Neuroblastoma (NB) is a common pediatric solid tumor with high lethality. Most patients present with high-risk features and succumb to chemoresistant disease due to disabled tumor apoptosis pathways. Bcl2 homology-domain, or BH, proteins (such as Bcl2, Mcl1, Bak, and Bax) largely govern a cell's response to chemotherapy by mediating mitochondrial reaction to stressors that activate specific pro-death BH3 proteins. Many tumor types depend on altered BH protein interactions for survival. Our preliminary data shows that NB heterogeneously expresses Mcl1 and Bcl2 that may prevent apoptosis by sequestering active BH3 death signals. Further, BH3 mimetic peptides mimicking the death domain of BHS-only proteins potently induce NB apoptosis both in vitro and in vivo. Novel chemical modifications to stabilize peptide secondary structure improve serum stability and potency. We propose to exploit the knowledge of deregulated apoptotic pathways in NB to design rational pro-death therapeutic strategies with the following Aims: 1) Determine BH protein:protein interactions responsible for aberrant mitochondrial apoptosis in NB;2) Assess the efficacy and potency of chemically modified BH3-domain peptides against NB cell lines both in vitro and in vivo;and 3) Demonstrate improved potency of BH3 peptides in these models when combined with tyrosine kinase inhibitors targeting receptors that mediate survival, proliferation and chemoresponse in neuroblastoma. This proposal lays out a 5-year research and training program that will help the principle investigator transition to become an independent researcher with the ultimate goal of becoming an R01-funded physician-scientist. Her mentors and advisors are leaders in the field of apoptosis, neuroblastoma, and experimental therapeutics. She will take advantage of the ample resources offered through the environments of both the Children's Hospital of Philadelphia and the University of Pennsylvania to foster her career development. Relevance. Neuroblastoma is a highly lethal tumor with no curative therapy following relapse. Current treatments are ineffective and new treatment depends on the identification of therapies that target tumor-specific biology. BH3 peptides that potently kill NB and other cancer cells prove promising as translational pro-death therapeutics given recent novel chemical modifications to improve peptide structure. Combining BH3 peptides with clinically available kinase inhibitors demonstrates that targeting both survival signaling and apoptosis using rationally chosen agents will provide a novel and effective approach to treating cancers resistant to current conventional treatment modalities.
|Goldsmith, K C; Lestini, B J; Gross, M et al. (2010) BH3 response profiles from neuroblastoma mitochondria predict activity of small molecule Bcl-2 family antagonists. Cell Death Differ 17:872-82|