Exploring a new therapy for neuroblastoma: silencing of Doublecortin-like kinase, a microtubule-binding protein

Researcher: 
Carla Verissimo

Neuroblastoma is one of the most common childhood cancers.
Microtubule-destabilizing agents are used in the treatment of these
tumors in human patients. However, resistance to chemotherapeutic
agents and systemic toxicity make neuroblastoma a difficult drug target.
In our previous work, we found that doublecortin-like kinase (DCLK)
gene transcripts are crucial microtubule-associated proteins for
correct proliferation and differentiation of neuroprogenitor cells.
Gene expression profiling revealed a high expression of these
transcripts in neuroblastoma patients. Furthermore, these transcripts
are endogenously expressed specifically in neuroblasts but are not
found in other cell types. Suppression of DCLK by short interfering RNA
(siRNA) disrupted the mitotic spindles in neuroblastoma cells and gene
expression profiling showed that several affected pathways are linked
to cell cycle, differentiation and apoptosis. Apoptotic cell death of
neuroblastoma cells by DCLK knockdown was further confirmed by a
variety of assays. Furthermore, we showed a successful delivery of
siRNA targeting DCLK to neuroblastoma cells by using specific
peptide-siRNA conjugates.
In conclusion, silencing of the DCLK gene by siRNA interference is a
novel potential therapeutic approach for neuroblastoma with the promise
of combining high specificity with fewer side effects. Peptide-siRNA
conjugates might be the tool needed for specific neuroblastoma
delivery.

06/07/2009