Approches mathématiques multi-niveaux pour l'étude de la croissance des tumeurs : Application à la morphogenèse du cancer du sein et ciblage thérapeutique de l'angiogenèse du cancer du côlon

Cancer is one of the leading causes of death in Europe. The mechanisms involved in tumour growth are qualitatively known, but we are still unable to precisely predict how a given tumour will evolve, nor estimate with certainty the optimal therapeutic protocol for each patient.It is well understood that mathematical modelling could give part of the answer to these questions. That is why during this thesis we considered the building of mathematical formalisms to describe tumour growth and the action of anti-cancer treatments. In particular, we investigated the molecular to tissular mechanisms of cancer development and angiogenesis through the building of a continuous multi-scale model. We were able to reproduce the effect of anti- angiogenesis treatments on tumour growth, and qualitatively study an optimal therapeutic protocol of anti-angiogenic combined with cytotoxic drugs. This multi-scale model integrates a mathematical representation of the signalling pathways of VEGF (Vascular Endothelial Growth Factor). We detail the development of this model which is based solely on information available in the literature and dedicated databases. In another approach, we considered a discrete, cell-based model to reproduce the development of spheroid structures of mammary epithelial cells. This model considers the behaviour of these cells when observed while grown in vitro in an appropriate medium. We were able to highlight the different mechanisms involved in the morphogenesis of wild and mutated cells structures.This work shows the importance of the multi-scale formalism we used to integrate the knowledge and data related to the study of cancer treatment.Les cancers sont l’une des causes majeures de mortalité dans le monde. Les mécanismes en jeu dans la croissance tumorale sont qualitativement connus, mais on se sait pas à l’heure actuelle prédire précisément quel sera le développement d’une tumeur donnée, ni estimer de façon certaine le protocole thérapeutique optimal pour chaque patient. Il est entendu que la modélisation mathématique pourrait apporter des éléments de réponse à ces questions. Durant cette thèse on s'est alors intéressé à la construction de formalismes mathématiques pour décrire la croissance tumorale et l’action de traitement anti-cancéreux. En particulier, on s'est intéressé à la prise en compte des mécanismes aussi bien moléculaires que cellulaires et tissulaires, par la construction d’un modèle continu, multi-échelles, de croissance de tumeur solide et d’angiogenèse. A partir de ce modèle, nous a pu envisager de façon qualitative un protocole optimal de combinaison entre un anti-angiogénique et une chimiothérapie.Le modèle multi-échelles inclut une représentation mathématique des voies de signalisation du VEGF dont on détaille la construction.Dans une autre approche, on a considéré un modèle discret, cellule-centré, reproduisant le développement de sphéroïdes de cellules épithéliales mammaires telles qu’observées lorsque ces cellules sont cultivées in vitro. On a pu mettre en évidence les différents mécanismes cellulaires impliqués dans la morphogenèse de structures composées de cellules saines, et celles composées de cellules mutées.Ces contributions montrent l’intérêt du formalisme multi-échelles adopté pour intégrer les connaissances et données sous-jacentes à l’étude du traitement des tumeurs

A Model Based Approach for Translation in Oncology - From Xenografts to RECIST

A major problem in drug development is translating results from preclinical studies to the clinical setting. Therefore, we evalu ate the translational potential of semi mechanistic tumor models (based on xenograft data) to predict clinical oncology results (RECISTdata). Two commonly used translational methods are evaluated: (1) replacement with human PK, and (2) allometric scaling of PD pa rameters. We then compute optimal scaling coefficients given the observed clinical data and relate them to the standard allom etr icexponents in method (2). The analysis is performed for three drug combinations: binimetinib/encorafenib (shown below), binime tin ib/ribociclib, and cetuximab/encorafenib

Optimized scaling of translational factors in oncology: from xenografts to RECIST

Purpose: Tumor growth inhibition (TGI) models are regularly used to quantify the PK–PD relationship between drug concentration and\ua0in vivo\ua0efficacy in oncology. These models are typically calibrated with data from xenograft mice and before being used for clinical predictions, translational methods have to be applied. Currently, such methods are commonly based on replacing model components or scaling of model parameters. However, difficulties remain in how to accurately account for inter-species differences. Therefore, more research must be done before xenograft data can fully be utilized to predict clinical response. Method: To contribute to this research, we have calibrated TGI models to xenograft data for three drug combinations using the nonlinear mixed effects framework. The models were translated by replacing mice exposure with human exposure and used to make predictions of clinical response. Furthermore, in search of a better way of translating these models, we estimated an optimal way of scaling model parameters given the available clinical data. Results: The predictions were compared with clinical data and we found that clinical efficacy was overestimated. The estimated optimal scaling factors were similar to a standard allometric scaling exponent of − 0.25. Conclusions: We believe that given more data, our methodology could contribute to increasing the translational capabilities of TGI models. More specifically, an appropriate translational method could be developed for drugs with the same mechanism of action, which would allow for all preclinical data to be leveraged for new drugs of the same class. This would ensure that fewer clinically inefficacious drugs are tested in clinical trials

