Drugs bind to their target proteins, which interact with downstream effectors and ultimately perturb the transcriptome of a cancer cell. These perturbations reveal information about their source, i.e., drugs’ targets. Here, we investigate whether these perturbations and protein interaction networks can uncover drug targets and key pathways. We performed the first systematic analysis of over 500 drugs from the Connectivity Map. First, we show that the gene expression of drug targets is usually not significantly affected by the drug perturbation. Hence, expression changes after drug treatment on their own are not sufficient to identify drug targets. However, ranking of candidate drug targets by network topological measures prioritizes the targets. We introduce a novel measure, local radiality, which combines perturbed genes and functional interaction network information. The new measure outperforms other methods in target prioritization and proposes cancer-specific pathways from drugs to affected genes for the first time. Local radiality identifies more diverse targets with fewer neighbors and possibly less side effects.

Continuing tyrosine kinase inhibitor (TKI)-mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia (CML) and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of those patients with optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. We use a mathematical model to analyze and consistently describe biphasic treatment responses from TKI-treated patients from two independent clinical phase III trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence to suggest that TKI dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, who have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose without decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose-halving should be considered as a long-term treatment option for CML patients with good response under continuing maintenance therapy with TKIs. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and treatment costs.

Recent clinical findings in patients with chronic myeloid leukemia (CML) suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitor (TKI) treatment substantially depends on an individual's leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will remain in treatment-free remission (TFR). Here, we used an ordinary differential equation model for CML, which explicitly includes an antileukemic immunologic effect, and applied it to 21 patients with CML for whom BCR-ABL1/ABL1 time courses had been quantified before and after TKI cessation. Immunologic control was conceptually necessary to explain TFR as observed in about half of the patients. Fitting the model simulations to data, we identified patientspecific parameters and classified patients into three different groups according to their predicted immune system configuration ("immunologic landscapes"). While one class of patients required complete CML eradication to achieve TFR, other patients were able to control residual leukemia levels after treatment cessation. Among them were a third class of patients that maintained TFR only if an optimal balance between leukemia abundance and immunologic activation was achieved before treatment cessation. Model simulations further suggested that changes in the BCR-ABL1 dynamics resulting from TKI dose reduction convey information about the patient-specific immune system and allow prediction of outcome after treatment cessation. This inference of individual immunologic configurations based on treatment alterations can also be applied to other cancer types in which the endogenous immune system supports maintenance therapy, long-term disease control, or even cure.Significance: This mathematical modeling approach provides strong evidence that different immunologic configurations in patients with CML determine their response to therapy cessation and that dose reductions can help to prospectively infer different risk groups.See related commentary by Triche Jr, p. 2083

Longitudinal monitoring of BCR-ABL transcript levels in peripheral blood of CML patients treated with tyrosine kinase inhibitors (TKI) revealed a typical biphasic response. Although second generation TKIs like dasatinib proved more efficient in achieving molecular remission compared to first generation TKI imatinib, it is unclear how individual responses differ between the drugs and whether mechanisms of drug action can be deduced from the dynamic data. We use time courses from the DASISION trial to address statistical differences in the dynamic response between first line imatinib vs. dasatinib treatment cohorts and we analyze differences between the cohorts by fitting an established mathematical model of functional CML treatment to individual time courses. On average, dasatinib-treated patients show a steeper initial response, while the long-term response only marginally differed between the treatments. Supplementing each patient time course with a corresponding confidence region, we illustrate the consequences of the uncertainty estimate for the underlying mechanisms of CML remission. Our model suggests that the observed BCR-ABL dynamics may result from different, underlying stem cell dynamics. These results illustrate that the perception and description of CML treatment response as a dynamic process on the level of individual patients is a prerequisite for reliable patient-specific response predictions and treatment optimizations.

Background: Individualization and patient-specific optimization of treatment is a major goal of modern health care. One way to achieve this goal is the application of high-resolution diagnostics together with the application of targeted therapies. However, the rising number of different treatment modalities also induces new challenges: Whereas randomized clinical trials focus on proving average treatment effects in specific groups of patients, direct conclusions at the individual patient level are problematic. Thus, the identification of the best patient-specific treatment options remains an open question. Systems medicine, specifically mechanistic mathematical models, can substantially support individual treatment optimization. In addition to providing a better general understanding of disease mechanisms and treatment effects, these models allow for an identification of patient-specific parameterizations and, therefore, provide individualized predictions for the effect of different treatment modalities. Results: In the following we describe a software framework that facilitates the integration of mathematical models and computer simulations into routine clinical processes to support decision-making. This is achieved by combining standard data management and data exploration tools, with the generation and visualization of mathematical model predictions for treatment options at an individual patient level. Conclusions: By integrating model results in an audit trail compatible manner into established clinical workflows, our framework has the potential to foster the use of systems-medical approaches in clinical practice. We illustrate the framework application by two use cases from the field of haematological oncology.

The availability of several methods to unambiguously mark individual cells has strongly fostered the understanding of clonal developments in hematopoiesis and other stem cell driven regenerative tissues. While cellular barcoding is the method of choice for experimental studies, patients that underwent gene therapy carry a unique insertional mark within the transplanted cells originating from the integration of the retroviral vector. Close monitoring of such patients allows accessing their clonal dynamics, however, the early detection of events that predict monoclonal conversion and potentially the onset of leukemia are beneficial for treatment. We developed a simple mathematical model of a self-stabilizing hematopoietic stem cell population to generate a wide range of possible clonal developments, reproducing typical, experimentally and clinically observed scenarios. We use the resulting model scenarios to suggest and test a set of statistical measures that should allow for an interpretation and classification of relevant clonal dynamics. Apart from the assessment of several established diversity indices we suggest a measure that quantifies the extension to which the increase in the size of one clone is attributed to the total loss in the size of all other clones. By evaluating the change in relative clone sizes between consecutive measurements, the suggested measure, referred to as maximum relative clonal expansion (mRCE), proves to be highly sensitive in the detection of rapidly expanding cell clones prior to their dominant manifestation. This predictive potential places the mRCE as a suitable means for the early recognition of leukemogenesis especially in gene therapy patients that are closely monitored. Our model based approach illustrates how simulation studies can actively support the design and evaluation of preclinical strategies for the analysis and risk evaluation of clonal developments.

Over the past decades, quantitative methods linking theory and observation became increasingly important in many areas of life science. Subsequently, a large number of mathematical and computational models has been developed. The BioModels database alone lists more than 140,000 Systems Biology Markup Language (SBML) models. However, while the exchange within specific model classes has been supported by standardisation and database efforts, the generic application and especially the re-use of models is still limited by practical issues such as easy and straight forward model execution. MAGPIE, a Modeling and Analysis Generic Platform with Integrated Evaluation, closes this gap by providing a software platform for both, publishing and executing computational models without restrictions on the programming language, thereby combining a maximum on flexibility for programmers with easy handling for non-technical users. MAGPIE goes beyond classical SBML platforms by including all models, independent of the underlying programming language, ranging from simple script models to complex data integration and computations. We demonstrate the versatility of MAGPIE using four prototypic example cases. We also outline the potential of MAGPIE to improve transparency and reproducibility of computational models in life sciences. A demo server is available at magpie.imb.medizin.tu-dresden.de.

IntroductionDiscontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for Chronic Myeloid Leukemia (CML) patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials.MethodsHere, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success.ResultsOur systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Our results further suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI.DiscussionOur findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.