Turnover Modulates the Need for a Cost of Resistance in Adaptive Therapy

Strobl, Maximilian; West, Jeffrey; Viossat, Yannick; Damaghi, Mehdi; Robertson-Tessi, Mark; Brown, Joel S.; Gatenby, Robert A.; Maini, Philip K.; Anderson, Alexander R.A.

doi:10.1158/0008-5472.can-20-0806

Cited by 73 publications

(95 citation statements)

References 59 publications

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“…Previous work by our group and others [15,16,19,22] (n 0 , f R )=(75%,1%)). Lines and shading indicate mean and standard deviation, respectively.…”

Section: High Tumour Cell Density and Low Initial Resistance Fractionmentioning

confidence: 70%

“…To understand the impact of space we compare the ABM to the following ODE model which we have studied previously in [22]:…”

Section: Comparison With the Non-spatial Modelmentioning

confidence: 99%

“…We set K = l 2 and used the same parameter values as for the agent-based simulation otherwise (Table 1). The equations were solved using the RK5(4) explicit Runge-Kutta scheme [28] provided in Scipy (for further details see [22]). Adopted from [13].…”

Section: Comparison With the Non-spatial Modelmentioning

confidence: 99%

“…We previously showed, in a non-spatial model, that high tumour cell turnover rates may increase the benefits of adaptive therapy [22]. To test whether this prediction holds true if spatial interactions are taken into account, we repeat our analysis from the previous section with a cell turnover rate of 30% relative to the proliferation rate, which is the value we previously estimated for prostate cancer [22]. For simplicity, we assume the same death rate for both sensitive and resistant cells and that dead cells are immediately removed from the domain.…”

Section: Turnover Increases the Mean Time Gained By Adaptive Therapy mentioning

confidence: 99%

“…On the other hand, death of a Figure 4. Comparing the spatial (ABM) with the non-spatial (ODE) model from [22]. Lines and shading denote the mean and standard deviation, respectively.…”

Section: The Impact Of Turnover Is Reduced By the Neighbourhood Sizementioning

confidence: 99%

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Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

Strobl

Gallaher

West

et al. 2020

Preprint

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(1) Background: Adaptive therapy aims to tackle cancer drug resistance by leveraging intra-tumoural competition between drug-sensitive and resistant cells. Motivated by promising results in prostate cancer there is growing interest in extending this approach to other cancers. Here we present a theoretical study of intra-tumoural competition during adaptive therapy, to identify under which circumstances it will be superior to aggressive treatment, and how it can be improved through combination treatment; (2) Methods: We study a 2-D, on-lattice, agent-based tumour model. We examine the impact of different micro-environmental factors on the comparison between continuous drug administration and the adaptive schedule pioneered in the first-in-human clinical trial. (3) Results: We show that the degree of crowding, the initial resistance fraction, the presence of possible resistance costs, and the rate of tumour cell turnover are key determinants of the benefit of adaptive therapy. Subsequently, we investigate whether combination with treatments which amplify proliferation or which target cell turnover can prolong tumour control. While the former increases competition, we find that only the latter can robustly improve time to progression; (4) Conclusion: Our work helps to identify selection factors for adaptive therapy and provides stepping stones towards the rational design of multi-drug adaptive regimens.

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“…Previous work by our group and others [15,16,19,22] (n 0 , f R )=(75%,1%)). Lines and shading indicate mean and standard deviation, respectively.…”

Section: High Tumour Cell Density and Low Initial Resistance Fractionmentioning

confidence: 70%

“…To understand the impact of space we compare the ABM to the following ODE model which we have studied previously in [22]:…”

Section: Comparison With the Non-spatial Modelmentioning

confidence: 99%

Section: Comparison With the Non-spatial Modelmentioning

confidence: 99%

Section: Turnover Increases the Mean Time Gained By Adaptive Therapy mentioning

confidence: 99%

“…On the other hand, death of a Figure 4. Comparing the spatial (ABM) with the non-spatial (ODE) model from [22]. Lines and shading denote the mean and standard deviation, respectively.…”

Section: The Impact Of Turnover Is Reduced By the Neighbourhood Sizementioning

confidence: 99%

See 3 more Smart Citations