System-level analysis of neuroblastoma tumor-initiating cells implicates AURKB as a novel drug target for neuroblastoma
MetadataShow full item record
Purpose: Neuroblastoma (NB) is an aggressive tumor of the developing peripheral nervous system that remains difficult to cure in the advanced stages. The poor prognosis for high-risk NB patients is associated with common disease recurrences that fail to respond to available therapies. NB tumor-initiating cells (TICs), isolated from metastases and primary tumors, may escape treatment and contribute to tumor relapse. New therapies that target the TICs may therefore prevent or treat tumor recurrences. Experimental Design: We undertook a system-level characterization of NB TICs to identify potential drug targets against recurrent NB. We used next-generation RNA sequencing and/or human exon arrays to profile the transcriptomes of 11 NB TIC lines from six NB patients, revealing genes that are highly expressed in the TICs compared with normal neural crest-like cells and unrelated cancer tissues. We used gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry to confirm the presence of proteins corresponding to the most abundant TIC-enriched transcripts, thereby providing validation to the gene expression result. Results: Our study revealed that genes in the BRCA1 signaling pathway are frequently misexpressed in NB TICs and implicated Aurora B kinase as a potential drug target for NB therapy. Treatment with a selective AURKB inhibitor was cytotoxic to NB TICs but not to the normal neural crest-like cells. Conclusion: This work provides the first high-resolution system-level analysis of the transcriptomes of 11 primary human NB TICs and identifies a set of candidate NB TIC-enriched transcripts for further development as therapeutic targets. ©2010 AACR.
Showing items related by title, author, creator and subject.
Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ - independent resolution of treated-turmors and CD4+ -dependent systemic and memory responsesJackaman, Connie; Nelson, Delia (2012)Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or ...
Macrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced CachexiaDuong, L.; Radley-Crabb, H.; Gardner, J.; Tomay, F.; Dye, D.; Grounds, M.; Pixley, F.; Nelson, Delia; Jackaman, Connie (2018)Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials. The immune system plays a critical role ...
Tan, K.; Danquah, M.; Sidhu, Amandeep; Ongkudon, C.; Lau, S. (2017)Cancer is a leading cause of global mortality. Whilst anticancer awareness programs have increased significantly over the years, scientific research into the development of efficient and specific drugs to target cancerous ...