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Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide
Sang-Soo Kim1,2, Joe B Harford2, Manish Moghe1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Abstract:
Intrinsic therapeutic resistance especially in cancer stem cells (CSCs) together with extensive tumor cell infiltration and restricted permeation of the blood-brain barrier (BBB) by drugs may all contribute to the treatment failure in patients with glioblastoma multiforme (GBM). Accumulating evidence suggests that long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a role in tumor cell infiltration and therapeutic resistance of GBM. Using our tumor-targeted nanocomplex, we have modulated the expression of MALAT1 and investigated its impact on GBM cells. Importantly, our nanocomplex is able to target CSCs that are considered to be the prime culprits in therapeutic resistance and recurrence of GBM. Attenuation of MALAT1 by RNA interference significantly lowered the growth, motility and stemness of GBM cells. In addition, silencing of MALAT1 clearly improved the sensitivity of GBM cells to chemotherapeutic agents including the current first-line therapy of GBM [temozolomide (TMZ)]. In animal models of GBM, tumor involution with a modest but statistically significant survival benefit was achieved with concurrent treatment of TMZ and nanocomplex-mediated silencing of MALAT1. These results suggest that combining standard TMZ treatment with lncRNA-targeting therapies using our nanocomplex could substantially enhance the very poor prognosis for GBM patients.
Insights
Targeting MALAT1 long non-coding RNA (lncRNA) in glioblastoma stem cells (CSCs) with a novel nanocomplex overcomes therapeutic resistance. This approach enhances sensitivity to temozolomide (TMZ) chemotherapy, improving outcomes for glioblastoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- Glioblastoma multiforme (GBM) presents therapeutic challenges due to intrinsic resistance in cancer stem cells (CSCs), tumor infiltration, and poor drug penetration across the blood-brain barrier (BBB).
- The long non-coding RNA (lncRNA) MALAT1 is implicated in GBM's tumor cell infiltration and therapeutic resistance.
Purpose of the Study:
- To investigate the role of MALAT1 in GBM and evaluate a tumor-targeted nanocomplex for modulating its expression.
- To assess the impact of MALAT1 attenuation on GBM cell growth, motility, stemness, and chemosensitivity.
Main Methods:
- Development and application of a tumor-targeted nanocomplex to modulate MALAT1 expression in GBM cells.
- Utilizing RNA interference to silence MALAT1 in GBM cells and CSCs.
- In vitro assessment of GBM cell proliferation, migration, and stem-like properties.
- Evaluation of GBM cell sensitivity to temozolomide (TMZ) post-MALAT1 silencing.
- In vivo studies using GBM animal models treated with TMZ and nanocomplex-mediated MALAT1 silencing.
Main Results:
- Nanocomplex successfully targeted CSCs, crucial for GBM resistance and recurrence.
- MALAT1 silencing significantly reduced GBM cell growth, motility, and stemness.
- Silencing MALAT1 enhanced GBM cell sensitivity to TMZ, the standard first-line therapy.
- Combined TMZ treatment and nanocomplex-mediated MALAT1 silencing led to tumor regression and improved survival in GBM animal models.
Conclusions:
- Nanocomplex-mediated MALAT1 silencing is a promising strategy to overcome therapeutic resistance in GBM.
- Combining standard TMZ therapy with lncRNA-targeting strategies holds potential for improving the prognosis of GBM patients.
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