Perceptions, experiences and health sector responses to intimate partner violence in Malawi: the centrality of context

BACKGROUND: The health sector has ‘duty of care’ to provide comprehensive health services to survivors of violence, to act as a referral point, to collect and document evidence, to report data on violence and to engage in preventive services. In Malawi, 48% of women experience some form of intimate partner violence (IPV) and a significant number report conditions requiring health care services, although few actually report to health services, which are in turn limited in scope and availability. Understanding how health care providers, relevant stakeholders and IPV survivors perceive the role of health care services in IPV is necessary to promote the development of context-relevant and sustainable health care interventions. AIM: To understand the health service responses to IPV in Malawi from a wide range of perspectives OBJECTIVES: i) to critically analyze written legislation, policy and strategy documents in relation to IPV and the health sector in Malawi; ii) to describe the perceptions and experiences of IPV and of health sector responses among survivors of violence, community members, health care workers and other key stakeholders in Malawi; iii) to estimate the extent of intimate partner and sexual violence from a health service uptake perspective using proxy determinants at one referral hospital in Malawi iv) To explore the policy implications of the study findings for the health sector responses in Malawi METHODS: In 2011, a multi-method situation analysis was conducted in three areas of Blantyre district, with additional data collected in Mangochi and Lilongwe districts. Seventeen relevant national documents were analyzed. A total of 10 focus group discussions (FGDs), 2 small groups and 14 individual interviews (IIs) were conducted with health care providers; 18 FGDs and one small group discussion were conducted with male and female, urban and rural community members; 12 in-depth interviews (IDIs) with survivors; 26 key informant interviews (KIIs) with donor agencies, GBV service providers, religious institutions; police officers and other stakeholders were conducted. A review of 3,567 register records for the month of January 2011 was done in Queen Elizabeth Central Hospital and police records on violence cases in Blantyre for the same month were reviewed. Qualitative data was analyzed using the ‘framework’ approach, assisted by NVIVO 9 software. Hospital records were analyzed using Epi Info™. Feminist approaches and the ecological framework for analysis of violence informed data analysis and interpretation. A range of quality assurance measures were undertaken and data were triangulated across all methods: policy analysis, interviews and records reviews. FINDINGS: A review of legislation and policy combined with qualitative stakeholder interviews revealed conflicts, gaps and lack of awareness of the available documents that undermined coordinated health sector responses. Survivors, community members and health care workers revealed that IPV is perceived as a massive, though under-recognised problem. IPV in its various forms was seen as widespread and normalised, except perhaps in the perceived severe forms (such as femicide and child rape). IPV, though considered as shameful, was not necessarily a very private matter with involvement of neighbours, families, friends and significant others. Various factors at individual, interpersonal, society and institutional levels were described as affecting under-reporting, access to services and responses from sources of support. The review of registered data confirmed that IPV is generally underreported in health services and that relying on trauma as a proxy for IPV against women would prove difficult to implement. This multi-method approach highlighted the importance of diagnostic identification and the difficulties of universal screening. The actual role of health services in IPV seemed fuzzy from the service user’s perspectives and narrowly confined to the bio-medical model or acute model of health service provision. However, both potential service users and health care providers were optimistic about new developments such as ‘One Stop Centres’ and about the potential role of health services, particularly those linked to HIV programmes. They suggested these be provided as a continuum from prevention to rehabilitation. CONCLUSIONS: This study found a range of laws and policies that define and promote action to prevent IPV in Malawi. These have had some positive influences on both community norms and health sector responses. However, ineffective promotion has limited their effectiveness. In addition there are gaps and inconsistencies that reduce their potential in guiding the health sector response to IPV. The study explored stakeholders’ perceptions of IPV, the health sector response and the factors shaping it. This revealed a complex web of interconnected socio-economic, cultural, political and institutional factors. Perceptions of violence are culturally normative and related to gender roles and expectations. The inclusion of male voices on IPV against men, and using emic definitions of violence revealed conflicts between women’s and men’s interpretations of IPV, particularly with regard to sexual violence and the transgression of gender and marital roles. The specific socio-economic and cultural context strongly favours a conflict resolution model of responding to violence, which raises questions about the mandate and the potential roles of the health sector. Most stakeholders perceive IPV as a significant problem and recognise multiple impacts on health. However there is a clear disconnect between the magnitude of the problem and the health sector response. Nevertheless, the health sector is well placed to play a leadership role and has some resources, such as HIV Testing and Counselling staff and curricula to offer in a multi-sectoral response. Proxy determinants as reflected in the health service registers proved to be inadequate due to poor reporting and recording, and under-reporting to health services. Under-reporting was influenced by a range of inter-connected barriers to formal help-seeking, including normative attitudes and ineffective responses by both informal and formal sources of support. However, knowledge was generated about the challenges to recording and reporting IPV in this setting. The study findings suggested a number of key opportunities for improving the health sector response to IPV in Malawi that may be appropriate in this specific context and considered their potential sustainability

