Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34

By J. Wiggins, Lynnsie Ruffino, Kevin Kelnar, M. Omotola, Lubna Patrawala, D. Brown, A. Bader. Cancer Research, 2010

686 citations recorded by the source corpus.

Tumor suppressor microRNAs (miRNAs) provide a new opportunity to treat cancer. This approach, “miRNA replacement therapy”, is based on the concept that the re-introduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Here, we describe the development of a therapeutic formulation using chemically synthesized miR-34a and a lipid-based delivery vehicle that blocks tumor growth in mouse models of non-small cell lung cancer. This formulation is effective when administered locally or systemically. The anti-oncogenic effects are accompanied by an accumulation of miR-34a in the tumor tissue and downregulation of direct miR-34a targets. Intravenous delivery of formulated miR-34a does not induce an elevation of cytokines or liver and kidney enzymes in serum, suggesting that the formulation is well tolerated and does not induce an immune response. The data provide proof of concept for the systemic delivery of a synthetic tumor suppressor mimic, obviating obstacles associated with viral-based miRNA delivery and facilitating a rapid route for miRNA replacement therapy to the clinic.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/dd2456553aeda281a4f2170327b95fa097f89cd2

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In Cancer Research

In Immunology

Carlo Maria Croce

In Molecular Biology

Citations in the corpus

In vivo delivery of miRNAs for cancer therapy: Challenges and strategies (2014, background): “demonstrated that miR-34a formulated in a neutral lipid-based delivery vehicle achieved significant miRNA accumulation and downregulation of the target genes in the lung tumor tissues in NSCLC xenograft mouse models [136].”
MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy (2011, positive): “A miR-34 mimetic, delivered either intratumorally or systemically through tail vein injection, impaired tumorigenesis of NSCLC xenograft”
Development of microRNA therapeutics is coming of age (2014, positive): “In most cases, the miR-34 mimic was delivered directly by intratumoral injections, which is only therapeutically feasible for easily accessible and localized tumors that have not yet metastasized (Wiggins et al , 2010).”
Identification of miR-34a as a potent inhibitor of prostate cancer progenitor cells and metastasis by directly repressing CD44 (2011, neutral): “To this end, we used quantitative RT-PCR (qRT-PCR) to compare the miRNA expressio”
miR-34 – a microRNA replacement therapy is headed to the clinic (2012, background): “In discord with this view, however, the transient transfection of miR-34a had no noticeable effects in a series of non-cancerous cells (Wiggins et al., 2010).”
microRNAs in cancer (2013, background): “Mouse studies that evaluated the therapeutic delivery of tumor-suppressor miRNAs failed to find adverse events associated with the miRNAs and suggested that delivery of miRNA to normal tissues was well tolerated (41, 149).”