Spatial drug asymmetry modulates phenotypic diversity-migration relationships under resistance evolution DOI Creative Commons
Zhijian Hu, Yuzhen Wu, Kevin B. Wood

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract At long timescales, resistant phenotypes will emerge and be selected within the bacterial population as an evolutionary response to drug exposure. This phenomenon reduces efficacy of therapies thus compromises patient health. In spatially heterogeneous environments, recent evidence shows that migration can either promote or decelerate evolution antibiotic resistance, thereby affecting rate phenotype emergence. However, another important quantitative aspect resistance evolution—bacterial phenotypic diversity—has often been overlooked remains challenging investigate in extended systems, both experimentally clinically. order study how diversity is reshaped by across space, here we designed a minimal 2-well experimental system with spatial asymmetry. One well contained bacteriostatic (Linezolid) at minimum inhibitory concentration, while other served sanctuary just media. We found relationship between follows “Intermediate Disturbance Hypothesis” (IDH), disturbance each well. By varying selective concentrations, observed diversity-migration changes, IDH disappear. behavior was explained asymmetry parameter derived from two-phenotype growth-migration dynamic model. To further validate different asymmetries modulate through this parameter, applied bactericidal drug, Ampicillin, similar results. more complex scenario involving Linezolid four distinct phenotypes, including cross-resistant variants, emerged. Our successfully relationship, unique dynamics such multiple peaks appearing The generalist-specialist framework predicted these behaviors global fitness advantages. findings provide support theoretical explanations for emergence clinical settings, gut-lung translocation. These insights may pave way improved strategies manage evolution.

Язык: Английский

Conditional success of adaptive therapy: the role of treatment-pausing thresholds revealed by mathematical modeling DOI Open Access

Lanfei Sun,

Haifeng Zhang,

Kai Kang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

SUMMARY Adaptive therapy (AT) improves cancer treatment by controlling the competition between sensitive and resistant cells via holidays. This study highlights critical role of treatment-pausing thresholds in AT for tumors composed drug-sensitive cells. Using a Lotka-Volterra model, research compares with maximum tolerated dose intermittent therapy, showing that AT’s success largely depends on threshold at which is paused resumed, as well Three scenarios comparison others are identified: uniform-decline, conditionalimprove, uniform-improve, illustrating optimizing crucial effectiveness. Tumor composition, including initial tumor burden proportion cells, influences outcomes. Adjusting values enables to suppress subclones, preserving ultimately improving progression-free survival. These findings underscore importance personalized strategies management enhancing long-term therapeutic

Язык: Английский

Процитировано

0
Stackelberg Evolutionary Games of Cancer Treatment: What Treatment Strategy to Choose if Cancer Can be Stabilized? DOI Creative Commons
Mónica L. Salvioli, Hasti Garjani, Mohammadreza Satouri

и другие.

Dynamic Games and Applications, Год журнала: 2024, Номер unknown

Опубликована: Дек. 14, 2024

Abstract We present a game-theoretic model of polymorphic cancer cell population where the treatment-induced resistance is quantitative evolving trait. When stabilization tumor burden possible, we expand into Stackelberg evolutionary game, physician leader and cells are followers. The chooses treatment dose to maximize an objective function that proxy patient’s quality life. In response, evolve level maximizes their proliferation survival. Assuming in its ecological equilibrium, compare outcomes three different strategies: giving maximum tolerable throughout, corresponding standard care for most metastatic cancers, ecologically enlightened therapy, anticipates short-run, response treatment, but not evolution evolutionarily both consequences treatment. Of therapeutic strategies, therapy leads highest values function, lowest dose, resistance. Conversely, our model, worst

Язык: Английский

Процитировано

3
Deciphering population-level response under spatial drug heterogeneity on microhabitat structures DOI Creative Commons
Zhijian Hu, Kevin B. Wood

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Abstract Bacteria and cancer cells live in a spatially heterogeneous environment, where migration shapes the microhabitat structures critical for colonization metastasis. The interplay between growth, migration, structure complicates prediction of population responses to drugs, such as clearance or sustained posing longstanding challenge. Here, we disentangle growth-migration dynamics identify that decline is determined by two decoupled terms: spatial growth variation term term. Notably, can be interpreted dynamic-related centrality measure. For fixed drug arrangements, show interpreting these centralities reveals how different network structures, even with identical edge densities, numbers, heterogeneity, lead distinct population-level responses. Increasing density shifts response from clearance, supporting an inversed centrality-connectivity relationship, mirroring effects higher rates. Furthermore, derive sufficient condition robust across various rate regardless spatial-temporal fluctuations induced drugs. Additionally, demonstrate varying maximum growth-to-death ratio, drug-bacteria interactions, profiles minimal phase emerges. These findings address key challenges predicting provide insights into divergent clinical outcomes under dosages. This work may offer new method treatment potential approaches optimizing explicit dosing strategies.

Язык: Английский

Процитировано

0
Dynamic Behaviors of a Periodic System with Threshold Policy-Guided Periodic and Intermittent Therapy of Tumor DOI
Biao Tang,

Yanni Xiao,

Jianhong Wu

и другие.

SIAM Journal on Applied Mathematics, Год журнала: 2025, Номер 85(1), С. 366 - 392

Опубликована: Фев. 18, 2025

Язык: Английский

Процитировано

0
Optimal adaptive cancer therapy based on evolutionary game theory DOI Creative Commons

Zhiqing Li,

Xuewen Tan, Yao Yu

и другие.

