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What Fuels a “Domino Effect” in Cancer Drug Resistance?
KAIST researchers have identified mechanisms that relay prior acquired resistance to the first-line chemotherapy to the second-line targeted therapy, fueling a “domino effect” in cancer drug resistance. Their study featured in the February 7 edition of Science Advances suggests a new strategy for improving the second-line setting of cancer treatment for patients who showed resistance to anti-cancer drugs.
Resistance to cancer drugs is often managed in the clinic by chemotherapy and targeted therapy. Unlike chemotherapy that works by repressing fast-proliferating cells, targeted therapy blocks a single oncogenic pathway to halt tumor growth. In many cases, targeted therapy is engaged as a maintenance therapy or employed in the second-line after front-line chemotherapy.
A team of researchers led by Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering and the KAIST Institute for Health Science and Technology (KIHST) has discovered an unexpected resistance signature that occurs between chemotherapy and targeted therapy. The team further identified a set of integrated mechanisms that promotes this kind of sequential therapy resistance.
“There have been multiple clinical accounts reflecting that targeted therapies tend to be least successful in patients who have exhausted all standard treatments,” said the first author of the paper Mark Borris D. Aldonza. He continued, “These accounts ignited our hypothesis that failed responses to some chemotherapies might speed up the evolution of resistance to other drugs, particularly those with specific targets.”
Aldonza and his colleagues extracted large amounts of drug-resistance information from the open-source database the Genomics of Drug Sensitivity in Cancer (GDSC), which contains thousands of drug response data entries from various human cancer cell lines. Their big data analysis revealed that cancer cell lines resistant to chemotherapies classified as anti-mitotic drugs (AMDs), toxins that inhibit overacting cell division, are also resistant to a class of targeted therapies called epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs).
In all of the cancer types analyzed, more than 84 percent of those resistant to AMDs, representatively ‘paclitaxel’, were also resistant to at least nine EGFR-TKIs. In lung, pancreatic, and breast cancers where paclitaxel is often used as a first-line, standard-of-care regimen, greater than 92 percent showed resistance to EGFR-TKIs. Professor Kim said, “It is surprising to see that such collateral resistance can occur specifically between two chemically different classes of drugs.”
To figure out how failed responses to paclitaxel leads to resistance to EGFR-TKIs, the team validated co-resistance signatures that they found in the database by generating and analyzing a subset of slow-doubling, paclitaxel-resistant cancer models called ‘persisters’.
The results demonstrated that paclitaxel-resistant cancers remodel their stress response by first becoming more stem cell-like, evolving the ability to self-renew to adapt to more stressful conditions like drug exposures. More surprisingly, when the researchers characterized the metabolic state of the cells, EGFR-TKI persisters derived from paclitaxel-resistant cancer cells showed high dependencies to energy-producing processes such as glycolysis and glutaminolysis.
“We found that, without an energy stimulus like glucose, these cells transform to becoming more senescent, a characteristic of cells that have arrested cell division. However, this senescence is controlled by stem cell factors, which the paclitaxel-resistant cancers use to escape from this arrested state given a favorable condition to re-grow,” said Aldonza.
Professor Kim explained, “Before this research, there was no reason to expect that acquiring the cancer stem cell phenotype that dramatically leads to a cascade of changes in cellular states affecting metabolism and cell death is linked with drug-specific sequential resistance between two classes of therapies.”
He added, “The expansion of our work to other working models of drug resistance in a much more clinically-relevant setting, perhaps in clinical trials, will take on increasing importance, as sequential treatment strategies will continue to be adapted to various forms of anti-cancer therapy regimens.”
This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF-2016R1C1B2009886), and the KAIST Future Systems Healthcare Project (KAISTHEALTHCARE42) funded by the Korean Ministry of Science and ICT (MSIT). Undergraduate student Aldonza participated in this research project and presented the findings as the lead author as part of the Undergraduate Research Participation (URP) Program at KAIST.
< Figure 1. Schematic overview of the study. >
< Figure 2. Big data analysis revealing co-resistance signatures between classes of anti-cancer drugs. >
Publication:
Aldonza et al. (2020) Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms. Science Advances, Vol. 6, No. 6, eaav7416. Available online at http://dx.doi.org/10.1126/sciadv.aav7416
Profile: Prof. Yoosik Kim, MA, PhD
ysyoosik@kaist.ac.kr
https://qcbio.kaist.ac.kr/
Assistant Professor
Bio Network Analysis Laboratory
Department of Chemical and Biomolecular Engineering
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr
Daejeon, Republic of Korea
Profile: Mark Borris D. Aldonza
borris@kaist.ac.kr
Undergraduate Student
Department of Biological Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr
Daejeon, Republic of Korea
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2020.02.10 View 13867 -
KAIST Awarded the IPBC R&D Institution Team of the Year
KAIST was awarded the R&D Institution Team of the Year during the annual IPBC (Intellectual Property Business Congress) Asia 2019 held in Tokyo October 28-30. IPBC is a conference dedicated to IP value creation strategies hosted by IAM Media, a world’s leading IP business media platform.
