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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.

抽象的三阴性乳腺癌 (TNBC) 是最具侵袭性、复发性和高度转移性的乳腺癌之一与其他乳腺癌亚型相比，乳腺肿瘤的临床结果更差。虽然中位数转移性乳腺癌患者的生存期约为 2-5 年，具体取决于亚型，转移性 TNBC 患者从治疗之日起总生存期约为 1 年，其中大多数显示早期转移至肺部以及其他远处器官的肿瘤病例。 TNBC 的特点是雌激素受体 (ER)、孕激素受体 (PR) 和人体表皮的水平低至检测不到生长因子受体2（HER2），因此不能通过临床靶向治疗来治疗。更糟糕的是，脑转移预计平均生存期不到一年，并大大降低治疗效果因为大多数靶向治疗无法穿过血脑屏障（BBB）。化疗通常是只能求助于 TNBC 患者，但最终会出现化疗耐药性，因此强调需要改进替代干预措施。 TNBC 肿瘤的一个重要子集表达人类表皮生长因子受体 3 (HER3/ErbB3)，与抵抗、转移和侵入大脑有关。 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，增加的转移性 TNBC 肿瘤上 HER3 的细胞表面密度可能会吸引 HER3 靶向载体递送杀肿瘤剂。我们开发了一种嵌合的内体溶解肿瘤侵袭蛋白 HPK，它使用 HER3 在实验模型中穿透转移性和耐药性肿瘤，包括 TNBC。 HPK可以自组装与小核酸形成血清稳定的纳米衣壳（NC），逃避免疫抑制和绕过通过模仿通过 HER3 进入肿瘤细胞的重要配体来消除肿瘤屏障。系统性 HPK NC 异种移植乳腺癌模型显示由于 HER3 增加而优先在继发性肿瘤中积累与转移有关。全身 HPK NC 也可以穿过 BBB19 并在颅内 (IC) 中积累 TNBC 肿瘤使用 HER3 介导这两种途径。 HPK NC 进行化疗可减少 IC TNBC 的生长，但化疗耐药性仍可能出现。当前的研究将测试 HPK 的 siRNA 靶向递送能力沉默主转录调节因子 FOXC1，该调节因子驱动 TNBC 生长、转移和化学耐药性。为了增强 RNAi 的治疗效力，我们将用 5'-三磷酸修饰 siRNA (5'ppp) 标签可以激活细胞固有的抗病毒反应，导致肿瘤自杀。综上我们假设HPK可以封装针对FOXC1的5'ppp修饰的siRNA，形成纳米- 核衣壳生物颗粒通过结合以下物质对转移性肿瘤发起多管齐下的攻击： HER3 靶向肿瘤渗透、主调节基因靶标沉默以及表位介导肿瘤自杀。