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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


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.



Publications

Evaluation Of Screening Strategies For Pre-malignant Lesions Using A Biomathematical Approach
Authors: Jeon J. , Meza R. , Moolgavkar S.H. , Luebeck E.G. .
Source: Mathematical Biosciences, 2008 May; 213(1), p. 56-70.
PMID: 18374369
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Analysis of lung cancer incidence in the Nurses' Health and the Health Professionals' Follow-Up Studies using a multistage carcinogenesis model.
Authors: Meza R. , Hazelton W.D. , Colditz G.A. , Moolgavkar S.H. .
Source: Cancer Causes & Control : Ccc, 2008 Apr; 19(3), p. 317-28.
PMID: 18058248
Related Citations

Age Effects And Temporal Trends In Adenocarcinoma Of The Esophagus And Gastric Cardia (united States)
Authors: Jeon,J. , Luebeck,E.G. , Moolgavkar,S.H. .
Source: Cancer Causes & Control : Ccc, 2006 Sep; 17(7), p. 971-81.
PMID: 16841264
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Gestational Mutations And Carcinogenesis
Authors: Meza,R. , Luebeck,E.G. , Moolgavkar,S.H. .
Source: Mathematical Biosciences, 2005 Oct; 197(2), p. 188-210.
PMID: 16087198
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A Generalized Luria-delbrück Model
Authors: Dewanji,A. , Luebeck,E.G. , Moolgavkar,S.H. .
Source: Mathematical Biosciences, 2005 Oct; 197(2), p. 140-52.
PMID: 16137718
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Modulation Of Liver Tumorigenesis In Connexin32-deficient Mouse
Authors: Luebeck E.G. , Buchmann A. , Schneider D. , Moolgavkar S.H. , Schwarz M. .
Source: Mutation Research, 2005-02-15 00:00:00.0; 570(1), p. 33-47.
PMID: 15680401
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Commentary: Fifty Years Of The Multistage Model: Remarks On A Landmark Paper
Authors: Moolgavkar,S.H. .
Source: International Journal Of Epidemiology, 2004 Dec; 33(6), p. 1182-3.
PMID: 15319398
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Multistage Carcinogenesis And The Incidence Of Human Cancer
Authors: Moolgavkar,S.H. , Luebeck,E.G. .
Source: Genes, Chromosomes & Cancer, 2003 Dec; 38(4), p. 302-6.
PMID: 14566848
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Exploring Heterogeneity In Tumour Data Using Markov Chain Monte Carlo
Authors: de Gunst M.C. , Dewanji A. , Luebeck E.G. .
Source: Statistics In Medicine, 2003-05-30 00:00:00.0; 22(10), p. 1691-707.
PMID: 12720305
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Multistage Carcinogenesis And The Incidence Of Colorectal Cancer
Authors: Luebeck E.G. , Moolgavkar S.H. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2002-11-12 00:00:00.0; 99(23), p. 15095-100.
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 E.G. , Heidenreich W.F. , Hazelton W.D. , Paretzke H.G. , Moolgavkar S.H. .
Source: Radiation Research, 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 M.C. , Luebeck E.G. .
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 S.H. , Luebeck E.G. , Buchmann A. , Bock K.W. .
Source: Toxicology And Applied Pharmacology, 1996 May; 138(1), p. 31-42.
PMID: 8658510
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Allelic Instability In Mitosis: A Unified Model For Dominant Disorders
Authors: Zheng C.J. , Byers B. , Moolgavkar S.H. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 1993-11-01 00:00:00.0; 90(21), p. 10178-82.
PMID: 8234274
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On The Use Of Historical Control Data To Estimate Dose Response Trends In Quantal Bioassay
Authors: Prentice R.L. , Smythe R.T. , Krewski D. , Mason M. .
Source: Biometrics, 1992 Jun; 48(2), p. 459-78.
PMID: 1637972
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Multistage Carcinogenesis: Population-based Model For Colon Cancer
Authors: Moolgavkar S.H. , Luebeck E.G. .
Source: Journal Of The National Cancer Institute, 1992-04-15 00:00:00.0; 84(8), p. 610-8.
PMID: 1313509
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Effects Of Polychlorinated Biphenyls In Rat Liver: Quantitative Analysis Of Enzyme-altered Foci
Authors: Luebeck E.G. , Moolgavkar S.H. , Buchmann A. , Schwarz M. .
Source: Toxicology And Applied Pharmacology, 1991 Dec; 111(3), p. 469-84.
PMID: 1684071
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Two-mutation Model For Carcinogenesis: Joint Analysis Of Premalignant And Malignant Lesions
Authors: Dewanji A. , Moolgavkar S.H. , Luebeck E.G. .
Source: Mathematical Biosciences, 1991 Apr; 104(1), p. 97-109.
PMID: 1804458
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Stochastic Analysis Of Intermediate Lesions In Carcinogenesis Experiments
Authors: Luebeck E.G. , Moolgavkar S.H. .
Source: Risk Analysis : An Official Publication Of The Society For Risk Analysis, 1991 Mar; 11(1), p. 149-57.
PMID: 1828119
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The Role Of Somatic Mutations And Cell Replication Kinetics In Quantitative Cancer Risk Assessment
Authors: Moolgavkar S.H. , Luebeck E.G. .
Source: Progress In Clinical And Biological Research, 1991; 369, p. 469-79.
PMID: 1835095
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Quantitative Analysis Of Enzyme-altered Foci In Rat Hepatocarcinogenesis Experiments--i. Single Agent Regimen
Authors: Moolgavkar S.H. , Luebeck E.G. , de Gunst M. , Port R.E. , Schwarz M. .
Source: Carcinogenesis, 1990 Aug; 11(8), p. 1271-8.
PMID: 2143703
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A Two-mutation Model For Radon-induced Lung Tumors In Rats
Authors: Moolgavkar S.H. , Cross F.T. , Luebeck G. , Dagle G.E. .
Source: Radiation Research, 1990 Jan; 121(1), p. 28-37.
PMID: 2153988
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A Stochastic Two-stage Model For Cancer Risk Assessment. Ii. The Number And Size Of Premalignant Clones
Authors: Dewanji A. , Venzon D.J. , Moolgavkar S.H. .
Source: Risk Analysis : An Official Publication Of The Society For Risk Analysis, 1989 Jun; 9(2), p. 179-87.
PMID: 2762604
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Cigarette Smoking And Lung Cancer: Reanalysis Of The British Doctors' Data
Authors: Moolgavkar S.H. , Dewanji A. , Luebeck G. .
Source: Journal Of The National Cancer Institute, 1989-03-15 00:00:00.0; 81(6), p. 415-20.
PMID: 2783979
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A Stochastic Two-stage Model For Cancer Risk Assessment. I. The Hazard Function And The Probability Of Tumor
Authors: Moolgavkar S.H. , Dewanji A. , Venzon D.J. .
Source: Risk Analysis : An Official Publication Of The Society For Risk Analysis, 1988 Sep; 8(3), p. 383-92.
PMID: 3201016
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