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.

抽象的三重阴性乳腺癌（TNBC）是最具侵略性，经常性和高度转移性与其他乳腺癌亚型相比，临床预后较差的乳腺肿瘤。而中位数转移性乳腺癌患者的生存率约为2 - 5年，具体取决于亚型转移性TNBC的患者从治疗时期起约1年的总生存率约1年肿瘤病例表现出早期转移到肺以及其他远处的器官。 TNBC的特征是低至不可检测的雌激素受体（ER），孕酮受体（PR）和人表皮生长因子受体2（HER2），因此无法使用临床靶向疗法进行治疗。更糟糕的是，大脑转移的平均存活率不到一年，并且大幅度降低了治疗选项由于大多数靶向疗法无法越过血脑屏障（BBB）。化学疗法通常是仅适用于TNBC患者，但化学耐药性最终发展，从而强调了对改进的替代干预措施。 TNBC肿瘤的显着子集表达人表皮生长因子受体3（HER3/ERBB3）与耐药性，转移和侵袭大脑相关。 Her3 缺乏受体激酶活性，因此不能被酪氨酸激酶抑制剂抑制。但是，增加了转移性TNBC肿瘤上HER3的细胞表面密度可能会吸引以Her3为目标的载体。肿瘤剂。我们已经开发了一种使用HER3 在实验模型中穿透包括TNBC在内的转移性和抗性肿瘤。 HPK可以自组装与避免免疫抑制和旁路的小核酸形成血清稳定的纳米capsids（NCS）肿瘤屏障通过模仿基本的配体，该配体通过HER3进入肿瘤细胞。全身HPK NCS 异种移植乳腺癌模型由于HER3增加而显示出在二次肿瘤中的优先积累与转移有关。全身HPK NC还可以在颅内（IC）中穿越BBB19和丙烯酸 TNBC肿瘤使用HER3介导了这两条路线。提供化学疗法的HPK NCS降低了IC TNBC的生长，但是化学抗性仍然可以发展。当前的研究将测试HPK靶向siRNA的靶向沉默主转录调节剂FOXC1，该调节器驱动TNBC增长，转移和化学抗性。为了增强RNAi的治疗效力，我们将用5'-三磷酸盐修改siRNA （5'PPPP）可以激活导致肿瘤自杀的细胞内部抗病毒反应的标签。我们完全取走了假设HPK可以封装针对FOXC1形成纳米的5'PPP修饰的siRNA 核素生物粒子通过结合起来对转移性肿瘤发出多管齐下的攻击 HER3靶向肿瘤渗透，对主调节基因靶标的沉默和表位介导的肿瘤自杀。