Targeting β-Catenin with Tumor-Selective RNAi Nanoparticles
RNA interference (RNAi) technology has enabled the inhibition of previously undruggable targets at the mRNA level. Whereas clinical applications of RNAi have proven to be most successful for targeting mRNAs in the normal liver, drug delivery challenges have hindered its application in oncology. Ganesh and colleagues have identified and characterized potent tumor-selective RNAi nanoparticles, capable of silencing β-catenin mRNA and protein in both primary and metastatic tumors. Demonstration of strong efficacy against Wnt-dependent colorectal and hepatocellular tumors suggest a good opportunity for clinical development for this novel class of oligonucleotide-based therapeutics.
ST-11 Is a New Brain-Penetrant Antitubulin Agent
Disrupting microtubule function represents a promising approach to treat glioblastoma multiforme (GBM), a devastating and intractable subtype of cancer, but antitubulin agents suffer from poor brain penetrance. Cherry and colleagues report the identification of a new brain-penetrant antitubulin agent, ST-11, that destabilizes microtubules, promotes chromosomal lingering that disrupts mitosis, and activates apoptosis in GBM cells. ST-11 reaches the brain after peripheral injection and dose-dependently reduces tumor burden in an orthotopic GBM mouse model without producing overt side effects. These findings indicate that ST-11 represents a promising scaffold to develop novel therapeutic modalities to treat GBM.
Novel Molecular Format of Bifunctional MHC I Antibody Fusions
Mimicking a viral infection can increase the antigenicity of tumor cells. Peptide–MHC class I complexes flag infected cells for their elimination by CD8 T effector cells. Technical flaws have hampered the idea of antibody-mediated delivery of peptide–MHC class I complexes to tumor cells for a long time. Schmittnaegel and colleagues overcame these technical issues with a new class of peptide MHC class I–fused antibodies named pMHC-IgGs. The new format can be expressed as a full immunoglobulin fusion and can be designed as mono- or bivalent antibodies and enable advancement of the concept towards clinical testing.
POSTN Regulates Resistance to Antiangiogenic Therapy
Antiangiogenic therapy is a promising option for the treatment of glioma and other solid tumors, but resistance remains a formidable challenge. Park and colleagues discovered POSTN is responsible for acquired resistance to antiangiogenic therapy in glioma stem-like cells. Resistance to antiangiogenic therapy regulated by POSTN was associated with increased expression of mesenchymal markers. The combination of antiangiogenic therapy with downregulated expression of POSTN by shRNA dramatically reduced resistance-signaling and tumor invasion but extended overall animal survival significantly. These findings provide important basis for the development of the treatment for glioblastoma patients and identify POSTN as a novel therapeutic target in glioblastoma.
- ©2016 American Association for Cancer Research.