Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives.
Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives.
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DOI：
10.3934/mbe.2021315
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发表时间：
2021-07-21
期刊：
影响因子：
--
通讯作者：
Adler FR
中科院分区：
文献类型：
--
作者：
Buhler CK;Terry RS;Link KG;Adler FR
当根除是不可能的，癌症治疗的目的是延迟耐药性的出现，同时尽量减少癌症的负担和治疗。适应性疗法可以实现这些目标，其成功基于三个假设：抗性是昂贵的，敏感细胞与抗性细胞竞争，治疗减少了敏感细胞的数量。我们使用一系列数学模型和治疗策略来研究控制细胞群体和延迟耐药性出现之间的权衡。这些模型扩展了博弈论和竞争模型，增加了四个额外的组成部分：1）Allee效应，其中细胞群体在低群体规模下生长较慢，2）与癌细胞竞争的健康细胞，3）抑制癌细胞的免疫细胞，以及4）对生长因子（如雄激素）的资源竞争。在比较最大耐受剂量、间歇性治疗和适应性治疗策略时，没有一种治疗选择能有力地打破这三种治疗目标之间的三方权衡。几乎所有的模型都显示出耐药细胞出现的时间和癌细胞负荷之间的紧密权衡，间歇性和适应性治疗遵循相同的曲线。对于大多数模型，一些适应性疗法比间歇性疗法更能延迟整体肿瘤生长，但代价是更高的细胞群。Allee效应打破了这些关系，一些适应性疗法表现不佳，因为它们未能充分治疗以使人群低于阈值。当根除是不可能的，没有治疗可以同时延迟耐药性的出现，限制癌细胞总数，并尽量减少治疗。简单的数学模型可以在设计平衡这些竞争目标的下一代疗法中发挥作用。
When eradication is impossible, cancer treatment aims to delay the emergence of resistance while minimizing cancer burden and treatment. Adaptive therapies may achieve these aims, with success based on three assumptions: resistance is costly, sensitive cells compete with resistant cells, and therapy reduces the population of sensitive cells. We use a range of mathematical models and treatment strategies to investigate the tradeoff between controlling cell populations and delaying the emergence of resistance. These models extend game theoretic and competition models with four additional components: 1) an Allee effect where cell populations grow more slowly at low population sizes, 2) healthy cells that compete with cancer cells, 3) immune cells that suppress cancer cells, and 4) resource competition for a growth factor like androgen. In comparing maximum tolerable dose, intermittent treatment, and adaptive therapy strategies, no therapeutic choice robustly breaks the three-way tradeoff among the three therapeutic aims. Almost all models show a tight tradeoff between time to emergence of resistant cells and cancer cell burden, with intermittent and adaptive therapies following identical curves. For most models, some adaptive therapies delay overall tumor growth more than intermittent therapies, but at the cost of higher cell populations. The Allee effect breaks these relationships, with some adaptive therapies performing poorly due to their failure to treat sufficiently to drive populations below the threshold. When eradication is impossible, no treatment can simultaneously delay emergence of resistance, limit total cancer cell numbers, and minimize treatment. Simple mathematical models can play a role in designing the next generation of therapies that balance these competing objectives.
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影响因子：
3
作者：
Ideta, Aiko Miyamura;Tanaka, Gouhei;Aihara, Kazuyuki
通讯作者：
Aihara, Kazuyuki
影响因子：
3.1
作者：
Ballesta, Annabelle;Clairambault, Jean
通讯作者：
Clairambault, Jean
DOI：
10.1038/ncpuro1296
发表时间：
2009-02
期刊：
NATURE CLINICAL PRACTICE UROLOGY
影响因子：
--
作者：
Harris, William P.;Mostaghel, Elahe A.;Nelson, Peter S.;Montgomery, Bruce
通讯作者：
Montgomery, Bruce
影响因子：
4.1
作者：
Aguade-Gorgorio, Guim;Sole, Ricard
通讯作者：
Sole, Ricard
影响因子：
4.6
作者：
Hirata Y;Morino K;Akakura K;Higano CS;Aihara K
通讯作者：
Aihara K