Personalized Medicine for Neuroblastoma: Moving from Static Genotypes to Dynamic Simulations of Drug Response

Abstract

High-risk neuroblastoma is an aggressive childhood cancer that is characterized by high rates of chemoresistance and frequent metastatic relapse. A number of studies have characterized the genetic and epigenetic landscape of neuroblastoma, but due to a generally low mutational burden and paucity of actionable mutations, there are few options for applying a comprehensive personalized medicine approach through the use of targeted therapies. Therefore, the use of multi-agent chemotherapy remains the current standard of care for neuroblastoma, which also conceptually limits the opportunities for developing an effective and widely applicable personalized medicine approach for this disease. However, in this review we outline potential approaches for tailoring the use of chemotherapy agents to the specific molecular characteristics of individual tumours by performing patient-specific simulations of drug-induced apoptotic signalling. By incorporating multiple layers of information about tumour-specific aberrations, including expression as well as mutation data, these models have the potential to rationalize the selection of chemotherapeutics contained within multi-agent treatment regimens and ensure the optimum response is achieved for each individual patient.

Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma

“…These genetic mechanisms of chemoresistance are known to occur in relapsed high-risk neuroblastoma tumors, occasionally resulting in actionable mutations that are rarely present at diagnosis ( 4 , 5 ). Emerging precision medicine approaches are now aiming to treat these tumors with targeted therapies ( 6 ). However, it is becoming apparent that strategies capable of improving the efficacy of first-line treatments, and thereby reducing the occurrence of relapse, are more likely to result in robust improvements in patient outcome ( 1 ).…”

Hibiscus Flower and Olive Leaf Extracts Activate Apoptosis in SH-SY5Y Cells

“…Unfortunately, surgery is not possible in more than 70% of patients as the disease is unresectable and metastatic, and thus multi-agent and multi-modal therapy remain the only options [ 2 ]. Chemotherapy is mainly based on a combination of drugs such as doxorubicin, vincristine, cyclophosphamide, etopomide, topetecan and cisplatin [ 4 ]. Although highly beneficial, it lacks selectivity and has severe side effects in both short and long terms, as survivors commonly have permanent health problems from the therapy received during childhood [ 5 ].…”