Our mathematical/computational Preliminary Studies emphasize the analysis of experimental data collected by our multidisciplinary team at Center of Cancer Systems Biology in conjunction with human data from the literature, to construct a predictive model of dynamic steps in carcinogenesis ? Initiation consists of one or more comparatively rapid genomic or epigenetic alterations;the alterations produce cell clones that may become dysplastic or hyperplastic and are at risk for being transformed. ? Promotion, according to one common view, involves the proliferation of initiated, and thus premalignant, cells. Promotion may take many years and the cell lineages may incur additional alterations. ? (Malignant) transformation is a further genomic or epigenetic alteration in an initiated/promoted lineage. Sometimes, transformation is considered to be one point mutation in a key gene, but other models consider larger scale DNA changes (e.g. deletions, duplications, translocations and inversions, aneuploidy, or horizontal transfer) and/or consider multiple alterations instead of just one alteration. ? Progression occurs as a malignant cell lineage evolves in interaction with its microenvironment, often becoming increasingly malignant and invasive. Genomic instability is a common feature. Many computational models implement all or part of this timeline, often with additional steps (reviewed, e.g., in [Cox &Huber 2007;Little et al. 2008a]). One basic implementation is the classic two-stage clonal expansion (TSCE) model, which emphasizes probabilistic promotion. """"""""Two-stage"""""""" refers to initiation to pre-malignancy (stage 1) and transformation to malignancy (stage 2).

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National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Wilkie, Kathleen P; Hahnfeldt, Philip (2017) Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation. Bull Math Biol 79:1426-1448
Benzekry, Sebastien; Lamont, Clare; Barbolosi, Dominique et al. (2017) Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth. Cancer Res 77:5183-5193
Gao, Xuefeng; Sishc, Brock J; Nelson, Christopher B et al. (2016) Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(-/low) Stem Cell Phenotype. Front Oncol 6:138
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Pellicciotta, Ilenia; Marciscano, Ariel E; Hardee, Matthew E et al. (2015) Development of a novel multiplexed assay for quantification of transforming growth factor-? (TGF-?). Growth Factors 33:79-91
Benzekry, Sebastian; Tuszynski, Jack A; Rietman, Edward A et al. (2015) Design principles for cancer therapy guided by changes in complexity of protein-protein interaction networks. Biol Direct 10:32
Beheshti, Afshin; Benzekry, S├ębastien; McDonald, J Tyson et al. (2015) Host age is a systemic regulator of gene expression impacting cancer progression. Cancer Res 75:1134-43
Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula (2015) Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett 358:100-106
Poleszczuk, Jan; Hahnfeldt, Philip; Enderling, Heiko (2015) Evolution and phenotypic selection of cancer stem cells. PLoS Comput Biol 11:e1004025
Benzekry, Sebastien; Beheshti, Afshin; Hahnfeldt, Philip et al. (2015) Capturing the Driving Role of Tumor-Host Crosstalk in a Dynamical Model of Tumor Growth. Bio Protoc 5:

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