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Grant Details

Grant Number: 5R01CA140657-04 Interpret this number
Primary Investigator: Maley, Carlo
Organization: University Of California, San Francisco
Project Title: Modeling Neoplastic Progression in Barrett's Esophagus
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Our long-term goals are to understand the evolutionary dynamics of neoplastic progression and to develop effective interventions that can prevent or delay cancer. Neoplasms progress to malignancy through a process of clonal evolution. However, the dynamics of that evolution are poorly understood. We propose to develop an agent-based computational model of neoplastic progression in Barrett's esophagus as a tool to study the dynamics of neoplastic progression and to integrate the genetic, pathological, clinical, and epidemiological data on this disease. We will represent the cells of the Barrett's epithelium as the agents of the model so that we can capture the genetic diversity and evolutionary dynamics that drive neoplastic progression. Barrett's esophagus is a human, pre-malignant condition in which the squamous lining of the esophagus is replaced by a crypt structured intestinal metaplasia. Barrett's esophagus is the only known precursor to esophageal adenocarcinoma, the incidence of which is increasing faster than any other cancer in the Western world. However, most people with Barrett's esophagus never develop cancer, so there is an urgent need for methods to predict risk of progression and intervene in patients at high risk. We will carry out a sensitivity analysis of our model to identify the model parameters that are likely to make the best biomarkers for cancer risk prediction and targets for cancer prevention interventions. Key aspects of neoplastic progression in Barrett's esophagus are unknown and will have to be measured to develop a comprehensive, predictive model of the disease. We have previously shown that the genetic diversity of clones of cells, at a single time point, within Barrett's epithelium is predictive of future progression to cancer. This is either because genetic diversity increases during progression or because high-risk patients have high, constant levels of genetic diversity compared to low-risk patients. We have shown that we can use a cell lineage assay based on detecting mutations in a panel of 244 highly mutable microsatellites in single cells, to measure genetic diversity among cells in Barrett's esophagus. We will determine how genetic diversity changes over time, in 60 well-characterized patients with Barrett's esophagus, and fit the parameters of the model to those results using approximate Bayesian computation. We will test whether or not non-steroidal anti-inflammatory drug (NSAID) use, which is associated with a dramatic reduction in cancer risk in Barrett's esophagus, is associated with a decrease in genetic diversity among cells. We will also measure the density of crypts in a cohort of 243 patients with Barrett's esophagus at two time points to 1) determine the number of crypts that should be simulated in the model in order to represent the tissue, 2) determine if crypt density changes over time, 3) test if the number or density of crypts predicts progression to cancer and 4) test for an association between NSAID use and crypt density. This project will result in an improved understanding of neoplastic progression in Barrett's esophagus and a model that can act as a predictive tool for identifying promising targets for intervention and biomarker development. PUBLIC HEALTH RELEVANCE: Once a tumor has invaded other organs, it is very difficult to cure. Thus, we are now focusing on preventing cancer before it becomes incurable. In particular, we study Barrett's esophagus, a pre-malignant condition that can develop into esophageal cancer. This is an important disease because the incidence of esophageal cancer is increasing faster than any other cancer in the United States. However, most patients with Barrett's esophagus will never develop cancer, so there is a need to understand the process by which Barrett's cells evolve malignancy and identify patients at high risk, so that we can focus our medical resources, and the inherent risks of any interventions, on them. We are proposing to develop computational models of the evolution of malignancy in Barrett's esophagus and to measure the dynamics of that process in biopsies from patients with Barrett's esophagus. These models will help to identify good biomarkers for measuring cancer risk in patients with Barrett's esophagus as well as targets for cancer prevention. Our methods should be generalizable to other pre-malignant conditions.

