Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

SIMPLE SUMMARY: Neuroblastoma is a rare type of cancer that usually affects children. The high-risk patients’ expected survival rate is less than 50%. One reason is the lack of precision in the standard treatment protocol: a one-size-fits-all multi-modal therapy. The study presented in this paper was designed to address this deficit by optimising the use of two chemotherapeutic agents—vincristine and cyclophosphamide—during induction chemotherapy—the part of the protocol that shrinks the primary tumour before surgical removal. We combined a mathematical model and an optimisation algorithm to identify the best chemotherapy schedules for a cohort of virtual patients with different initial tumour compositions. Our results reveal novel strategies to exploit a pair of drugs with different levels of efficacy, provide a platform on which to individualise induction chemotherapy, and lay the foundation for a personalised therapy that leverages targeted therapies, multi-region sequencing, liquid biopsies, and modern computational methods to improve today’s multi-modal therapy. ABSTRACT: Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system.