们假设HPK可以包封针对FOXC 1 5 ′ ppp修饰的siRNA，核衣壳生物颗粒，通过以下组合对转移性肿瘤发起多管齐下的攻击： HER 3靶向的肿瘤穿透、主调节基因靶点的沉默和表位介导的肿瘤转移。肿瘤自杀。