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Publications

Temporal and spatial evolution of somatic chromosomal alterations: a case-cohort study of Barrett's esophagus.
Authors: Li X, Galipeau PC, Paulson TG, Sanchez CA, Arnaudo J, Liu K, Sather CL, Kostadinov RL, Odze RD, Kuhner MK, Maley CC, Self SG, Vaughan TL, Blount PL, Reid BJ
Source: Cancer Prev Res (Phila), 2014 Jan;7(1), p. 114-27.
EPub date: 2013 Nov 19.
PMID: 24253313
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Life history trade-offs in cancer evolution.
Authors: Aktipis CA, Boddy AM, Gatenby RA, Brown JS, Maley CC
Source: Nat Rev Cancer, 2013 Dec;13(12), p. 883-92.
EPub date: 2013 Nov 11.
PMID: 24213474
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NSAIDs modulate clonal evolution in Barrett's esophagus.
Authors: Kostadinov RL, Kuhner MK, Li X, Sanchez CA, Galipeau PC, Paulson TG, Sather CL, Srivastava A, Odze RD, Blount PL, Vaughan TL, Reid BJ, Maley CC
Source: PLoS Genet, 2013 Jun;9(6), p. e1003553.
EPub date: 2013 Jun 13.
PMID: 23785299
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Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.
Authors: Humphries A, Cereser B, Gay LJ, Miller DS, Das B, Gutteridge A, Elia G, Nye E, Jeffery R, Poulsom R, Novelli MR, Rodriguez-Justo M, McDonald SA, Wright NA, Graham TA
Source: Proc Natl Acad Sci U S A, 2013 Jul 2;110(27), p. E2490-9.
EPub date: 2013 Jun 13.
PMID: 23766371
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An evolutionary explanation for the presence of cancer nonstem cells in neoplasms.
Authors: Sprouffske K, Athena Aktipis C, Radich JP, Carroll M, Nedelcu AM, Maley CC
Source: Evol Appl, 2013 Jan;6(1), p. 92-101.
EPub date: 2012 Nov 26.
PMID: 23397439
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Modelling the evolution of genetic instability during tumour progression.
Authors: S Datta R, Gutteridge A, Swanton C, Maley CC, Graham TA
Source: Evol Appl, 2013 Jan;6(1), p. 20-33.
EPub date: 2012 Nov 26.
PMID: 23396531
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Cancer in light of experimental evolution.
Authors: Sprouffske K, Merlo LM, Gerrish PJ, Maley CC, Sniegowski PD
Source: Curr Biol, 2012 Sep 11;22(17), p. R762-71.
PMID: 22975007
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Natural resistance to cancers: a Darwinian hypothesis to explain Peto's paradox.
Authors: Roche B, Hochberg ME, Caulin AF, Maley CC, Gatenby RA, Misse D, Thomas F
Source: BMC Cancer, 2012 Sep 3;12, p. 387.
EPub date: 2012 Sep 3.
PMID: 22943484
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Spatial structure increases the waiting time for cancer.
Authors: Martens EA, Kostadinov R, Maley CC, Hallatschek O
Source: New J Phys, 2011 Nov 1;13, p. null.
EPub date: 2011 Nov 28.
PMID: 22707911
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Clonal evolution in cancer.
Authors: Greaves M, Maley CC
Source: Nature, 2012 Jan 18;481(7381), p. 306-13.
EPub date: 2012 Jan 18.
PMID: 22258609
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Overlooking evolution: a systematic analysis of cancer relapse and therapeutic resistance research.
Authors: Aktipis CA, Kwan VS, Johnson KA, Neuberg SL, Maley CC
Source: PLoS One, 2011;6(11), p. e26100.
EPub date: 2011 Nov 17.
PMID: 22125594
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An in vitro co-culture model of esophageal cells identifies ascorbic acid as a modulator of cell competition.
Authors: Merlo LM, Kosoff RE, Gardiner KL, Maley CC
Source: BMC Cancer, 2011 Oct 25;11, p. 461.
EPub date: 2011 Oct 25.
PMID: 22026449
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Dispersal evolution in neoplasms: the role of disregulated metabolism in the evolution of cell motility.
Authors: Aktipis CA, Maley CC, Pepper JW
Source: Cancer Prev Res (Phila), 2012 Feb;5(2), p. 266-75.
EPub date: 2011 Sep 19.
PMID: 21930797
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Development and characterization of an organotypic model of Barrett's esophagus.
Authors: Kosoff RE, Gardiner KL, Merlo LM, Pavlov K, Rustgi AK, Maley CC
Source: J Cell Physiol, 2012 Jun;227(6), p. 2654-9.
PMID: 21882191
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Solving the puzzle of metastasis: the evolution of cell migration in neoplasms.
Authors: Chen J, Sprouffske K, Huang Q, Maley CC
Source: PLoS One, 2011 Apr 27;6(4), p. e17933.
EPub date: 2011 Apr 27.
PMID: 21556134
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New strategies in Barrett's esophagus: integrating clonal evolutionary theory with clinical management.
Authors: Reid BJ, Kostadinov R, Maley CC
Source: Clin Cancer Res, 2011 Jun 1;17(11), p. 3512-9.
EPub date: 2011 Apr 15.
PMID: 21498395
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Accurate reconstruction of the temporal order of mutations in neoplastic progression.
Authors: Sprouffske K, Pepper JW, Maley CC
Source: Cancer Prev Res (Phila), 2011 Jul;4(7), p. 1135-44.
EPub date: 2011 Apr 13.
PMID: 21490131
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Peto's Paradox: evolution's prescription for cancer prevention.
Authors: Caulin AF, Maley CC
Source: Trends Ecol Evol, 2011 Apr;26(4), p. 175-82.
PMID: 21296451
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A comprehensive survey of clonal diversity measures in Barrett's esophagus as biomarkers of progression to esophageal adenocarcinoma.
Authors: Merlo LM, Shah NA, Li X, Blount PL, Vaughan TL, Reid BJ, Maley CC
Source: Cancer Prev Res (Phila), 2010 Nov;3(11), p. 1388-97.
EPub date: 2010 Oct 12.
PMID: 20947487
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Theory for the evolution of diffusible external goods.
Authors: Driscoll WW, Pepper JW
Source: Evolution, 2010 Sep;64(9), p. 2682-7.
PMID: 20394658
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New models of neoplastic progression in Barrett's oesophagus.
Authors: Pavlov K, Maley CC
Source: Biochem Soc Trans, 2010 Apr;38(2), p. 331-6.
PMID: 20298178
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The role of genetic diversity in cancer.
Authors: Merlo LM, Maley CC
Source: J Clin Invest, 2010 Feb;120(2), p. 401-3.
EPub date: 2010 Jan 25.
PMID: 20101092
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