A cautionary tale on using tumour growth rate to predict survival

 View ORCID ProfileHitesh Mistry, Fernando Ortega

doi: https://doi.org/10.1101/109934

This article is a preprint and has not been peer-reviewed [what does this mean?].

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Abstract

A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. We found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial we found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

http://biorxiv.org/content/early/2017/02/20/109934

Allele Frequency Spectrum in a Cancer Cell Population

Hisashi Ohtsuki, Hideki Innan

 

Abstract

A cancer grows from a single cell, thereby constituting a large cell population. In this work, we are interested in how mutations accumulate in a cancer cell population. We provide a theoretical framework of the stochastic process in a cancer cell population and obtain near exact expressions of allele frequency spectrum or AFS (only continuous approximation is involved) from both forward and backward treatments under a simple setting; all cells undergo cell division and die at constant rates, b and d, respectively, such that the entire population grows exponentially. This setting means that once a parental cancer cell is established, in the following growth phase, all mutations are assumed to have no effect on b or d (i.e., neutral or passengers). Our theoretical results show that the difference from organismal population genetics is mainly in the coalescent time scale, and the mutation rate is defined per cell division, not per time unit (e.g., generation). Except for these two factors, the basic logic are very similar between organismal and cancer population genetics, indicating that a number of well established theories of organismal population genetics could be translated to cancer population genetics with simple modifications.

doi: http://biorxiv.org/content/early/2017/01/30/104158 

 

 

Heterogeneity in the tumour size dynamics differentiates Vemurafenib, Dabrafenib and Trametinib in metastatic melanoma

Hitesh Mistry, David Orrell, Raluca Eftimie

 

Abstract

Molecular heterogeneity in tumours leads to variability in drug response both between patients and across lesions within a patient. These sources of variability could be explored through analysis of routinely collected clinical trial imaging data. We applied a mathematical model of tumour growth to analyse both within and between patient variability in tumour size dynamics to clinical data from three drugs, Vemurafenib, Dabrafenib and Trametinib, used in the treatment of metastatic melanoma. The analysis revealed: 1) existence of homogeneity in drug response and resistance development within a patient; 2) tumour shrinkage rate does not relate to rate of resistance development; 3) Vemurafenib and Dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates. Overall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.

Keywords: heterogeneity, vemurafenib, dabrafenib, trametinib, melanoma, metastasis 

doi: http://biorxiv.org/content/early/2017/01/26/103366

 

 

Microenvironmental cooperation promotes early spread and bistability of a Warburg-like phenotype

Jorge Fernandez-de-Cossio-Diaz, Andrea De Martino, Roberto Mulet

(Submitted on 24 Jan 2017)

We introduce an in silico model for the initial spread of an aberrant phenotype with Warburg-like overflow metabolism within a healthy homeostatic tissue in contact with a nutrient reservoir (the blood), aimed at characterizing the role of the microenvironment for aberrant growth. Accounting for cellular metabolic activity, competition for nutrients, spatial diffusion and their feedbacks on aberrant replication and death rates, we obtain a phase portrait where distinct asymptotic whole-tissue states are found upon varying the tissue-blood turnover rate and the level of blood-borne primary nutrient. Over a broad range of parameters, the spreading dynamics is bistable as random fluctuations can impact the final state of the tissue. Such a behaviour turns out to be linked to the re-cycling of overflow products by non-aberrant cells. Quantitative insight on the overall emerging picture is provided by a spatially homogeneous version of the model.

link: https://arxiv.org/abs/1701.06781

Novel computational method for predicting polytherapy switching strategies to overcome tumor heterogeneity and evolution

 

Vanessa D Jonsson, Colin M Blakely, Luping Lin, Saurabh Asthana, Victor Olivas, Matthew A Gubens, Nikolai Matni, Boris C Bastian, Barry S Taylor, John C Doyle, Trever G Bivona

 

