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

Hamis, Sara; Kohandel, Mohammad; Dubois, Ludwig; Yaromina, Ala; Lambin, Philippe; Powathil, Gibin

doi:10.1101/856443

Cited by 3 publications

(6 citation statements)

References 55 publications

(137 reference statements)

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“…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 efficacy 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.…”

Section: Discussionmentioning

confidence: 99%

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

Wiel

Jackson-Patel

Niemans

et al. 2021

Molecular Cancer Therapeutics

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AA and CPG are co-inventors on patents assigned to Health Innovation Ventures (PCT/WO 2014031012 A1). AH, JT, and LD have shares in the company Convert Pharmaceuticals, and LD has a non-issue, non-licensed patent on LSRT (N2024889). JBS and AVP have served as scientific consultants to Convert Pharmaceuticals. AH, ST, and SD have been prior employees of Convert Pharmaceuticals. PL reports -within and outside the submitted work -grants or sponsored research agreements from Varian Medical, Oncoradiomics, ptTheragnostic/DNAmito, Convert Pharmaceuticals, and Health Innovation Ventures. He received an advisor/presenter fee and/or reimbursements of travel costs/external grant writing fee and/or kind manpower contribution from Oncoradiomics, BHV, Merck, Varian, Elekta, ptTheragnostic, and Convert Pharmaceuticals. PL has shares in the company Oncoradiomics SA, Convert Pharmamaceuticals, LivingMed Biotech, and Comunicare Solutions, and is co-inventor of two issues patents with royalties on radiomics (PCT/NL2014/050248, PCT/NL2014/050728) licensed to Oncoradiomics, one issue patent on mtDNA (PCT/EP2014/059089) licensed to ptTheragnostic/DNAmito, three non-patented inventions (software) licensed to ptTheragnostic/DNAmito and Oncoradiomics and Health Innovation Ventures, and three non-issues, non-licensed patents on Deep Learning-Radiomics and LSRT (N2024482, N2024889, N2024889).

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Section: Discussionmentioning

confidence: 99%

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

Wiel

Jackson-Patel

Niemans

et al. 2021

Molecular Cancer Therapeutics

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“…ABMs can also be coupled to detailed models of tumour blood flow, angiogenesis and vascular remodelling to understand how their impact on tumour heterogeneity and the emergence of hypoxic regions [70]. Such detailed ABMs also permit investigation of treatments in which radiotherapy is combined with hypoxiaactivated prodrugs [71].…”

Section: Model Extensionsmentioning

confidence: 99%

The Hallmarks of Mathematical Oncology

Bull

Byrne

2022

Proc. IEEE

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Over the past twenty-five years there has been an unparalleled increase in understanding of cancer biology. This transformation is exemplified by Hanahan and Weinberg's decision in 2011 to expand their original Hallmarks of Cancer from six traits to ten! At the same time, mathematical modelling has emerged as a natural tool for unravelling the complex processes that contribute to the initiation and progression of tumours, for testing hypotheses about experimental and clinical observations, and assisting with the development of new approaches for improving its treatment. This article starts by reviewing some of the earliest models of tumour growth and tumour responses to radiotherapy. Following Hanahan and Weinberg's lead, attention then focuses on how closer collaboration with cancer scientists and access to experimental data is stimulating the development of new and increasingly detailed models which account, for example, for tumour-immune interactions and immunotherapy. The article concludes by discussing the ways in which mathematical modelling is being integrated with experimental and clinical work and outlining how this could improve disease diagnosis and the delivery of effective personalised treatments to cancer patients. As such, the article serves as an introduction to mathematical modelling of cancer and its treatments, suitable for researchers seeking to enter the field.

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“…cells with a partial pressure of oxygen (pO 2 ) value of 10 mmHg or less [20]) display arrest (i.e. delay) in the G1 phase of the cell cycle [21]. As is described bellow, details regarding oxygen dynamics are included in the in vivo model, but not in the in vitro model.…”

Section: Oxygen Distribution and Influence On Cellsmentioning

confidence: 99%

“…In vivo oxygen distribution and responses: Within solid tumours, oxygen concentrations typically vary and hypoxic regions are common tumour features [21,18,22]. Avoiding complicated details of vasculature in the model, we here approximate the oxygen as diffusing in from 'outside the tumour'.…”

Section: Oxygen Distribution and Influence On Cellsmentioning

confidence: 99%

“…It is matched to fit data points extracted from a previous mathematical study by Alarcon et al [15], 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 [21]. 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.…”

Section: Oxygen Distribution and Influence On Cellsmentioning

confidence: 99%

See 1 more Smart Citation

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

Hamis

Yates

Chaplain

et al. 2019

Preprint

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The ATR (ataxia telangiectasia mutated and rad3-related kinase) inhibitor AZD6738 is an anti-cancer drug that potentially hinders tumour proliferation by targeting cellular DNA damage responses. In this study, we combine a systems pharmacology approach with an agent-based modelling approach to simulate AZD6738 treatment responses in silico. The mathematical model is governed by a set of empirically observable rules. By adjusting only the rules, whilst keeping the fundamental mathematical framework and model parameters intact, the mathematical model can first be calibrated by in vitro data and thereafter be used to successfully predict treatment responses in human tumour xenografts in vivo qualitatively, and quantitatively up to approximately 10 days post tumour injection.The deoxyribonucleic acid (DNA) in human cells is perpetually exposed to influences that are potentially harmful. These influences can be derived from both exogenous and endogenous sources and events [1, 2]. Exogenous sources include ultraviolet radiation, ionising radiation (IR) and chemotherapeutic drugs [1], whilst erroneous DNA replication is an example an endogenous event yielding DNA damage [1]. Regardless of the source, a multitude of intracellular events are triggered when the DNA in a cell is damaged. For example, cells may respond to DNA damage by activating DNA repair mechanisms, cell cycle arrest or, in cases of severe DNA damage, apoptosis [3]. Cellular responses to DNA damage are mainly governed by the DNA damage response (DDR) pathway, which comprises a complex network of signaling pathways [3]. The DDR pathway has many functionalities. Amongst other things, the DDR pathway monitors DNA integrity and repairs DNA damage in order to maintain genomic stability in cells. The DDR pathway also governs DNA replication and cell cycle progression, and it controls apoptosis [1,4]. From this, it is clear that the DDR pathway is crucial for maintaining cell viability. When DNA repair is needed, the DDR activates effector proteins [1]. Included in the group of effector proteins are approximately 450 proteins associated with the DDR [4], out of which the two main regulators for cell cycle checkpoints are ataxia telangiectasia mutated kinase (ATM) and ataxia telangiectasia mutated and rad3-related kinase (ATR) [2]. ATM and ATR are two proteins belonging to the enzyme family phosphatidyilinositol-3-OH-kinases (PI3K), and they both play central roles when cells respond to DNA damage [3].The two principle types of DNA lesions are double-strand DNA breaks and single-strand DNA breaks [1]. Double-strand breaks are typically induced by IR [2], and ATM is the central protein involved in repairing double-strand breaks [1]. Single-strand breaks are a common result of replication stress [5] and the repair of single-strand DNA breaks is mainly attributed to ATR activity. ATR is active in the checkpoint in the intra-S phase of the cell cycle, both under undamaged circumstances and in response to DNA damage [3]. Although cross-talk between ATM and ATR regulat...

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

Cited by 3 publications

References 55 publications

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

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

The Hallmarks of Mathematical Oncology

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

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