Modelling of the cancer cell cycle as a tool for rational drug development: A systems pharmacology approach to cyclotherapy

Jackson, Robert; Veroli, Giovanni Y. Di; Koh, Siang-Boon; Goldlust, Ian S.; Richards, Frances M.; Jodrell, Duncan I.

doi:10.1371/journal.pcbi.1005529

Cited by 14 publications

(3 citation statements)

References 47 publications

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“…Gemcitabine is selectively cytotoxic to cells in S-phase. Synergy between palbociclib and gemcitabine is supported by pharmacokinetic modeling (35) but was antagonistic in human pancreatic cancer cell lines (36). Characterizing the mechanistic coupling of specific regimens that regulate CDK4/6 activity with genotoxic compounds will be critical to maximize cytotoxic effects.…”

Section: Combining Conventional Chemotherapy With Cell Cycle Modulatomentioning

confidence: 99%

Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy

2018

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Preclinical and clinical development of agents that inhibit cell-cycle progression have brought an understanding of the feasibility of targeting various cell-cycle regulators in patients with cancer. Small molecule inhibitors targeting key proteins that participate in cell-cycle progression including the cyclin-dependent kinases and checkpoint kinases induce cell-cycle arrest and apoptosis in neoplastic cells. Early phase I studies demonstrate targeted inhibitors can be administered safely in adult and pediatric cancer patients, but these agents generally show limited clinical benefits as single agents. In this review, we discuss biological mechanisms that support dual combination strategies of cell-cycle inhibition with chemotherapeutic agents that are anticipated to achieve rationally targeted therapies for cancer patients. The rationale for evaluating these combination strategies is that DNA damage renders tumors highly responsive to irreversible cell-cycle arrest therapy. This approach is predicted to generate less intensive therapies and to maximize the efficacy of individual agents against solid tumors and hematologic malignancies. .

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Section: Combining Conventional Chemotherapy With Cell Cycle Modulatomentioning

confidence: 99%

Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy

2018

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“…Increased expression of cell cycle-related genes has been reported in NKTCL [ 39 ]. Platinum, gemcitabine, and etoposide are cell cycle-specific DNA damaging agents [ 52 – 54 ], which are prevalently used in NKTCL chemotherapy. For advanced or relapsed/refractory NKTCL, CR rate of P-GEMOX (peg-asparaginase, gemcitabine, and oxaliplatin) is 51.4% of 35 patients, with 2-year PFS and OS rate of 38.6% and 64.7% [ 55 ].…”

Section: Introductionmentioning

confidence: 99%

Advances in multiple omics of natural-killer/T cell lymphoma

Xiong

Zhao

2018

J Hematol Oncol

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Natural-killer/T cell lymphoma (NKTCL) represents the most common subtype of extranodal lymphoma with aggressive clinical behavior. Prevalent in Asians and South Americans, the pathogenesis of NKTCL remains to be fully elucidated. Using system biology techniques including genomics, transcriptomics, epigenomics, and metabolomics, novel biomarkers and therapeutic targets have been revealed in NKTCL. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Another genome-wide association study reports that single nucleotide polymorphisms mapping to the class II MHC region on chromosome 6 contribute to lymphomagenesis. Alterations of oncogenic signaling pathways janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), WNT, and NOTCH, as well as epigenetic dysregulation of microRNA and long non-coding RNAs, are also frequently observed in NKTCL. As for metabolomic profiling, abnormal amino acids metabolism plays an important role on disease progression of NKTCL. Of note, through targeting multiple omics aberrations, clinical outcome of NKTCL patients has been significantly improved by asparaginase-based regimens, immune checkpoints inhibitors, and histone deacetylation inhibitors. Future investigations will be emphasized on molecular classification of NKTCL using integrated analysis of system biology, so as to optimize targeted therapeutic strategies of NKTCL in the era of precision medicine.

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“…The model of the lac operon was based upon [8,9] and [11]. The model of MAP kinase signalling is based upon that of Brightman and Fell [21], and the model of PI3K signalling was adapted from [22]. The models were coded in the C programming language and compiled using the GNU compiler collection (gcc) release 4.6.2.…”

Section: Methodsmentioning

confidence: 99%

The Boolean Kinetics of signal transduction

Jackson¹

2017

Integr Cancer Sci Therap

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Volume 4(5): 1-8 with electronic circuits [3]. Information is processed in the nervous system by networks of neurons, each of which, at any particular time, is either charged or discharged, without a stable intermediate state.We shall here concentrate on an evolutionarily more primitive form of information processing, the control of gene expression by signalling pathways, and will show that these pathways can be described as Boolean logic circuits.A recurring concept in Boolean logic is that of material implication: The statement A → B (A implies B) means that if A is true, then B is true. In many computer languages this is expressed as IF A THEN B. This is clearly an underlying rule of biochemical systems. In the presence of an enzyme that converts substance A to substance B, if A is present, then B will be present. Unlike chemical kinetics or enzyme kinetics, which are concerned with amounts of substances and rates of their interconversion, here we are only concerned with whether B is present (TRUE) or not (FALSE). The three basic relationships of Boolean algebra are AND, OR, and NOT. To make adenosine 5'-phosphate (AMP) in a cell, in the presence of adenosine kinase, we need its two substrates, adenosine and ATP. If both are present, AMP will be present. If either substrate is absent, AMP will be absent. In fact, in addition to this so-called salvage pathway, some cells, particularly liver cells, can make AMP by the alternative (de novo) pathway, from adenylosuccinate (SAMP), in presence of the enzyme adenylosuccinate lyase [4]. We could express this asThe Boolean Kinetics of signal transduction Robert C Jackson* Pharmacometrics Ltd., UK AbstractHeredity and environment interact at the level of gene expression, controlled by transcription networks, which in turn are driven by signalling pathways. Unlike metabolic pathways, what is transmitted by signalling pathways is information, not matter. Since RNA polymerase II is a limiting resource, only a fraction of the genome can be transcribed at any time. Despite the importance of signalling pathways in the control of gene expression, we know very little about their detailed kinetics. We show here that some transcription networks follow Boolean kinetics: their inputs are a combination of IF→THEN, AND, OR and NOT information and their output is either ON or OFF. A kinetic model of the lac operon in E.coli predicted Boolean kinetics. Such pathways act as monostable systems: their normal, resting state is OFF, and following an input, which may be very weak, and very transient, they amplify and prolong the signal sufficiently to activate the appropriate transcription network, after which (assuming the input signal has now ceased) they revert to the OFF state. A computer model of the MAP kinase pathway of eukaryotic cells also predicted Boolean kinetics. Cross-talk effects between signalling pathways result in the entire signalling network acting as a complex interactive system. Inhibitors of signalling pathways may have all-or-none effects on transcription, making the...

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Modelling of the cancer cell cycle as a tool for rational drug development: A systems pharmacology approach to cyclotherapy

Cited by 14 publications

References 47 publications

Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy

Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy

Advances in multiple omics of natural-killer/T cell lymphoma

The Boolean Kinetics of signal transduction

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