Spatial structure impacts adaptive therapy by shaping intra-tumoral competition.
Spatial structure impacts adaptive therapy by shaping intra-tumoral competition.
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DOI：
10.1038/s43856-022-00110-x
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Anderson, Alexander R. A.
中科院分区：
文献类型：
--
作者：
Strobl, Maximilian A. R.;Gallaher, Jill;West, Jeffrey;Robertson-Tessi, Mark;Maini, Philip K.;Anderson, Alexander R. A.
适应性治疗旨在利用药物敏感细胞和耐药细胞之间的资源竞争来解决癌症耐药性问题。在这里，我们提出了适应性治疗过程中肿瘤内竞争的理论研究，以探讨在何种情况下它将优于积极治疗。我们开发和分析了一个简单的，二维的，基于晶格的，基于药物的肿瘤模型，其中细胞被分类为完全药物敏感或耐药。随后，我们将该模型与相应的非空间常微分方程模型进行比较，并拟合65例生化复发后接受间歇性雄激素剥夺治疗的前列腺癌患者的纵向前列腺特异性抗原数据。利用我们模型的基于个体的本质，我们明确地展示了适应性治疗过程中对耐药性的竞争性抑制，并研究了不同因素（如初始抗性分数或抗性成本）如何改变竞争。这不仅证实了我们对适应性治疗的理论认识，而且还揭示了耐药细胞之间的竞争可能在实体瘤的适应性治疗中发挥比以前认为的更重要的作用。最后，我们提出了两个案例研究，证明了我们工作的意义：(i)适应性治疗的数学模型，（ii）间歇性雄激素剥夺治疗期间前列腺癌患者的肿瘤内动力学，这是适应性治疗的先驱。我们的工作表明，肿瘤的空间结构是适应性治疗的一个重要因素，并为适应性治疗如何利用特异性间和特异性内竞争来控制耐药性提供了见解。传统上，癌症治疗的重点是最大限度地杀死肿瘤细胞，以达到治愈的目的，但这种积极的治疗可能为耐药细胞的生长开辟空间。相比之下，适应性治疗旨在通过调整治疗来利用药物敏感细胞和耐药细胞之间的竞争，将肿瘤维持在可容忍的大小，同时保留药物敏感细胞。这种方法正在试验中进行测试，但尚未广泛使用，因为需要更深入地了解细胞-细胞竞争。在这里，我们使用了一个数学模型来研究在持续和适应性治疗过程中抵抗细胞的竞争强度，以及与谁竞争，并将我们的见解应用于前列腺癌的激素治疗，其中适应性治疗最近已成功试验。我们的研究结果为适应性治疗如何起作用提供了新的见解，并表明，通过塑造细胞竞争，肿瘤的空间结构在决定治疗反应方面很重要。Strobl等人开发了一种基于agent的适应性治疗下肿瘤细胞耐药空间模型。利用这个模型，他们研究了肿瘤的空间结构如何影响肿瘤内药物敏感和耐药克隆对治疗的竞争动态。
Adaptive therapy aims to tackle cancer drug resistance by leveraging resource competition between drug-sensitive and resistant cells. Here, we present a theoretical study of intra-tumoral competition during adaptive therapy, to investigate under which circumstances it will be superior to aggressive treatment. We develop and analyse a simple, 2-D, on-lattice, agent-based tumour model in which cells are classified as fully drug-sensitive or resistant. Subsequently, we compare this model to its corresponding non-spatial ordinary differential equation model, and fit it to longitudinal prostate-specific antigen data from 65 prostate cancer patients undergoing intermittent androgen deprivation therapy following biochemical recurrence. Leveraging the individual-based nature of our model, we explicitly demonstrate competitive suppression of resistance during adaptive therapy, and examine how different factors, such as the initial resistance fraction or resistance costs, alter competition. This not only corroborates our theoretical understanding of adaptive therapy, but also reveals that competition of resistant cells with each other may play a more important role in adaptive therapy in solid tumours than was previously thought. To conclude, we present two case studies, which demonstrate the implications of our work for: (i) mathematical modelling of adaptive therapy, and (ii) the intra-tumoral dynamics in prostate cancer patients during intermittent androgen deprivation treatment, a precursor of adaptive therapy. Our work shows that the tumour’s spatial architecture is an important factor in adaptive therapy and provides insights into how adaptive therapy leverages both inter- and intra-specific competition to control resistance. Cancer therapy traditionally focuses on maximising tumour cell kill with the aim of achieving a cure, but such aggressive treatment can open up space for drug-resistant cells to grow. In contrast, adaptive therapy aims to leverage competition between drug-sensitive and resistant cells by adjusting treatment to maintain the tumour at a tolerable size, whilst preserving drug-sensitive cells. This approach is being tested in trials but is not yet widely used as deeper understanding of cell-cell competition is required. Here, we used a mathematical model to investigate how strongly, and with whom, resistant cells compete during continuous and adaptive therapy, and applied our insights to hormone therapy in prostate cancer where adaptive therapy has recently been successfully trialed. Our results provide new insights into how adaptive therapy works and show that, by shaping cell competition, the tumour’s spatial architecture is important in determining therapy response. Strobl et al. develop an agent-based spatial model of drug resistance in tumour cells under adaptive therapy. Using this model, they investigate how the tumour’s spatial architecture impacts intratumoural competitive dynamics of drug-sensitive vs. -resistant clones in response to therapy.
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影响因子：
8.8
作者：
El-Kenawi, Asmaa;Gatenbee, Chandler;Gillies, Robert
通讯作者：
Gillies, Robert
影响因子：
17.1
作者：
Enriquez-Navas PM;Kam Y;Das T;Hassan S;Silva A;Foroutan P;Ruiz E;Martinez G;Minton S;Gillies RJ;Gatenby RA
通讯作者：
Gatenby RA
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1126/science.aad3292
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baym M;Stone LK;Kishony R
通讯作者：
Kishony R
影响因子：
8.7
作者：
Bourguet, D;Desquilbet, M;Lemarié, S
通讯作者：
Lemarié, S