Approches mathématiques multi-niveaux pour l'étude de la croissance des tumeurs (Application à la morphogenèse du cancer du sein et ciblage thérapeutique de l'angiogenèse du cancer du côlon)

Les cancers sont l une des causes majeures de mortalité dans le monde. Les mécanismes en jeu dans la croissance tumorale sont qualitativement connus, mais on se sait pas à l heure actuelle prédire précisément quel sera le développement d une tumeur donnée, ni estimer de façon certaine le protocole thérapeutique optimal pour chaque patient. Il est entendu que la modélisation mathématique pourrait apporter des éléments de réponse à ces questions. Durant cette thèse on s'est alors intéressé à la construction de formalismes mathématiques pour décrire la croissance tumorale et l action de traitement anti-cancéreux. En particulier, on s'est intéressé à la prise en compte des mécanismes aussi bien moléculaires que cellulaires et tissulaires, par la construction d un modèle continu, multi-échelles, de croissance de tumeur solide et d angiogenèse. A partir de ce modèle, nous a pu envisager de façon qualitative un protocole optimal de combinaison entre un anti-angiogénique et une chimiothérapie.Le modèle multi-échelles inclut une représentation mathématique des voies de signalisation du VEGF dont on détaille la construction.Dans une autre approche, on a considéré un modèle discret, cellule-centré, reproduisant le développement de sphéroïdes de cellules épithéliales mammaires telles qu observées lorsque ces cellules sont cultivées in vitro. On a pu mettre en évidence les différents mécanismes cellulaires impliqués dans la morphogenèse de structures composées de cellules saines, et celles composées de cellules mutées.Ces contributions montrent l intérêt du formalisme multi-échelles adopté pour intégrer les connaissances et données sous-jacentes à l étude du traitement des tumeurs.Cancer is one of the leading causes of death in Europe. The mechanisms involved in tumour growth are qualitatively known, but we are still unable to precisely predict how a given tumour will evolve, nor estimate with certainty the optimal therapeutic protocol for each patient.It is well understood that mathematical modelling could give part of the answer to these questions. That is why during this thesis we considered the building of mathematical formalisms to describe tumour growth and the action of anti-cancer treatments. In particular, we investigated the molecular to tissular mechanisms of cancer development and angiogenesis through the building of a continuous multi-scale model. We were able to reproduce the effect of anti- angiogenesis treatments on tumour growth, and qualitatively study an optimal therapeutic protocol of anti-angiogenic combined with cytotoxic drugs. This multi-scale model integrates a mathematical representation of the signalling pathways of VEGF (Vascular Endothelial Growth Factor). We detail the development of this model which is based solely on information available in the literature and dedicated databases. In another approach, we considered a discrete, cell-based model to reproduce the development of spheroid structures of mammary epithelial cells. This model considers the behaviour of these cells when observed while grown in vitro in an appropriate medium. We were able to highlight the different mechanisms involved in the morphogenesis of wild and mutated cells structures.This work shows the importance of the multi-scale formalism we used to integrate the knowledge and data related to the study of cancer treatment.LYON-ENS Sciences (693872304) / SudocSudocFranceF

Exposure-response modeling improves selection of radiation and radiosensitizer combinations

A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate

Modeling long-term tumor growth and kill after combinations of radiation and radiosensitizing agents

