Combining hypoxia-activated prodrugs and radiotherapy in silico: Impact of treatment scheduling and the intra-tumoural oxygen landscape

Abstract

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico: (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.

Targeting cellular DNA damage responses in cancer: Anin vitro-calibrated agent-based model simulating monolayer and spheroid treatment responses to ATR-inhibiting drugs

“…The ABM considered in this study is an extension of a mathematical model that has previously been used to study tumour growth and treatment responses to chemotherapy, radiotherapy, hyperthermia and hypoxia-activated prodrugs (Powathil et al, 2012b;Hamis et al, 2020a;Powathil et al, 2015;Hamis et al, 2018Hamis et al, , 2019Bruningk et al, 2018). In recent years, several ABMs have been developed for the purpose of describing various aspects of cancer dynamics (Metzcar et al, 2019), and it should be noted that the modelling approach proposed in Figure 1 is not conceptually limited to usage with the ABM described in this study.…”

“…where maxx ,tu K(x, t u ) denotes the maximum occurring K(x, t u )-value at the time point t u and h is a scaling factor that is included in order to classify cells with oxygen levels of 10%, or less, as hypoxic (Powathil et al, 2012b;Hamis et al, 2020a). Low cellular oxygen levels have been shown to delay cell cycle progression by inducing arrest in, particularly, the G1 phase of the cell cycle (Alarcon et al, 2004).…”

“…It is matched to fit data points extracted from a previous mathematical study by Alarcon et al (Alarcon et al, 2004), in which a Tyson-Novak cell cycle model is extended to incorporate the action of p27, a protein that is up-regulated under hypoxia and delays cell cycle progression. Data-fitting yields the parameter values a 1 = 0.9209, a 2 = 0.8200, a 3 = −0.2389 (Hamis et al, 2020a). Thus the fraction of an agent's doubling time spent in the G1 state is G1DF (K(x, t)) • Θ G1 , where G1DF (K(x, t)) = 1 for normoxic cells.…”

Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506

“…Therefore, gaining a greater mechanistic understanding of the factors and their complex interplay in determining the antitumor effects of CP-506 is essential for successful clinical translation. Despite the clear monotherapeutic activity of CP-506, it should be noted that the therapeutic e cacy of HAPs is predicted to be the greatest when combined with other treatment modalities such as chemo-and radiotherapy(47). Since HAPs mainly target the hypoxic tumor cells, the therapeutic potential can theoretically be enhanced by a different treatment modality that kills aerobic cells.…”

Multiscale Modelling and Analysis of Tumour Growth and Treatment Strategies

“…concentrations typically vary and hypoxic regions are common tumour features [168,169,201]. Avoiding complicated details of vasculature in the model, we here approximate oxygen as diusing in from`outside the boundary of the tumour'.…”