Evren Gürkan-Çavusoglu

Case Western Reserve University

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Alexandru Almasan

Cleveland Clinic Lerner College of Medicine

Kenneth A. Loparo

Case Western Reserve University

Aydan M. Erkmen

Middle East Technical University

Timothy J. Kinsella

Brown University

Mengdi Qian

Case Western Reserve University

İE

İsmet Erkmen

Middle East Technical University

Jane E. Schupp

West Virginia University

Chenhui Ma

Lanzhou University

Mohammad Azhar Aziz

Govind Ballabh Pant University of Agriculture and Technology

Stephen P. Banks

Commonwealth Scientific and Industrial Research Organisation

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Case Western Reserve University

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University Hospitals of Cleveland

University Hospitals Case Medical Center

Louis Stokes Cleveland VA Medical Center

Middle East Technical University

Case Comprehensive Cancer Center

Icahn School of Medicine at Mount Sinai

Washington University in St. Louis

Cleveland Clinic Lerner College of Medicine

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Computational analysis of androgen receptor dependent radiosensitivity in prostate cancer

Mengdi Qian Alexandru Almasan Evren Gürkan-Çavusoglu

In this study, we quantitatively analyze the mechanism by which androgen deprivation therapy (ADT) is enhancing radiosensitivity in prostate cancer (PCa) patients. It has been shown in laboratory experiments, as well as in patient data in the literature, that the androgen receptor (AR) reduces the effectiveness of ionizing radiation treatment by enhancing the non-homologous end joining (NHEJ) repair of radiation damage. The suppression of AR by ADT suppresses the activity of NHEJ that leads to radiosensitivity in PCa patients. In this paper, we have studied this positive interaction between AR and NHEJ using mathematical models of the NHEJ that we have developed using both the experimental and clinical data for PCa. Our results show that the biological observation of suppression of AR by ADT leading to down-regulation of the first NHEJ protein Ku and NHEJ is a plausible biological mechanism that explains both the experimental and clinical observations in the literature. The presented analysis is the first step in quantitatively analyzing possible treatment scenarios to find the optimal treatment strategies for PCa using the combination treatment with ADT, NHEJ inhibitors, and IR.

Radiosensitivity

Non-homologous end joining

10.1109/embc.2016.7590976

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Citations (3)

Sickle cell disease biochip: a functional red blood cell adhesion assay for monitoring sickle cell disease

Translational research (2016)

Yunus Alapan Ceonne Kim Anima Adhikari Kayla Gray Evren Gürkan-Çavusoglu

Acute chest syndrome

Endothelial Activation

10.1016/j.trsl.2016.03.008

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Citations (70)

Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model

PLoS Computational Biology (2022)

Chenhui Ma Alexandru Almasan Evren Gürkan-Çavusoglu

5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization.

Pharmacodynamics

10.1371/journal.pcbi.1010685

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Abstract 2707: Quantitative analysis of the role of androgen receptor in radiation treatment for prostate cancer

Cancer Research (2016)

Mengdi Qian Alexandru Almasan Evren Gürkan-Çavusoglu

Abstract The purpose of this study is to quantitatively investigate the mechanism of androgen receptor (AR) and non-homologous end joining (NHEJ) interaction after and ionizing radiation (IR) and androgen deprivation therapy (ADT) treatment. In most clinical treatment approaches, a combination of ADT and IR is used in order to improve prostate patients’ overall survival probability. It is found that AR interacts with NHEJ pathway, a major double strand break (DSB) repair pathway. We have developed a mathematical model of the NHEJ pathway that is composed of a series of ordinary differential equations. The kinetic rate constants constitute the unknown parameters of the model and we have estimated these parameters using least square estimation. The data sets used in the parameter estimation were obtained from the literature and they were from both in vitro experiments as well as clinical data from prostate cancer patients. Both sets of data demonstrated the effects of AR on DSB repair by NHEJ. The in vitro data suggest that AR enhances DSB repair by inducing expression/activity of DNA-PKcs, which is a key protein in NHEJ. The clinical data show that the effect is through the first NHEJ protein complex that is recruited to DSB, Ku70/80. We have developed the models for IR treatment alone or in combination with ADT to determine which of these mechanisms can explain the behavior in both data sets simultaneously. We have carried out sensitivity analysis and identifiability tests on all the parameters from both models in order to determine the parameters that are reliably estimated. We have shown that when the rate constant for the initiation protein Ku70/80 is decreased to half in the IR+ADT case compared to the IR only case, the model outputs captured the observations in both experimental and clinical data. The rate constant for Ku70/80 is proved to be both sensitive and identifiable, indicating that the two-fold difference in the rate constants of IR only and IR+ADT cases is biologically relevant. Therefore, we conclude that when ADT is applied, AR significantly slows down the kinetic activity of Ku70/80, thus the DSB repair by NHEJ. The suppression of AR activity through ADT has the potential to enhance the IR treatment outcomes for the prostate cancer patients that are resistant to IR-only treatment. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gurkan-Cavusoglu. Quantitative analysis of the role of androgen receptor in radiation treatment for prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2707.