Purpose: Radiation therapy, whether given alone or in combination with chemical agents, is one of the cornerstones of oncology. We develop a quantitative model that describes tumor growth during and after treatment with radiation and radiosensitizing agents. The model also describes long-term treatment effects including tumor regrowth and eradication. Methods: We challenge the model with data from a xenograft study using a clinically relevant administration schedule and use a mixed-effects approach for model-fitting. We use the calibrated model to predict exposure combinations that result in tumor eradication using Tumor Static Exposure (TSE). Results: The model is able to adequately describe data from all treatment groups, with the parameter estimates taking biologically reasonable values. Using TSE, we predict the total radiation dose necessary for tumor eradication to be 110\ua0Gy, which is reduced to 80 or 30\ua0Gy with co-administration of 25 or 100\ua0mg\ua0kg\ua0−1\ua0of a radiosensitizer. TSE is also explored via a heat map of different growth and shrinkage rates. Finally, we discuss the translational potential of the model and TSE concept to humans. Conclusions: The new model is capable of describing different tumor dynamics including tumor eradication and tumor regrowth with different rates, and can be calibrated using data from standard xenograft experiments. TSE and related concepts can be used to predict tumor shrinkage and eradication, and have the potential to guide new experiments and support translations from animals to humans

Modeling of radiation therapy and radiosensitizing agents in tumor xenografts

III-36\ua0Tim\ua0Cardilin\ua0Modeling of radiation therapy and radiosensitizing agents in tumor xenografts\ua0Tim Cardilin (1,2), Joachim Almquist (1), Mats Jirstrand (1), Astrid Zimmermann (3), Floriane Lignet (4), Samer El Bawab (4), and Johan Gabrielsson (5)(1) Fraunhofer-Chalmers Centre, Gothenburg, Sweden, (2) Department of Mathematical Sciences, Chalmers University of Technology and Gothenburg University, Gothenburg, Sweden, (3) Merck, Translational Innovation Platform Oncology, Darmstadt, Germany, (4) Merck, Global Early Development - Quantitative Pharmacology, Darmstadt, Germany, (5) Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, SwedenObjectives:\ua0To conceptually and mathematically describe the treatment effects of radiation and radiosensitizing agents on tumor volume in xenografts with respect to short- and long-term effects.Methods:\ua0Data were generated in FaDu xenograft mouse models, where animals were treated with radiation given either as monotherapy (2 Gy per dose) or together with an early-discovery radiosensitizing agent (25 or 100 mg/kg per dose) that interferes with the repair of the DNA damage induced by irradiation. Animals received treatment following a clinically-relevant administration schedule with doses five days a week for six weeks. Tumor diameters were measured by caliper twice a week for up to 140 days. A pharmacodynamic tumor model was adapted from a previously-published model [1,2]. The improved model captures both short- and long-term treatment effects including tumor eradication and tumor regrowth. Short-term radiation effects are described by allowing lethally irradiated cells up to one more cell division before apoptosis. Long-term radiation effects are described by an irreversible decrease in tumor growth rate. The radiosensitizing agent was assumed to stimulate both processes. The model also includes a natural death rate of cancer cells. The model was calibrated to the xenograft data using a mixed-effects approach based on the FOCE method that was implemented in Mathematica [3]. Between-subject variability was accounted for in initial tumor volume, as well as in the short- and long-term radiation effects.Results:\ua0Data across all treatment groups were well-described by the model. All model parameters were estimated with acceptable precision and biologically reasonable values. Vehicle growth was approximately exponential during the observed time period with an estimated tumor doubling time of approximately 5 days. Tumor growth following radiation therapy resulted in significant tumor regression followed by either tumor eradication (2 animals) or slow regrowth (7 animals). The short- and long-term effects incorporated into the tumor model were able to account for both of these scenarios. A simple analysis shows that if the tumor growth rate is decreased below the natural death rate, the tumor will be eradicated. Otherwise, the tumor will regrow but at a slower rate compared to pre-treatment. The model predicts that each fraction of radiation (2 Gy) results in lethal damage in 15 % of viable cells, and that a total dose above 120 Gy will eradicate the tumor. Tumor growth following combination therapy with a lower dose (25 mg/kg) resulted in more cases of tumor eradication (6 animals) and fewer cases of regrowth (3 animals), whereas combination therapy with the higher dose (100 mg/kg) resulted in tumor eradication in all 9 animals. When radiation therapy was complemented by radiosensitizing treatment (100 mg/kg per dose), each fraction of 2 Gy was estimated to kill 25 % of viable cells, and the total radiation dose required for tumor eradication was decreased by a factor four to 30 Gy.Conclusions:\ua0A tumor model has been developed to describe the treatment effects of radiation therapy, as well as combination therapies involving radiation, in tumor xenografts. The model distinguishes between short- and long-term effects of radiation treatment and can describe different tumor dynamics, including tumor eradication and tumor regrowth at different rates. The novel tumor model can be used to predict treatment outcomes for a broad range of treatments including radiation therapy and combination therapies with different radiosensitizing agents.References:\ua0[1] Cardilin T, Almquist J, Jirstrand M, Zimmermann A, El Bawab S, Gabrielsson J. Model-based evaluation of radiation and radiosensitizing agents in oncology. CPT: Pharmacometrics & Syst. Pharmacol.\ua0(2017).[2] Cardilin T, Zimmermann A, Jirstrand M, Almquist J, El Bawab S, Gabrielsson J. Extending the Tumor Static Concentration Curve to average doses – a combination therapy example using radiation therapy. PAGE 25 (2016) Abstr 5975 [www.page-meeting.org/?abstract=5975].[3] Almquist J, Leander J, Jirstrand M. Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood. J Pharmacokinet Pharmacodyn (2015) 42: 191-209

