Overall my laboratory focuses elucidating the molecular pathogenesis of neuroblastoma and using this information to develop novel cancer specific therapies. Neuroblastoma accounts for almost 15% of all pediatric cancer deaths and is the most common malignant solid tumor of childhood. This cancer is derived from the embryologic neural crest and arises within the neural crest derived peripheral sympathetic nervous system most often as a large primary mass with the abdomen in the abdomen or thorax. Half of all neuroblastoma presents as high stage metastatic disease which is initially chemo-responsive. However, the majority of patients with high risk disease suffer a relapse which is usually resistant to any further genotoxic chemotherapy.
Neuroblastoma represents a major clinical challenge in pediatric oncology and a large amount of research has gone into developing transgenic models, drug testing, and biologic and genomic studies to define the pathogenesis and response to drugs. The MYCN and ALK oncogenes as well as LIN28b microRNA modulator are all implicated as drivers Neuroblastoma. This cancer is uniformly p53 wild type at diagnosis, develops in very young still developing infants and children (mean age is 22 months), and is biologically heterogeneous (some types will spontaneously regress while others rapidly progress and are inexorably fatal).
My laboratory is attacking this problem from several perspectives:
1) Testing new small molecule inhibitors to activate p53:
Suppression of p53 is critical for both the pathogenesis of neuroblastoma and its resistance to chemotherapy. We have found that MDM2 plays an important role in this process in neuroblastoma by promoting the degradation of p53 and possibly activating angiogenesis. We currently are testing several new promising small molecule inhibitors (Roche compound R7112 and its analogues) to generate preclinical data supporting potential upcoming pediatric trials. These drugs have completed early phase trials in adults and appear well tolerated.
2) Modulation of epigenetics to induce differentiation: Neuroblastoma appears to arise from a block in progressive differentiation of early neural crest precursors. Retinoic acid derivatives can induce further differentiation and have limited but clinically significant effects in patients. We are investigating a novel pathway towards differentiation based on findings that CHAF1A is highly expressed in patient samples and its expression strongly correlates with undifferentiated poor prognosis disease. Knockdown experiments have confirmed that CHAF1A blocks differentiation in vivo (manuscript in preparation). This gene is a critical chromatin chaperone and is known to regulate histone modifications (H3K9me3) on chromatin during DNA repair and cell division. Identification of specific targets down stream CHAF1A and evaluation of novel histone methyltransferase inhibitors is ongoing in the laboratory.
3) Targeting neuroblastoma cancer stem cells: In collaboration with former faculty member Dr. Eugene Kim, we have recently defined a novel cancer stem cell (CSC) subpopulation of neuroblastoma. As CSCs are thought to drive relapse (primary cause of death in neuroblastoma) and promote drug resistance, we are actively pursuing ways to specifically target this population in neuroblastoma. Importantly, these cells express CSF3R (Aka CD114) which is the receptor for the hematopoietic cytokine G-CSF which activates a number of downstream pro-growth and anti-apoptotic pathways.
CSCs are highly similar to induced pluripotent stem cells (iPSCs) which undergo specific epigenetic, microRNA and genetic changes during the process of cellular reprogramming. our laboratory is investigating the molecular mechanisms acting to maintain the distinct self-renewing tumorigenic subpopulation in neuroblastoma.
We plan to also test specific approaches to inhibit this population in orthotopic xenograft experiments.
Jason Shohet, MD, PhD