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Modeling and Analysis of Hormone and Mitogenic Signal Integration in Prostate Cancer

Katharine V. Rogers, Joseph A. Wayman, Ryan Tasseff, Caitlin Gee, Matthew P. DeLisa, Jeffrey D. Varner
doi: https://doi.org/10.1101/058552
Katharine V. Rogers
School of Chemical and Biomolecular Engineering Cornell University, Ithaca NY 14853
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Joseph A. Wayman
School of Chemical and Biomolecular Engineering Cornell University, Ithaca NY 14853
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Ryan Tasseff
School of Chemical and Biomolecular Engineering Cornell University, Ithaca NY 14853
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Caitlin Gee
School of Chemical and Biomolecular Engineering Cornell University, Ithaca NY 14853
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Matthew P. DeLisa
School of Chemical and Biomolecular Engineering Cornell University, Ithaca NY 14853
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Jeffrey D. Varner
School of Chemical and Biomolecular Engineering Cornell University, Ithaca NY 14853
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  • For correspondence: jdvarner@purdue.edu
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Abstract

Prostate cancer is the most common cancer in men and the second leading cause of cancer related death in the United States. Androgens, such as testosterone, are required for androgen dependent prostate cancer (ADPC) growth. Androgen ablation in combination with radiation or chemotherapy remains the primary non-surgical treatment for ADPC. However, androgen ablation typically fails to permanently arrest cancer progression, often resulting in castration resistant prostate cancer (CRPC). In this study, we analyzed a population of mathematical models that described the integration of androgen and mitogenic signaling in androgen dependent and independent prostate cancer. An ensemble of model parameters was estimated from 43 studies of signaling in androgen dependent and resistant LNCaP cell lines. The model population was then validated by comparing simulations with an additional 33 data sets from LNCaP cell lines and clinical trials. Analysis of the model population suggested that simultaneously targeting the PI3K and MAPK pathways in addition to anti-androgen therapies could be an effective treatment for CRPC. We tested this hypothesis in both ADPC LNCaP cell lines and LNCaP derived CRPC C4-2 cells using three inhibitors: the androgen receptor inhibitor MDV3100 (enzalutamide), the Raf kinase inhibitor sorafenib, and the PI3K inhibitor LY294002. Consistent with model predictions, cell viability decreased at 72 hrs in the dual and triple inhibition cases in both the LNCaP and C4-2 cell lines, compared to treatment with any single inhibitor. Taken together, this study suggested that crosstalk between the androgen and mitogenic signaling axes led to robustness of CRPC to any single inhibitor. Model analysis predicted potentially efficacious target combinations which were confirmed by experimental studies in multiple cell lines, thereby illustrating the potentially important role that mathematical modeling can play in cancer.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 13, 2016.
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Modeling and Analysis of Hormone and Mitogenic Signal Integration in Prostate Cancer
Katharine V. Rogers, Joseph A. Wayman, Ryan Tasseff, Caitlin Gee, Matthew P. DeLisa, Jeffrey D. Varner
bioRxiv 058552; doi: https://doi.org/10.1101/058552
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Modeling and Analysis of Hormone and Mitogenic Signal Integration in Prostate Cancer
Katharine V. Rogers, Joseph A. Wayman, Ryan Tasseff, Caitlin Gee, Matthew P. DeLisa, Jeffrey D. Varner
bioRxiv 058552; doi: https://doi.org/10.1101/058552

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