ABSTRACT
Gliomas are notoriously aggressive, malignant brain tumors that have variable response to treatment. These patients often have poor prognosis, informed primarily by histopathology. Mathematical neuro-oncology (MNO) is a young and burgeoning field that leverages mathematical models to predict and quantify response to therapies. These mathematical models can form the basis of modern "precision medicine" approaches to tailor therapy in a patient-specific manner. Patient-specific models (PSMs) can be used to overcome imaging limitations, improve prognostic predictions, stratify patients, and assess treatment response in silico. The information gleaned from such models can aid in the construction and efficacy of clinical trials and treatment protocols, accelerating the pace of clinical research in the war on cancer. This review focuses on the growing translation of PSM to clinical neuro-oncology. It will also provide a forward-looking view on a new era of patient-specific MNO.
ABSTRACT
The explosive growth of molecular diagnostic tests introduces the possibility of increasing our understanding of disease mechanisms in the clinic and promises to improve target identification for new therapies. A new paradigm is emerging in drug discovery that is driven by these clinically derived data. Unfortunately, the translation of novel insights into useful therapies remains costly and difficult. New clinical trial design and open validation of markers may reduce these barriers to clinical utility.
Subject(s)
Drug Discovery/methods , Genomics/methods , Biomarkers, Pharmacological , Humans , Models, GeneticABSTRACT
We demonstrate a patient-specific method of adaptive IMRT treatment for glioblastoma using a multiobjective evolutionary algorithm (MOEA). The MOEA generates spatially optimized dose distributions using an iterative dialogue between the MOEA and a mathematical model of tumor cell proliferation, diffusion and response. Dose distributions optimized on a weekly basis using biological metrics have the potential to substantially improve and individualize treatment outcomes. Optimized dose distributions were generated using three different decision criteria for the tumor and compared with plans utilizing standard dose of 1.8 Gy/fraction to the CTV (T2-visible MRI region plus a 2.5 cm margin). The sets of optimal dose distributions generated using the MOEA approach the Pareto Front (the set of IMRT plans that delineate optimal tradeoffs amongst the clinical goals of tumor control and normal tissue sparing). MOEA optimized doses demonstrated superior performance as judged by three biological metrics according to simulated results. The predicted number of reproductively viable cells 12 weeks after treatment was found to be the best target objective for use in the MOEA.