Abstract

The success of targeted cancer therapy is limited by drug resistance that can result from tumor genetic heterogeneity. The current approach to address resistance typically involves initiating a new treatment after clinical/radiographic disease progression, ultimately resulting in futility in most patients. Towards a potential alternative solution, we developed a novel computational framework that uses human cancer profiling data to systematically identify dynamic, pre-emptive, and sometimes non-intuitive treatment strategies that can better control tumors in real-time. By studying lung adenocarcinoma clinical specimens and preclinical models, our computational analyses revealed that the best anti-cancer strategies addressed existing resistant subpopulations as they emerged dynamically during treatment. In some cases, the best computed treatment strategy used unconventional therapy switching while the bulk tumor was responding, a prediction we confirmed in vitro. The new framework presented here could guide the principled implementation of dynamic molecular monitoring and treatment strategies to improve cancer control.

Link: http://dx.doi.org/10.1101/086553

 

Optimal structure of heterogeneous stem cell niche: The importance of cell migration in delaying tumorigenesis

Leili Shahriyari, Ali Mahdipour Shirayeh

doi: http://dx.doi.org/10.1101/082982

This article is a preprint and has not been peer-reviewed [what does this mean?].

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Abstract

Studying the stem cell niche architecture is a crucial step for investigating the process of oncogenesis and obtaining an effective stem cell therapy for various cancers. Recently, it has been observed that there are two groups of stem cells in the stem cell niche collaborating with each other to maintain tissue homeostasis. One group comprises the border stem cells, which is responsible to control the number of non-stem cells as well as stem cells. The other group, central stem cells, regulates the stem cell niche. In the present study, we develop a bi-compartmental stochastic model for the stem cell niche to study the spread of mutants within the niche. The analytic calculations and numeric simulations, which are in perfect agreement, reveal that in order to delay the spread of mutants in the stem cell niche, a small but non-zero number of stem cell proliferations must occur in the central stem cell compartment. Moreover, the migration of border stem cells to the central stem cell compartment delays the spread of mutants. Furthermore, the fixation probability of mutants in the stem cell niche is independent of types of stem cell division as long as all stem cells do not divide fully asymmetrically. Additionally, the progeny of central stem cells have a much higher chance than the progeny of border stem cells to take over the entire niche.

http://biorxiv.org/content/early/2016/10/24/082982

3D Hybrid Modelling of Vascular Network Formation

3D hybrid modeling of vascular network formation

Holger Perfahl, Barry D Hughes, Tomas Alaracon, Philip K Maini, Mark C Lloyd, Matthias Reuss, Helen M Byrne

Abstract

We develop an agent-based model of vasculogenesis, the de novo formation of blood vessels. Endothelial cells in the vessel network are viewed as linearly elastic spheres and are of two types: vessel elements are contained within the network; tip cells are located at endpoints. Tip cells move in response to forces due to interactions with neighbouring vessel elements, the local tissue environment, chemotaxis and a persistence force modeling their tendency to continue moving in the same direction. Vessel elements experience similar forces but not chemotaxis. An angular persistence force representing local tissue interactions stabilises buckling instabilities due to proliferation. Vessel elements proliferate, at rates that depend on their degree of stretch: elongated elements proliferate more rapidly than compressed elements. Following division, new cells are more likely to form new sprouts if the parent vessel is highly compressed and to be incorporated into the parent vessel if it is stretched. 

Model simulations reproduce key features of vasculogenesis. Parameter sensitivity analyses reveal significant changes in network size and morphology on varying the chemotactic sensitivity of tip cells, and the sensitivities of the proliferation rate and sprouting probability to mechanical stretch. Varying chemotactic sensitivity also affects network directionality. Branching and network density are influenced by the sprouting probability. Glyphs depicting multiple network properties show how network quantities change over time and as model parameters vary. We also show how glyphs constructed from in vivo data could be used to discriminate between normal and tumour vasculature and, ultimately, for model validation. We conclude that our biomechanical hybrid model generates vascular networks similar to those generated from in vitro and in vivo experiments.

Link:	arXiv:1610.00661 [q-bio.QM]