BH3 profiling to define therapy resistance classes in neuroblastoma.

The failure of cancer therapy to control tumor growth results from alterations in the pathways that control cell death decisions within tumors. Although the alterations cancer cells develop to gain a survival advantage are diverse, most ultimately lead to the disruption of death signals that should be Òturned onÓ when lethal stress is encountered. A family of Bcl2-homology (or BH) proteins are responsible for responding to these stressors to initiate a death signal when sufficient stress is present. Accordingly, cancer cells alter their BH proteins to block these death signals and maintain a survival bias even when chemotherapy or radiotherapy is given.

 Recognition of this important pathway has led to the development of experimental drugs called ÒBH3 mimeticsÓ that directly interact with BH proteins to restore death signaling. Since cancer cells are more dependent on defective BH death signaling for their survival they are more sensitive to these therapeutics than are normal cells. The innovation in this application is the use of a novel unbiased functional test to define the BH changes responsible for the survival bias in high-risk NBs. We have already identified several different resistance subtypes. Importantly, our results show these can help triage available BH3 mimetics to the patients most likely to respond. We propose to focus our efforts on relapsed NB as this subset provides the greatest clinical challenge and these patients may benefit most from the rational integration of BH3 mimetic therapies.