Human neuroblastoma (NB) is the most common childhood extracranial tumor arising from the sympathetic nervous system. It is also a clinically heterogeneous disease that ranges from spontaneous regression to high- risk stage 4 disease. The cause of this disease remains elusive however, the amplification of N-myc occurred in roughly 30% of NB patients, which strongly correlated with advanced stage of disease and poor outcome. We discovered that N-myc targets INSM1, a transcription suppressor of neuroendocrine tumors. We also found that INSM1 modulates the PI3K/AKT/GSK3? signaling pathway through a positive-feedback loop resulting in stabilization of the N-myc protein. Therefore, INSM1 emerges as a critical player in facilitating NB cell growth and transformation. Using an INSM1-promoter driven luciferase screening-platform, we have recently identified a compound that negatively regulates the adenosine kinase (ADK) activity, INSM1 and N-myc expression, and NB tumor cell growth. These findings support the presence of a novel mechanism associated with the adenosine receptor-mediated signaling pathway, which is critical in regulating NB tumor cell growth. To investigate the underlying mechanism and to evaluate the therapeutic efficacy of this newly identified compound in human NB within the context of INSM1 and N-myc down regulation, we propose two specific aims.
Aim 1 is to investigate the ADK pathway controlling NB tumor cell growth.
Aim 2 is to target ADK and AR signaling pathways for the suppression of NB tumor growth in vivo. The long-term goal of this proposal is to develop a strategy of using novel ADKi and pathway-specific compounds as effective anti-NB drugs.
N-myc and INSM1 factors play critical roles in aggressive NB tumors. A screening-platform directed to the INSM1 promoter activity yielded a potent inhibitor that suppresses both INSM1 and N-myc expression and NB tumor cell growth. ADKi targets intracellular and extracellular adenosine balance in NB and functions as an effective new anti-NB drug.
