Evaluation of Targeted Polyamine Metabolism Inhibitors to Treat Children with High-risk Neuroblastomas
Neuroblastoma is a common childhood tumor arising within the peripheral nervous system. Activation of the MYC family of oncogenes (which includes the MYCN gene) commonly occurs in this tumor and provides a reliable marker of aggressive disease and poor clinical outcome.
Polyamines are organic cations that enhance DNA and RNA transcription, translation and replication. They also specifically support many of the cellular processes that MYC genes activate in promoting cancer. In fact, nearly all of the genes involved in polyamine homeostasis appear to be regulated by MYC genes in a coordinated manner that leads to an expansion of polyamine levels in these tumors.
Because elevated levels of polyamines are required by MYC-activated tumors (as compared with normal surrounding tissues), suppression of polyamine biosynthesis may provide an attractive therapeutic approach to treating these cancers.
Michael D. Hogarty, MD, and researchers at the Center for Childhood Cancer Research demonstrated that broad deregulation of polyamine regulatory genes, including ODC1 (a bona fide oncogene that encodes the rate-limiting enzyme in polyamine synthesis), is a signature feature of neuroblastoma with MYCN amplification. Moreover, additional high-risk neuroblastomas with alternative MYC activation also highly expressed this pathway. Indeed, overexpression of ODC1 was associated with aggressive disease and death from tumor progression across all high-risk neuroblastomas.
Additional studies revealed that the polyamine synthesis inhibitor α-difluoromethylornithine (DMFO), in combination with individual chemotherapy drugs used to treat neuroblastoma, exhibited potent anti-tumor activity in complementary models of the disease, including highly lethal human tumors xenografted into mice and genetically engineered transgenic mice predisposed to developing neuroblastoma that mimics the MYCN amplified type.
These effects were enhanced in these models with the addition of the nonsteroidal anti-inflammatory drug celecoxib, which indirectly interferes with polyamine metabolism. Additional polyamine pathway inhibitors are available and may further contribute to cancer cell killing in these models.
The results of these studies led to the development of a Phase I clinical study (conducted in collaboration with the New Approaches to Neuroblastoma Therapy consortium), which is currently underway. The goal of this study is to evaluate the safety and effectiveness of a combination of DFMO and celecoxib plus cyclophosphamide and topotecan as a treatment for children with relapsed neuroblastoma.