Human+Frontiers+Science+Program
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Mathematical Modeling Makes a Breakthrough for a New CRSD Medication
PhD Candidate Dae Wook Kim (Left) and Professor Jae Kyoung Kim (Right)
- Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy -
Mathematicians’ new modeling has identified major sources of interspecies and inter-individual variations in the clinical efficacy of a clock-modulating drug: photosensitivity and PER2 level. This enabled precision medicine for circadian disruption.
A KAIST mathematics research team led by Professor Jae Kyoung Kim, in collaboration with Pfizer, applied a combination of mathematical modeling and simulation tools for circadian rhythms sleep disorders (CRSDs) to analyze the animal data generated by Pfizer. This study was reported in Molecular Systems Biology as the cover article on July 8.
Pharmaceutical companies have conducted extensive studies on animals to determine the candidacy of this new medication. However, the results of animal testing do not always translate to the same effects in human trials. Furthermore, even between humans, efficacy differs across individuals depending on an individual’s genetic and environmental factors, which require different treatment strategies.
To overcome these obstacles, KAIST mathematicians and their collaborators developed adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions.
A circadian rhythm is a 24-hour cycle in the physiological processes of living creatures, including humans. A biological clock in the hypothalamic suprachiasmatic nucleus in the human brain sets the time for various human behaviors such as sleep.
A disruption of the endogenous timekeeping system caused by changes in one’s life pattern leads to advanced or delayed sleep-wake cycle phase and a desynchronization between sleep-wake rhythms, resulting in CRSDs. To restore the normal timing of sleep, timing of the circadian clock could be adjusted pharmacologically.
Pfizer identified PF-670462, which can adjust the timing of circadian clock by inhibiting the core clock kinase of the circadian clock (CK1d/e). However, the efficacy of PF-670462 significantly differs between nocturnal mice and diurnal monkeys, whose sleeping times are opposite.
The research team discovered the source of such interspecies variations in drug response by performing thousands of virtual experiments using a mathematical model, which describes biochemical interactions among clock molecules and PF-670462. The result suggests that the effect of PF-670462 is reduced by light exposure in diurnal primates more than in nocturnal mice. This indicates that the strong counteracting effect of light must be considered in order to effectively regulate the circadian clock of diurnal humans using PF-670462.
Furthermore, the team also found the source of inter-patients variations in drug efficacy using virtual patients whose circadian clocks were disrupted due to various mutations. The degree of perturbation in the endogenous level of the core clock molecule PER2 affects the efficacy.
This explains why the clinical outcomes of clock-modulating drugs are highly variable and certain subtypes are unresponsive to treatment. Furthermore, this points out the limitations of current treatment strategies tailored to only the patient’s sleep and wake time but not to the molecular cause of sleep disorders.
PhD candidate Dae Wook Kim, who is the first author, said that this motivates the team to develop an adaptive chronotherapy, which identifies a personalized optimal dosing time of day by tracking the sleep-wake up time of patients via a wearable device and allows for a precision medicine approach for CRSDs.
Professor Jae Kyoung Kim said, "As a mathematician, I am excited to help enable the advancement of a new drug candidate, which can improve the lives of so many patients. I hope this result promotes more collaborations in this translational research.”
This research was supported by a Pfizer grant to KAIST (G01160179), the Human Frontiers Science Program Organization (RGY0063/2017), and a National Research Foundation (NRF) of Korea Grant (NRF-2016 RICIB 3008468 and NRF-2017-Fostering Core Leaders of the Future Basic Science Program/ Global Ph.D. Fellowship Program).
Figure 1. Interspecies and Inter-patients Variations in PF-670462 Efficacy
Figure 2. Journal Cover Page
Publication:
Dae Wook Kim, Cheng Chang, Xian Chen, Angela C Doran, Francois Gaudreault, Travis Wager, George J DeMarco, and Jae Kyoung Kim. 2019. Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular Systems Biology. EMBO Press, Heidelberg, Germany, Vol. 15, Issue No. 7, Article, 16 pages. https://doi.org/10.15252/msb.20198838
Profile: Prof. Jae Kyoung Kim, PhD
jaekkim@kaist.ac.kr
http://mathsci.kaist.ac.kr/~jaekkim
Associate Professor
Department of Mathematical Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Dae Wook Kim, PhD Candidate
0308kdo@kaist.ac.kr
http://mathsci.kaist.ac.kr/~jaekkim
PhD Candidate
Department of Mathematical Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Dr. Cheng Chang, PhD
cheng.chang@pfizer.com
Associate Director of Clinical Pharmacology
Clinical Pharmacology, Global Product Development
Pfizer
https://www.pfizer.com/ Groton 06340, USA
(END)
2019.07.09 View 33804 -
Professor Ju, to Receive Grants from HFSP
(Professor Young Seok Ju)
Professor Young Seok Ju from the Graduate School of Medical Science and Engineering was selected as a young investigator to receive research funds from the Human Frontiers Science Program.
The Human Frontiers Science Program (HFSP) was founded in 1989 with members of the G7 and European Union to stimulate innovative research in the field of life sciences.
Professor Ju placed third out of the eight teams that were selected from 158 applicants representing 60 countries. He is now the fourth Korean to receive a research grant as a young investigator. Professor Jae Kyoung Kim from the Department of Mathematical Sciences also received this prize last year, hence KAIST has produced grant recipients for two consecutive years.
Professor Ju is a medical doctor specializing in cancer genomics and computer biology. He has been studying somatic mutations and their functional consequences in human cancer in a bioinformatics way. He has published papers in international journals including Nature, Science, Genome Research, and Journal of Clinical Oncology.
With a title ‘Tracing AID/APOBEC- and MSI-mediated hyper-mutagenesis in the clonal evolution of gastric cancer,’ Professor Ju will receive 1.05 million dollars for three years along with Professor Bon-Kyoung Koo from the Institute of Molecular Biotechnology at Austrian Academy of Sciences, and Sinppert Hugo from University Medical Center Utrecht.
Professor Ju said, “As a young investigator, it is my great honor to receive this research fund from this organization. Through this internationally collaborative research, I will carry out groundbreaking research to understand the pathophysiology of cancers at a molecular level.”
2018.04.24 View 7440