Perceptions of the mental health impact of intimate partner violence and health service responses in Malawi

Background and objectives: This study explores the perceptions of a wide range of stakeholders in Malawi towards the mental health impact of intimate partner violence (IPV) and the capacity of health services for addressing these. Design: In-depth interviews (IDIs) and focus group discussions (FGDs) were conducted in three areas of Blantyre district, and in two additional districts. A total of 10 FGDs, 1 small group, and 14 IDIs with health care providers; 18 FGDs and 1 small group with male and female, urban and rural community members; 7 IDIs with female survivors; and 26 key informant interviews and 1 small group with government ministry staff, donors, gender-based violence service providers, religious institutions, and police were conducted. A thematic framework analysis method was applied to emerging themes. Results: The significant mental health impact of IPV was mentioned by all participants and formal care seeking was thought to be impeded by social pressures to resolve conflict, and fear of judgemental attitudes. Providers felt inadequately prepared to handle the psychosocial and mental health consequences of IPV; this was complicated by staff shortages, a lack of clarity on the mandate of the health sector, as well as confusion over the definition and need for ‘counselling’. Referral options to other sectors for mental health support were perceived as limited but the restructuring of the Ministry of Health to cover violence prevention, mental health, and alcohol and drug misuse under a single unit provides an opportunity. Conclusion: Despite widespread recognition of the burden of IPV-associated mental health problems in Malawi, there is limited capacity to support affected individuals at community or health sector level. Participants highlighted potential entry points to health services as well as local and national opportunities for interventions that are culturally appropriate and are built on local structures and resilience

Regulation of HIV self-testing in Malawi, Zambia and Zimbabwe: a qualitative study with key stakeholders.

INTRODUCTION: HIV self-testing (HIVST) is being introduced as a new way for more undiagnosed people to know their HIV status. As countries start to implement HIVST, assuring the quality and regulating in vitro diagnostics, including HIVST, are essential. We aimed to document the emerging regulatory landscape and perceptions of key stakeholders involved in HIVST policy and regulation prior to implementation in three low- and middle-income countries. METHODS: Between April and August 2016, we conducted semi-structured interviews in Malawi, Zambia and Zimbabwe to understand the relationships between different stakeholders on their perceptions of current and future HIVST regulation and the potential impact on implementation. We purposively sampled and interviewed 66 national-level key stakeholders from the Ministry of Health and the regulatory, laboratory, logistical, donor and non-governmental sectors. We used a thematic approach to analysis with an inductively developed common coding framework to allow inter-country comparison of emerging themes. RESULTS: In all countries, the national reference laboratory was monitoring the quality of HIVST kits entering the public sector. In Malawi, there was no legal mandate to regulate medical devices, in Zambia one regulatory body with a clear mandate had started developing regulations and in Zimbabwe the mandate to regulate was overlapping between two bodies. Stakeholders indicated that they had a poor understanding of the process and requirements for HIVST regulation, as well as lack of clarity and coordination between organizational roles. The need for good collaboration between sectors, a strong post-market surveillance model for HIVST and technical assistance to develop regulators capacity was noted as priorities. Key informants identified technical working groups as a potential way collaboration could be improved upon to accelerate the regulation of HIVST. CONCLUSION: Regulation of in vitro diagnostic devices, including HIVST, is now being recognized as important by regulators after a regional focus on pharmaceuticals. HIVST is providing an opportunity for each country to develop similar regulations to others in the region leading to a more coherent regulatory environment for the introduction of new devices