PLoS ONE, Год журнала: 2025, Номер 20(4), С. e0320677 - e0320677

Опубликована: Апрель 23, 2025

Cancer development is a dynamic and continuously evolving process, with the emergence of drug-resistant cancer cells being one primary reasons for failure traditional treatments. Adaptive therapy, as an emerging treatment strategy, increasingly applied in oncology. In this study, we incorporate pharmacokinetics into evolutionary game theory model propose optimal control problem constrained by maximum drug concentration tumor burden. Firstly, demonstrate existence problem. Secondly, using Pontryagin’s minimum principle, formulated structure to design adaptive therapy strategy. Finally, through numerical simulations, compare strategy other therapies treatments, further develop personalized plans different patient groups. The results that optimized effectively preserves high survival rate healthy during treatment. By maintaining drug-sensitive cell populations state low-level competition, approach prevents proliferation cells, reduces burden on patients, extends overall survival.

Язык: Английский

Процитировано

0
Personalized cancer treatment strategies incorporating irreversible and reversible drug resistance mechanisms DOI Creative Commons
Wei He, Matthew McCoy, Rebecca B. Riggins

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 4, 2024

ABSTRACT Despite advances in targeted cancer therapy, the promise of precision medicine has been limited by resistance to these treatments. In this study, we propose a mathematical modelling framework incorporating cellular heterogeneity, genetic evolutionary dynamics, and non-genetic plasticity, accounting for both irreversible reversible drug resistance. Previously proposed Dynamic Precision Medicine (DPM), personalized treatment strategy that designed individualized sequences simulations dynamics heterogeneous tumor. Here apply DPM joint model mechanisms, analyze simulation results compare efficacy various strategies. The indicate enhanced version superior patient outcomes compared with current approaches. Our provide insights into strategies tumors potentially leading improvements survival time patients.

Язык: Английский

Процитировано

0
Study protocol for Adaptive ChemoTherapy for Ovarian cancer (ACTOv): a multicentre phase II randomised controlled trial to evaluate the efficacy of adaptive therapy (AT) with carboplatin, based on changes in CA125, in patients with relapsed platinum-sensitive high-grade serous or high-grade endometrioid ovarian cancer DOI Creative Commons
Uma Mukherjee, Helen Hockings, Nicholas Counsell

и другие.

BMJ Open, Год журнала: 2024, Номер 14(12), С. e091262 - e091262

Опубликована: Дек. 1, 2024

Introduction Adaptive ChemoTherapy for Ovarian cancer (ACTOv) is a phase II, multicentre, randomised controlled trial, evaluating an adaptive therapy (AT) regimen with carboplatin in women relapsed, platinum-sensitive high-grade serous or endometrioid of the ovary, fallopian tube and peritoneum whose disease has progressed at least 6 months after day 1 last cycle platinum-based chemotherapy. AT novel, evolutionarily informed approach to treatment, which aims exploit intratumoral competition between drug-sensitive drug-resistant tumour subpopulations by modulating drug dose according patient’s own response round treatment. ACTOv first clinical trial this setting. Methods analysis 80 patients will be 1:1 standard (control) (investigational) arms. The starting maximum both arms area under curve (AUC) ×5 absolute nuclear medicine glomerular filtration rate. modify changes serum biomarker CA125, proxy measure total burden. Patients receive treatment intravenously every 21 days 12 cycles control investigational arms, respectively. primary endpoint modified progression-free survival (investigator-assessed using RECIST 1.1 (Response Evaluation Criteria Solid Cancers) compared baseline prerandomisation scan rather than radiological nadir), progression death from any cause. Secondary endpoints include acceptability, deliverability, compliance, toxicity, quality life overall survival. open National Health Service hospitals throughout UK, recruitment anticipated take 36 across 10 sites managed Cancer Research UK University College London Trials Centre. Ethics dissemination been reviewed received approval London—Dulwich Committee (REC). Results disseminated through publication peer-reviewed journals. Trial registration number NCT05080556 .

Язык: Английский

Процитировано

0
Spatial drug asymmetry modulates phenotypic diversity-migration relationships under resistance evolution DOI Creative Commons
Zhijian Hu, Yuzhen Wu, Kevin B. Wood

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract At long timescales, resistant phenotypes will emerge and be selected within the bacterial population as an evolutionary response to drug exposure. This phenomenon reduces efficacy of therapies thus compromises patient health. In spatially heterogeneous environments, recent evidence shows that migration can either promote or decelerate evolution antibiotic resistance, thereby affecting rate phenotype emergence. However, another important quantitative aspect resistance evolution—bacterial phenotypic diversity—has often been overlooked remains challenging investigate in extended systems, both experimentally clinically. order study how diversity is reshaped by across space, here we designed a minimal 2-well experimental system with spatial asymmetry. One well contained bacteriostatic (Linezolid) at minimum inhibitory concentration, while other served sanctuary just media. We found relationship between follows “Intermediate Disturbance Hypothesis” (IDH), disturbance each well. By varying selective concentrations, observed diversity-migration changes, IDH disappear. behavior was explained asymmetry parameter derived from two-phenotype growth-migration dynamic model. To further validate different asymmetries modulate through this parameter, applied bactericidal drug, Ampicillin, similar results. more complex scenario involving Linezolid four distinct phenotypes, including cross-resistant variants, emerged. Our successfully relationship, unique dynamics such multiple peaks appearing The generalist-specialist framework predicted these behaviors global fitness advantages. findings provide support theoretical explanations for emergence clinical settings, gut-lung translocation. These insights may pave way improved strategies manage evolution.

Язык: Английский

Процитировано

0