Nucleocapsid bioparticles eliciting multi-pronged attack on tumor metastases

点击翻译按钮获取中文摘要

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.