Preclinical differentiation/chemotherapy combination treatment in stage IV neuroblastoma
Mentor Name: John Powers
Neuroblastoma is a highly metastatic and heterogeneous pediatric tumor, frequently driven by genetic amplification of the MYCN oncogene. Longstanding health issues arise from genotoxic chemotherapy use in neuroblastoma patients, creating a persistent need for improved approaches using less genotoxic agents to improve lifelong health of cancer survivors. Current standard of care (SoC) for high-risk disease is typically divided into three phases: induction (chemotherapy and tumor resection), consolidation (myeloablative chemotherapy and stem cell transplant), and post-consolidation (including radiation, immunotherapy, and isotretinoin (INN)). INN, a pro-differentiation retinoid, is used during post-consolidation to reduce relapse and improve event free survival. Efforts to reduce the need or dosage requirements of genotoxic compounds are of significant continued importance. Utilizing reduced dosage of these combinatorial cancer therapeutics may improve overall health and survivorship in neuroblastoma patients and influence SoC in other childhood cancers.
Aim 1: Determine the effects of retinoid-chemotherapy combinations on diagnosis-derived neuroblastoma cells.
Both DNA damage and cellular differentiation result in slower growth as cells respond to damage or mature to more defined cell types, respectively. Induction SoC for high-risk neuroblastoma includes the use of several genotoxic drugs. Pro-differentiation retinoid delivery along with these agents may increase SoC efficacy and/or allow for lower levels of chemotherapeutic agents, thus improving overall patient survivorship. Ms. Kappil will use two stage IV neuroblastoma cell lines derived at the time of patient diagnosis, using dose curves of INN in conjunction with low doses of induction drugs cisplatin and etoposide and assess synergistic effects on cell growth by differentiation signaling combined with chemotherapeutic cytotoxicity.