Ku70

Androgen Suppression

Non-homologous end joining

10.1158/1538-7445.am2016-2707

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A comprehensive review of computational cell cycle models in guiding cancer treatment strategies

npj Systems Biology and Applications (2024)

Chenhui Ma Evren Gürkan-Çavusoglu

Abstract This article reviews the current knowledge and recent advancements in computational modeling of the cell cycle. It offers a comparative analysis of various modeling paradigms, highlighting their unique strengths, limitations, and applications. Specifically, the article compares deterministic and stochastic models, single-cell versus population models, and mechanistic versus abstract models. This detailed analysis helps determine the most suitable modeling framework for various research needs. Additionally, the discussion extends to the utilization of these computational models to illuminate cell cycle dynamics, with a particular focus on cell cycle viability, crosstalk with signaling pathways, tumor microenvironment, DNA replication, and repair mechanisms, underscoring their critical roles in tumor progression and the optimization of cancer therapies. By applying these models to crucial aspects of cancer therapy planning for better outcomes, including drug efficacy quantification, drug discovery, drug resistance analysis, and dose optimization, the review highlights the significant potential of computational insights in enhancing the precision and effectiveness of cancer treatments. This emphasis on the intricate relationship between computational modeling and therapeutic strategy development underscores the pivotal role of advanced modeling techniques in navigating the complexities of cell cycle dynamics and their implications for cancer therapy.

10.1038/s41540-024-00397-7

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Citations (8)

Abstract 225: Computational analysis of 5-fluorouracil antitumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model

Cancer Research (2021)

Chenhui Ma Alexandru Almasan Evren Gürkan-Çavusoglu

Abstract The purpose of this study is to develop a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to quantitatively analyze the treatment outcome of 5-fluorouracil (5-FU) in colon cancer. Predicting the outcome of chemotherapeutic agents plays an essential role in improving dose strategies. To that end, we have developed an integrated mechanistic PK/PD model to analyze the kinetics of tumor response to 5-FU treatment. Compared to the existing PK/PD models, our model is novel in the way it incorporates the 5-FU metabolism pathway and downstream antiproliferative events to provide a comprehensive model of treatment outcome. 5-FU has been widely used to treat cancers, including colon cancer. 5-FU metabolites can be incorporated into RNA, DNA and also interfere with thymidylate synthase (TS) catalytic activity, which is the main mechanism of 5-FU cytotoxicity. TS activity has been shown to be the predictor for treatment efficacy. The conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate catalyzed by TS is the sole intracellular de novo source of thymidylate. The formation of a ternary complex between fluorodeoxyuridylate (FdUMP) and TS obstructs the access of dUMP to the TS nucleotide-binding site. Resultant thymidine deprivation and dUMP accumulation give rise to the deoxynucleotide triphosphate (dNTP) pool imbalance, which could trigger S-phase specific DNA fragmentation, cell cycle arrest and apoptosis. In our PK model, compartmental analysis is developed to track the distribution of 5-FU from its entry into body to interstitial fluid outside the tumor cells and to its cellular uptake. In the cell model, the connection of TS inhibition and dNTP pool imbalance is implemented. In addition to the central plasma and peripheral tissue compartments, our model includes compartments for: 5-FU concentration in the extracellular fluids; intracellular 5-FU; 5-FU anabolites; genomic 5-FU in RNA, and in DNA; and, TS - FdUMP complex. Posttreatment free TS level is used to compute the perturbed TS catalytic activity. Using the model outcome on TS inhibition, we modeled the kinetics of dNTP pool perturbation. The dNTP pool imbalance leads to double strand break (DSB) formation that initiates DNA damage repair response, kinetics of which are also modeled. Our model uses the law of mass action and Michaelian kinetics and each molecular reaction is expressed as a nonlinear differential equation. Time course data from the literature are used in parameter estimation. Our simulation results successfully captured the kinetics of treatment outcome from the administration of the 5-FU to downstream effects in the tumor. The next step in our effort is to expand the model to include the tumor growth kinetics. Citation Format: Chenhui Ma, Alexandru Almasan, Evren Gurkan-Cavusoglu. Computational analysis of 5-fluorouracil antitumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 225.

Raltitrexed

10.1158/1538-7445.am2021-225

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REDUCING INCONSISTENCIES IN INTUITIONISTIC 2-WAY ADAPTIVE FUZZY CONTROL SYSTEMS

Evren Gürkan-Çavusoglu Aydan M. Erkmen İsmet Erkmen

10.1142/9789812792631_0035

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Citations (1)

Analysis of cell cycle dynamics using probabilistic cell cycle models

Annual International Conference of the IEEE Engineering in Medicine and Biology Society (2011)

Evren Gürkan-Çavusoglu Jane E. Schupp Timothy J. Kinsella Kenneth A. Loparo

In this study, we develop asynchronous probabilistic cell cycle models to quantitatively assess the effect of ionizing radiation on a human colon cancer cell line. We use both synchronous and asynchronous cell populations and follow treated cells for up to 2 cell cycle times. The model outputs quantify the changes in cell cycle dynamics following ionizing radiation treatment, principally in the duration of both Gi and G 2 /M phases.

Dynamics

10.1109/iembs.2011.6089914

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Citations (2)

Stable controller design for the T-S fuzzy model of a flexible-joint robot arm based on Lie algebra

Evren Gürkan-Çavusoglu S.P. Banks Aydan M. Erkmen

In this paper, we develop a novel approach for the stability of T-S fuzzy systems using the Lie algebra generated by the linear subsystems used in the T-S model. The theory is illustrated on the T-S fuzzy model of a flexible joint robot arm. We use our approach to design a controller satisfying our Lie algebra based stability criteria and demonstrate its performance on the robotic system.

10.1109/cdc.2003.1272321

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Citations (6)

Abstract 4533: In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer

Cancer Research (2017)

Mengdi Qian Alexandru Almasan Evren Gürkan-Çavusoglu

Abstract The purpose of this study is to quantitatively analyze the improved radiosensitivity of prostate cancer cells to ionizing radiation (IR) when radiation treatment is combined with androgen deprivation therapy (ADT). The double strand breaks (DSBs) induced by ionizing radiation are repaired primarily by non-homologous end joining (NHEJ). It is reported in the literature that NHEJ is impaired after ADT, which then results in increased radiosensitivity and better IR treatment outcomes in prostate cancer. In this study, we have used our models for NHEJ repair of DSBs under IR treatment and IR + ADT combination treatment conditions to determine how the combination treatment results in better outcomes. We have modeled the effect of multiple doses of IR that are delivered 24 hours apart to mimic the conventional, fractionated radiation treatment. The analysis results showed that the DSBs accumulate more in the case of combined treatment with ADT compared to faster and more efficient repair when only IR is applied. We have used the experimental data on relative cell numbers and relative sub-G1 cell numbers from the literature to determine the difference in the levels of DSBs that lead to cell death differences between the two treatment strategies. The literature data also shows that there is patient response variability to ADT in terms of the reduction in the levels of Ku70/80, which is the first NHEJ protein complex that is recruited to DSBs. We have modeled this patient variability in our models by introducing variability to Ku70/80 protein concentrations used in the simulations. Our simulation results agree with the observation from clinical data that lower concentration levels of Ku70/80 lead to better radiosensitization. The amount of IR can be adjusted with respect to the level of radiosensitization after ADT on a patient specific level to achieve a desired level of DSBs that will lead to maximum cell death; this dose optimization effort will be the next step in our quantitative analysis. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4533. doi:10.1158/1538-7445.AM2017-4533

Radiosensitivity

Ku70

Non-homologous end joining

Androgen Suppression

10.1158/1538-7445.am2017-4533

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