Journal Article

SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of Atypical Teratoid Rhabdoid Tumors

Harford, Joe, Kim, Sang-Soo, Chang, Esther, Rait, Antonina, Moghe, Manish, Donaldson, Kathryn

2024

Overview

Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.

• Publisher: Taylor & Francis Ltd,Dove Press,Dove,Dove Medical Press
• Subject: Animals / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Apoptosis / atypical teratoid rhabdoid tumor / Brain cancer / Brain Neoplasms - genetics / Brain Neoplasms - therapy / Cancer therapies / Cell cycle / Cell Line, Tumor / Cell Proliferation - drug effects / Chemotherapy / Cloning / Cytomegalovirus / Disease Models, Animal / Flow cytometry / gene therapy / Genetic Therapy - methods / Humans / lipid nanoparticle / Lipids / Liposomes / Mice / nanodelivery / Nanomedicine / Nanoparticles - chemistry / Original Research / Patients / Plasmids / Proteins / Radiation / Rhabdoid Tumor - drug therapy / Rhabdoid Tumor - genetics / Rhabdoid Tumor - therapy / Rhabdomyosarcoma / SMARCB1 / SMARCB1 Protein - genetics / Teratoma - genetics / Teratoma - therapy / Tumors