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SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of
Sang-Soo Kim1,2, Manish Moghe1, Antonina Rait1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
This study shows that restoring SMARCB1 gene function with a novel nanomedicine (scL-SMARCB1) effectively treats pediatric brain cancer (ATRT) in preclinical models. Combining this gene therapy with chemotherapy or radiation significantly improved survival rates.
Area of Science:
- Oncology
- Genetics
- Nanomedicine
Background:
- Atypical teratoid rhabdoid tumor (ATRT) is a rare and aggressive pediatric brain cancer.
- SMARCB1 gene inactivation is a key driver in most ATRT cases.
- Restoring SMARCB1 function presents a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of SMARCB1 gene therapy using a novel nanomedicine (scL-SMARCB1) in preclinical models of ATRT.
- To assess the potential of scL-SMARCB1 as a monotherapy and in combination with traditional treatments.
Main Methods:
- Development of scL-SMARCB1, a tumor-targeted immuno-lipid nanoparticle designed to deliver wild-type SMARCB1.
- Systemic administration of scL-SMARCB1 capable of crossing the blood-brain barrier.
- Testing scL-SMARCB1 in preclinical models of SMARCB1-deficient ATRT, both as a single agent and in combination with chemotherapy or radiation.
Main Results:
- scL-SMARCB1 restored SMARCB1 expression, inhibiting ATRT cell proliferation and inducing apoptosis and senescence.
- Systemic scL-SMARCB1 monotherapy demonstrated significant antitumor activity in mice with ATRT xenografts.
- Combination therapy with scL-SMARCB1 and cisplatin-based chemotherapy or radiation therapy resulted in substantially improved survival rates.
Conclusions:
- The scL-SMARCB1 nanomedicine effectively restores SMARCB1 function and exhibits potent antitumor activity against ATRT.
- Combining scL-SMARCB1 gene therapy with conventional chemoradiation offers a promising therapeutic approach for ATRT patients.
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