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.

We propose a model of cancer initiation and progression where tumor growth is modulated by an evolutionary coordination game. Evolutionary games of cancer are widely used to model frequency-dependent cell interactions with the most studied games being the Prisoner's Dilemma and public goods games. Coordination games, by their more obscure and less evocative nature, are left understudied, despite the fact that, as we argue, they offer great potential in understanding and treating cancer. In this paper we present the conditions under which coordination games between cancer cells evolve, we propose aspects of cancer that can be modeled as results of coordination games, and explore the ways through which coordination games of cancer can be exploited for therapy.

In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations.

Importance: While systemic therapy for disseminated cancer is often initially successful, malignant cells, using diverse adaptive strategies encoded in the human genome, almost invariably evolve resistance, leading to treatment failure. Thus, the Darwinian dynamics of resistance are formidable barriers to all forms of systemic cancer treatment but rarely integrated into clinical trial design or included within precision oncology initiatives. Observations: We investigate cancer treatment as a game theoretic contest between the physician's therapy and the cancer cells' resistance strategies. This game has 2 critical asymmetries: (1) Only the physician can play rationally. Cancer cells, like all evolving organisms, can only adapt to current conditions; they can neither anticipate nor evolve adaptations for treatments that the physician has not yet applied. (2) It has a distinctive leader-follower (or "Stackelberg") dynamics; the "leader" oncologist plays first and the "follower" cancer cells then respond and adapt to therapy. Current treatment protocols for metastatic cancer typically exploit neither asymmetry. By repeatedly administering the same drug(s) until disease progression, the physician "plays" a fixed strategy even as the opposing cancer cells continuously evolve successful adaptive responses. Furthermore, by changing treatment only when the tumor progresses, the physician cedes leadership to the cancer cells and treatment failure becomes nearly inevitable. Without fundamental changes in strategy, standard-of-care cancer therapy typically results in "Nash solutions" in which no unilateral change in treatment can favorably alter the outcome. Conclusions and Relevance: Physicians can exploit the advantages inherent in the asymmetries of the cancer treatment game, and likely improve outcomes, by adopting more dynamic treatment protocols that integrate eco-evolutionary dynamics and modulate therapy accordingly. Implementing this approach will require new metrics of tumor response that incorporate both ecological (ie, size) and evolutionary (ie, molecular mechanisms of resistance and relative size of resistant population) changes.

In metastatic castrate resistant prostate cancer (mCRPC), abiraterone is conventionally administered continuously at maximal tolerated dose until treatment failure. The majority of patients initially respond well to abiraterone but the cancer cells evolve resistance and the cancer progresses within a median time of 16 months. Incorporating techniques that attempt to delay or prevent the growth of the resistant cancer cell phenotype responsible for disease progression have only recently entered the clinical setting. Here we use evolutionary game theory to model the evolutionary dynamics of patients with mCRPC subject to abiraterone therapy. In evaluating therapy options, we adopt an optimal control theory approach and seek the best treatment schedule using nonlinear constrained optimization. We compare patient outcomes from standard clinical treatments to those with other treatment objectives, such as maintaining a constant total tumor volume or minimizing the fraction of resistant cancer cells within the tumor. Our model predicts that continuous high doses of abiraterone as well as other therapies aimed at curing the patient result in accelerated competitive release of the resistant phenotype and rapid subsequent tumor progression. We find that long term control is achievable using optimized therapy through the restrained and judicious application of abiraterone, maintaining its effectiveness while providing acceptable patient quality of life. Implementing this strategy will require overcoming psychological and emotional barriers in patients and physicians as well as acquisition of a new class of clinical data designed to accurately estimate intratumoral eco-evolutionary dynamics during therapy.

Metastatic prostate cancer is initially treated with androgen deprivation therapy (ADT). However, resistance typically develops in about 1 year – a clinical condition termed metastatic castrate-resistant prostate cancer (mCRPC). We develop and investigate a spatial game (agent based continuous space) of mCRPC that considers three distinct cancer cell types: (1) those dependent on exogenous testosterone (T⁺), (2) those with increased CYP17A expression that produce testosterone and provide it to the environment as a public good (T^P), and (3) those independent of testosterone (T⁻). The interactions within and between cancer cell types can be represented by a 3 × 3 matrix. Based on the known biology of this cancer there are 22 potential matrices that give roughly three major outcomes depending upon the absence (good prognosis), near absence or high frequency (poor prognosis) of T⁻ cells at the evolutionarily stable strategy (ESS). When just two cell types coexist the spatial game faithfully reproduces the ESS of the corresponding matrix game. With three cell types divergences occur, in some cases just two strategies coexist in the spatial game even as a non-spatial matrix game supports all three. Discrepancies between the spatial game and non-spatial ESS happen because different cell types become more or less clumped in the spatial game – leading to non-random assortative interactions between cell types. Three key spatial scales influence the distribution and abundance of cell types in the spatial game: i. Increasing the radius at which cells interact with each other can lead to higher clumping of each type, ii. Increasing the radius at which cells experience limits to population growth can cause densely packed tumor clusters in space, iii. Increasing the dispersal radius of daughter cells promotes increased mixing of cell types. To our knowledge the effects of these spatial scales on eco-evolutionary dynamics have not been explored in cancer models. The fact that cancer interactions are spatially explicit and that our spatial game of mCRPC provides in general different outcomes than the non-spatial game might suggest that non-spatial models are insufficient for capturing key elements of tumorigenesis.