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Grant Details

Grant Number: 5R01CA047658-16 Interpret this number
Primary Investigator: Moolgavkar, Suresh
Organization: Fred Hutchinson Cancer Research Center
Project Title: Biomathematical Approaches to Cancer
Fiscal Year: 2005
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Abstract

DESCRIPTION (provided by applicant): Clones of intermediate cells on the pathway to cancer, such as adenomatous polyps and altered hepatic foci, are often observed in humans and animals. These lesions provide insights into the earliest stages of the carcinogenic process. Because clonal expansion of cells that are partially transformed can increase the probability of cancer substantially, a quantitative understanding of these lesions is key to understanding cancer rates. The broad objective of this project is to continue the development of mathematical, statistical and computational tools, within the paradigm of multistage carcinogenesis, for the quantitative analyses of early lesions on the pathway to malignancy. The fundamental goals of these analyses are to study the temporal evolution of these lesions, to estimate the rate of initiation of the lesions, and the rates of cell division and apoptosis of the partially transformed cells that comprise the lesion. Information on such early lesions is typically available from initiation-promotion experiments, particularly in the rodent liver.In previous work mathematical expressions have been developed for the number and size distribution of intermediate lesions on the pathway to malignancy and used for analyses of initiation-promotion experiments in rat liver. This proposal plans to extend this work in light of new biological information. In addition to continuing work on analyses of liver foci in rodents, the research proposed here will investigate intermediate lesions in the human colon and in patients with Barrett's esophagus, a high-risk precursor condition for adenocarcinoma of the esophagus. In addition to the mathematical and statistical problems associated with clonal growth models within the paradigm of multistage carcinogenesis, both analyses of liver foci and analyses of lesions in Barrett's esophagus present diverse problems. Recognizing that modeling is an iterative process an integral part of this effort will be collaboration with experimentalists and human biologists, in particular Dr. Michael Schwarz, University of Tubingen, an expert on the rodent liver system, Dr. John Potter, an epidemiologist with expertise on colon cancer and Dr. Brian Reid, Director of the Seattle Barrett's Esophagus Project. The results of analyses will be used to help generate biologically relevant questions and hypotheses and to plan further experiments and studies, which, in turn, will lead to more refined models.

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Publications

Modulation of liver tumorigenesis in Connexin32-deficient mouse.
Authors: Luebeck EG, Buchmann A, Schneider D, Moolgavkar SH, Schwarz M
Source: Mutat Res, 2005 Feb 15;570(1), p. 33-47.
PMID: 15680401
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Exploring heterogeneity in tumour data using Markov chain Monte Carlo.
Authors: de Gunst MC, Dewanji A, Luebeck EG
Source: Stat Med, 2003 May 30;22(10), p. 1691-707.
PMID: 12720305
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Multistage carcinogenesis and the incidence of colorectal cancer.
Authors: Luebeck EG, Moolgavkar SH
Source: Proc Natl Acad Sci U S A, 2002 Nov 12;99(23), p. 15095-100.
EPub date: 2002 Nov 1.
PMID: 12415112
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Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.
Authors: Luebeck EG, Heidenreich WF, Hazelton WD, Paretzke HG, Moolgavkar SH
Source: Radiat Res, 1999 Oct;152(4), p. 339-51.
PMID: 10477911
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A method for parametric estimation of the number and size distribution of cell clusters from observations in a section plane.
Authors: de Gunst MC, Luebeck EG
Source: Biometrics, 1998 Mar;54(1), p. 100-12.
PMID: 9544509
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Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin.
Authors: Moolgavkar SH, Luebeck EG, Buchmann A, Bock KW
Source: Toxicol Appl Pharmacol, 1996 May;138(1), p. 31-42.
PMID: 8658510
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