Adaptive therapy, which anticipates and counters the evolution of resistance in cancer cells, has gained significant traction, especially following the success of the Zhang et al.'s protocol in treating metastatic castrate-resistant prostate cancer. While several adaptive therapies have now advanced to clinical trials, none currently incorporates migrastatics, i.e. treatments designed to inhibit cancer cell metastasis. In this study, we propose integrating migrastatics into adaptive therapy protocols and evaluate its potential benefits through a spatial game-theoretic model. Our results demonstrate that combining adaptive therapy with migrastatics effectively delays the onset of metastases and reduces both the number and size of metastases in most cancer scenarios analyzed. Including migrastatics to adaptive therapy not only extends the time to the first metastasis, but also enhances the overall efficacy of adaptive therapies. Our findings suggest a promising new direction for cancer treatment, where adaptive therapy, in combination with migrastatic agents, can target both the evolution of resistance and the metastatic spread of cancer cells.

Department of Advanced Computing Sciences Maastricht University 6229 EN Maastricht The Netherlands

Department of Cell Biology Charles University 2NP Prague Czech Republic

Institute for Health Systems Science Delft University of Technology 2628 BX Delft The Netherlands

Integrated Mathematical Oncology Department H Lee Moffitt Cancer Center and Research Institute Tampa FL 33612 USA

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Bray, F., Laversanne, M., Weiderpass, E. & Soerjomataram, I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. PubMed DOI

Ganesh, K. & Massagué, J. Targeting metastatic cancer. PubMed DOI PMC

Wan, L., Pantel, K. & Kang, Y. Tumor metastasis: moving new biological insights into the clinic. PubMed DOI

Gatenby, R. A. A change of strategy in the war on cancer. PubMed DOI

Dujon, A. M. et al. Identifying key questions in the ecology and evolution of cancer. PubMed DOI PMC

Ratain, M. J. & Mick, R. Model-guided determination of maximum tolerated dose in phase I clinical trials: A paradigm for dose selection in the era of targeted therapies. PubMed DOI

Gad, S. C. Maximum tolerated dose. In

Cree, I. A. & Charlton, P. Molecular chess? Hallmarks of anti-cancer drug resistance. PubMed PMC

Lage, H. An overview of cancer multidrug resistance: a still unsolved problem. PubMed DOI PMC

Dinić, J. et al. Repurposing old drugs to fight multidrug resistant cancers. PubMed

Staňková, K. Resistance games. PubMed

Strobl, M. et al. Turnover modulates the need for a cost of resistance in adaptive therapy. PubMed DOI PMC

Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive therapy. PubMed DOI PMC

West, J. et al. Towards multidrug adaptive therapy. PubMed DOI PMC

Luddy, K. A. et al. Evolutionary double-bind treatment using radiotherapy and nk cell-based immunotherapy in prostate cancer. PubMed DOI

West, J. et al. A survey of open questions in adaptive therapy: Bridging mathematics and clinical translation. PubMed PMC

Gluzman, M., Scott, J. G. & Vladimirsky, A. Optimizing adaptive cancer therapy: dynamic programming and evolutionary game theory. PubMed DOI PMC

Hockings, H. et al. Adaptive therapy exploits fitness deficits in chemotherapy-resistant ovarian cancer to achieve long-term tumor control. PubMed DOI PMC

Gevertz, J. L. et al. Delaying cancer progression by integrating toxicity constraints in a model of adaptive therapy. PubMed PMC

Soboleva, A., Grossmann, I., Dingemans, A.-M. C., Rezaei, J. & Staňková, K. Bringing evolutionary cancer therapy to clinic through a systems approach. PubMed PMC

Alvarez, F. E. & Viossat, Y. Tumor containment: a more general mathematical analysis. PubMed DOI

Viossat, Y. & Noble, R. A theoretical analysis of tumour containment. PubMed DOI PMC

Wölfl, B. et al. The contribution of evolutionary game theory to understanding and treating cancer. PubMed DOI PMC

Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. PubMed PMC

Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes. PubMed PMC

Gatenby, R. A., Artzy-Randrup, Y., Epstein, T., Reed, D. R. & Brown, J. S. Eradicating metastatic cancer and the eco-evolutionary dynamics of anthropocene extinctions. PubMed DOI PMC

Sleeman, J. & Steeg, P. S. Cancer metastasis as a therapeutic target. PubMed DOI PMC

Dillekås, H., Rogers, M. S. & Straume, O. Are 90% of deaths from cancer caused by metastases?. PubMed DOI PMC

Obenauf, A. C. & Massagué, J. Surviving at a Distance: Organ-Specific Metastasis. PubMed DOI PMC

Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging Biological Principles of Metastasis. PubMed DOI PMC

Sloan, E. K. & Chang, A. Wired to spread: Neural regulation of metastasis. PubMed DOI

Rösel, D., Fernandes, M., Sanz-Moreno, V. & Brábek, J. Migrastatics: Redirecting R&D in Solid Cancer Towards Metastasis?. PubMed DOI

