Multilevel cancer modeling in the clinical environment: Simulating the behavior of Wilms tumor in the context of the SIOP 2001/GPOH clinical trial and the ACGT project

Mathematical and computational tumor dynamics models can provide considerable insight into the relative importance and interdependence of related biological mechanisms. They may also suggest the existence of optimal treatment windows in the generic setting. Nevertheless, they cannot be translated into clinical practice unless they undergo a strict and thorough clinical validation and adaptation. In this context one of the major actions of the EC funded project ldquoAdvancing Clinico-Genomic Trials on Cancerrdquo (ACGT) is dedicated to the development of a patient specific four dimensional multiscale tumor model mimicking the nephroblastoma tumor response to chemotherapeutic agents according to the SIOP 2001/GPOH clinical trial. Combined administration of vincristine and dactinomycin is considered. The patient#x2019;s pseudoanonymized imaging, histopathological, molecular and clinical data are carefully exploited. The paper briefly outlines the basics of the model developed by the In Silico Oncology Group and particularly stresses the effect of stem/clonogenic, progenitor and differentiated tumor cells on the overall tumor dynamics. The need for matching the cell category transition rates to the cell category relative populations of free tumor growth for an already large solid tumor at the start of simulation has been clarified. A technique has been suggested and succesfully applied in order to ensure satisfaction of this condition. The concept of a nomogram matching the cell category transition rates to the cell category relative populations at the treatment baseline is introduced. Convergence issues are addressed and indicative numerical results are presented. Qualitative agreement of the modelpsilas behavior with the corresponding clinical trial experience supports its potential to constitute the basis for an optimization system within the clinical environment following completion of its clinical validation and optimization. In silico treatment experimentation in - - the patient individualized context is expected to constitute the primary application of the model.