IPBC Asia 2019 recognized the institutions and businesses that employed innovative IP strategies and management to produce the greatest IP value in 11 categories covering automotive, electronics, healthcare and biotechnology, internet and software, R&D institutions, semiconductors, industrials, mobile and telecommunications, Asia IP deals, Asia teams, and Asia individuals. This year, KAIST was recognized as one of the most active patentees in the Asia-Pacific region by significantly increasing its IP value through licensing and tech transfers.
Associate Vice President Kyung Cheol Choi of the Office of University-Industry Cooperation remarked, “We are so delighted to prove the strong research capacity of KAIST. This will help us accomplish our vision of being a leading university that creates global impact.”
2019.12.04 View 7713 -
KAIST and Google Jointly Develop AI Curricula
KAIST selected the two professors who will develop AI curriculum under the auspices of the KAIST-Google Partnership for AI Education and Research. The Graduate School of AI announced the two authors among the 20 applicants who will develop the curriculum next year. They will be provided 7,500 USD per subject.
Professor Changho Suh from the School of Electrical Engineering and Professor Yong-Jin Yoon from the Department of Mechanical Engineering will use Google technology such as TensorFlow, Google Cloud, and Android to create the curriculum.
Professor Suh’s “TensorFlow for Information Theory and Convex Optimization “will be used for curriculum in the graduate courses and Professor Yoon’s “AI Convergence Project Based Learning (PBL)” will be used for online courses. Professor Yoon’s course will explore and define problems by utilizing AI and experiencing the process of developing products that use AI through design thinking, which involves product design, production, and verification. Professor Suh’s course will discus“information theory and convergence,” which uses basic sciences and engineering as well as AI, machine learning, and deep learning.
2019.12.04 View 13217 -
Ultrafast Quantum Motion in a Nanoscale Trap Detected
< Professor Heung-Sun Sim (left) and Co-author Dr. Sungguen Ryu (right) >
KAIST researchers have reported the detection of a picosecond electron motion in a silicon transistor. This study has presented a new protocol for measuring ultrafast electronic dynamics in an effective time-resolved fashion of picosecond resolution. The detection was made in collaboration with Nippon Telegraph and Telephone Corp. (NTT) in Japan and National Physical Laboratory (NPL) in the UK and is the first report to the best of our knowledge.
When an electron is captured in a nanoscale trap in solids, its quantum mechanical wave function can exhibit spatial oscillation at sub-terahertz frequencies. Time-resolved detection of such picosecond dynamics of quantum waves is important, as the detection provides a way of understanding the quantum behavior of electrons in nano-electronics. It also applies to quantum information technologies such as the ultrafast quantum-bit operation of quantum computing and high-sensitivity electromagnetic-field sensing. However, detecting picosecond dynamics has been a challenge since the sub-terahertz scale is far beyond the latest bandwidth measurement tools.
A KAIST team led by Professor Heung-Sun Sim developed a theory of ultrafast electron dynamics in a nanoscale trap, and proposed a scheme for detecting the dynamics, which utilizes a quantum-mechanical resonant state formed beside the trap. The coupling between the electron dynamics and the resonant state is switched on and off at a picosecond so that information on the dynamics is read out on the electric current being generated when the coupling is switched on.
NTT realized, together with NPL, the detection scheme and applied it to electron motions in a nanoscale trap formed in a silicon transistor. A single electron was captured in the trap by controlling electrostatic gates, and a resonant state was formed in the potential barrier of the trap.
The switching on and off of the coupling between the electron and the resonant state was achieved by aligning the resonance energy with the energy of the electron within a picosecond. An electric current from the trap through the resonant state to an electrode was measured at only a few Kelvin degrees, unveiling the spatial quantum-coherent oscillation of the electron with 250 GHz frequency inside the trap.
Professor Sim said, “This work suggests a scheme of detecting picosecond electron motions in submicron scales by utilizing quantum resonance. It will be useful in dynamical control of quantum mechanical electron waves for various purposes in nano-electronics, quantum sensing, and quantum information”.
This work was published online at Nature Nanotechnology on November 4. It was partly supported by the Korea National Research Foundation through the SRC Center for Quantum Coherence in Condensed Matter. For more on the NTT news release this article, please visit https://www.ntt.co.jp/news2019/1911e/191105a.html
-ProfileProfessor Heung-Sun Sim
Department of PhysicsDirector, SRC Center for Quantum Coherence in Condensed Matterhttps://qet.kaist.ac.kr KAIST
-Publication:Gento Yamahata, Sungguen Ryu, Nathan Johnson, H.-S. Sim, Akira Fujiwara, and Masaya Kataoka. 2019. Picosecond coherent electron motion in a silicon single-electron source. Nature Nanotechnology (Online Publication). 6 pages. https://doi.org/10.1038/s41565-019-0563-2
2019.11.05 View 17457 -
A Mathematical Model Reveals Long-Distance Cell Communication Mechanism
How can tens of thousands of people in a large football stadium all clap together with the same beat even though they can only hear the people near them clapping?
A combination of a partial differential equation and a synthetic circuit in microbes answers this question. An interdisciplinary collaborative team of Professor Jae Kyoung Kim at KAIST, