Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs

Sun, Chien-Pin; Usui, Takane; Yu, Fuqu; Al‐Shyoukh, Ibrahim; Shamma, Jeff S.; Sun, Ren; Ho, Chih‐Ming

doi:10.1039/b815225j

Cited by 27 publications

(26 citation statements)

References 33 publications

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“…[23][24][25] In previous studies, only one objective function was considered, but here we show that cascade FSC can be used successfully to rapidly search combinations of multiple drugs for optimal doses to satisfy both high efficacy and low toxicity. In this work, we first used drug efficacy as the only endpoint objective criterion.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25] Previously, we focused only on rapid searching for highly efficacious drug combinations. [23][24][25] Here, we have successfully applied the FSC approach in our experiments to search for drug combinations that have high antiviral efficacy and then applied FSC in cascade to lower the doses of a toxic drug (ribavirin) for the treatment of HSV-1 using an in vitro infection model.…”

Section: Introductionmentioning

confidence: 99%

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Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity

Li¹,

Sanchez²,

Shahangian³

et al. 2012

IJN

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Background: Infectious diseases cause many molecular assemblies and pathways within cellular signaling networks to function aberrantly. The most effective way to treat complex, diseased cellular networks is to apply multiple drugs that attack the problem from many fronts. However, determining the optimal combination of several drugs at specific dosages to reach an endpoint objective is a daunting task. Methods: In this study, we applied an experimental feedback system control (FSC) method and rapidly identified optimal drug combinations that inhibit herpes simplex virus-1 infection, by only testing less than 0.1% of the total possible drug combinations. Results: Using antiviral efficacy as the criterion, FSC quickly identified a highly efficacious drug cocktail. This cocktail contained high dose ribavirin. Ribavirin, while being an effective antiviral drug, often induces toxic side effects that are not desirable in a therapeutic drug combination. To screen for less toxic drug combinations, we applied a second FSC search in cascade and used both high antiviral efficacy and low toxicity as criteria. Surprisingly, the new drug combination eliminated the need for ribavirin, but still blocked viral infection in nearly 100% of cases. Conclusion:This cascade search provides a versatile platform for rapid discovery of new drug combinations that satisfy multiple criteria.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity

Li¹,

Sanchez²,

Shahangian³

et al. 2012

IJN

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“…The top-down feedback system control (FSC) approach, on the other hand, can provide a quantitative and systematic method to derive the optimized drug cocktails to reach the best therapeutic outcome [18,19]. The FSC scheme uses close loop feedback control concept ( Figure 4) and combines experimental exploration with the search algorithm to reach the goal.…”

Section: Combinatorial Drug Treatmentmentioning

confidence: 99%

“…mutation and selection) are executed within the algorithms to allow for rapid convergence of the optimal solutions [16]. Very recently, the evolutionary computing schemes have been successfully implemented to identify potent drug combinations in a variety of biological systems towards desired phenotypic and genotypic destinies [18,19].…”

Section: The Top-down System Approachmentioning

confidence: 99%

System control-mediated drug delivery towards complex systems via nanodiamond carriers

2010

International Journal of Smart and Nano Materials

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Cells represent the basic units of life and contain an intertwined network of signaling and regulatory circuitries that drive the processes of life. These processes include the mediation of mechano-sensation, onset of and protection against disease, inflammation, and others. In the network of bio-complex systems, each pathway interacts nonlinearly with others through different molecular intermediates. As a result, specific functionalities can not be simply linked to the cellular molecules in isolation. A complex system generally possesses very rich information content that can be characterized by the following features: (i) they contain a large number of building blocks; (ii) their interactions among building blocks and with their environment; (iii) they display organization without an external organizing principle being applied; and (iv) they exhibit adaptability and robustness. These properties account for the innate intelligence of biology and its ability to regulate its homeostatic behavior. However, this same complexity underlies, in cancer for example, challenges towards disease management, as the addressing of singular pathways with therapeutic compounds is not sufficient. Therefore, combinatorial therapy often serves as a key strategy towards tumor suppression. Because iterative searching for optimized therapeutic combinations is indeed a daunting, if not preclusive task, we introduce the feedback system control (FSC) scheme, which may serve as a clinically relevant approach, provided a translational approach towards drug delivery is employed. Due to their innate biocompatibility, which has been comprehensively observed, as well as their ability to delivery virtually any type of therapeutic in a sustained fashion due to their unique surface properties, nanodiamonds may serve as a foundation for nanoenabled combinatorial therapy.

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“…They usually rely on sequential biological experimental observations to navigate the search space of possible combinations. In the process of testing these approaches, a number of drug delivery platforms have been designed for fast delivery of multidrug cocktails and integration of these machines with the software implementation of the search algorithms [30]. These search approaches do not incorporate any prior biological information or network model and are suitable when we have limited knowledge of the biological structure and when the possible drugs that can be combined to produce the optimal cocktail are restricted.…”

Section: Introductionmentioning

confidence: 99%

An Integrated Approach to Anti-Cancer Drug Sensitivity Prediction

Berlow

Haider

Wan

et al. 2014

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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A framework for design of personalized cancer therapy requires the ability to predict the sensitivity of a tumor to anticancer drugs. The predictive modeling of tumor sensitivity to anti-cancer drugs has primarily focused on generating functions that map gene expressions and genetic mutation profiles to drug sensitivity. In this paper, we present a new approach for drug sensitivity prediction and combination therapy design based on integrated functional and genomic characterizations. The modeling approach when applied to data from the Cancer Cell Line Encyclopedia shows a significant gain in prediction accuracy as compared to elastic net and random forest techniques based on genomic characterizations. Utilizing a Mouse Embryonal Rhabdomyosarcoma cell culture and a drug screen of 60 targeted drugs, we show that predictive modeling based on functional data alone can also produce high accuracy predictions. The framework also allows us to generate personalized tumor proliferation circuits to gain further insights on the individualized biological pathway.

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Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs

Cited by 27 publications

References 33 publications

Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity

Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity

System control-mediated drug delivery towards complex systems via nanodiamond carriers

An Integrated Approach to Anti-Cancer Drug Sensitivity Prediction

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