Karagiannis, G. S., Condeelis, J. S. & Oktay, M. H. Chemotherapy-induced metastasis: Molecular mechanisms, clinical manifestations. PubMed DOI PMC

Gandalovičová, A. et al. Migrastatics—anti-metastatic and anti-invasion drugs: Promises and challenges. PubMed DOI PMC

Raudenská, M. et al. Engine shutdown: migrastatic strategies and prevention of metastases. PubMed DOI

Škarková, A. et al. Educate, not kill: treating cancer without triggering its defenses. PubMed DOI

Behrenbruch, C. et al. Surgical stress response and promotion of metastasis in colorectal cancer: a complex and heterogeneous process. PubMed DOI

Bayer, P., Brown, J. S. & Staňková, K. A two-phenotype model of immune evasion by cancer cells. PubMed DOI

You, L. PubMed

Jones, B. C. et al. Dual targeting of mesenchymal and amoeboid motility hinders metastatic behavior. PubMed DOI PMC

Jobe, N. P. et al. Simultaneous blocking of IL-6 and IL-8 is sufficient to fully inhibit CAF-induced human melanoma cell invasiveness. PubMed DOI

Maiques, O. et al. A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma. PubMed DOI PMC

Riihimäki, M., Thomsen, H., Sundquist, K., Sundquist, J. & Hemminki, K. Clinical landscape of cancer metastases. PubMed DOI PMC

Henke, E., Nandigama, R. & Ergün, S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. PubMed PMC

Coggan, H. & Page, K. M. The role of evolutionary game theory in spatial and non-spatial models of the survival of cooperation in cancer: a review. PubMed DOI PMC

Gatenby, R. A. & Brown, J. S. The evolution and ecology of resistance in cancer therapy. PubMed DOI PMC

Gallaher, J. & Anderson, A. R. A. Evolution of intratumoral phenotypic heterogeneity: the role of trait inheritance. PubMed DOI PMC

Wu, A. et al. Cell motility and drug gradients in the emergence of resistance to chemotherapy. PubMed DOI PMC

Pressley, M. et al. Evolutionary dynamics of treatment-induced resistance in cancer informs understanding of rapid evolution in natural systems.

Satouri, M., Rezaei, J. & Staňková, K. Stability of the Darwinian dynamics: Effect of intraspecific competition and human intervention PubMed DOI PMC

Bayer, P. et al. Coordination games in cancer. PubMed DOI PMC

Bayer, P. & West, J. Games and the treatment convexity of cancer. DOI

Kaznatcheev, A., Peacock, J., Basanta, D., Marusyk, A. & Scott, J. G. Fibroblasts and alectinib switch the evolutionary games played by non-small cell lung cancer. PubMed DOI PMC

Arbabi Moghadam, S., Rezania, V. & Tuszynski, J. A. Cell death and survival due to cytotoxic exposure modelled as a two-state ising system. PubMed DOI PMC

Zhao, W. PubMed PMC

Gatenby, R. A., Zhang, J. & Brown, J. S. First strike – second strike strategies in metastatic cancer: Lessons from the evolutionary dynamics of extinction. PubMed PMC

Cunningham, J. J., Brown, J. S., Gatenby, R. A. & Staňková, K. Optimal control to develop therapeutic strategies for metastatic castrate resistant prostate cancer. PubMed DOI

Cunningham, J. J. et al. Optimal control to reach eco-evolutionary stability in metastatic castrate resistant prostate cancer. PubMed DOI PMC

Salvioli, M. et al. Stackelberg evolutionary games of cancer treatment: What treatment strategy to choose if cancer can be stabilized?. PubMed DOI PMC

Beerling, E., Oosterom, I., Voest, E., Lolkema, M. & van Rheenen, J. Intravital characterization of tumor cell migration in pancreatic cancer. PubMed PMC

Soboleva, A., Kaznatcheev, A., Cavill, R., Schneider, K. & Staňková, K. Validation of polymorphic Gompertzian model of cancer through in vitro and in vivo data. PubMed PMC

Garjani, H., Dubbeldam, J., Staňková, K. & Brown, J. S. Which evolutionary game-theoretic model best captures NSCLC dynamics?

Cess, C. G. & Finley, S. D. Calibrating agent-based models to tumor images using representation learning. PubMed DOI PMC

Rivera, M. et al. Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis. PubMed PMC

Lonardo, E., Cioffi, M., Sancho, P., Crusz, S. & Heeschen, C. Studying pancreatic cancer stem cell characteristics for developing new treatment strategies. PubMed DOI PMC

Nazari, S. S. Generation of 3D tumor spheroids with encapsulating basement membranes for invasion studies. PubMed PMC

Trelford, C. B. et al. LKB1 and STRAD promote epithelial ovarian cancer spheroid cell invasion. PubMed DOI PMC

Ghaffari Laleh, N. et al. Classical mathematical models for prediction of response to chemotherapy and immunotherapy. PubMed DOI PMC

Strobl, M. et al. To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy. PubMed DOI PMC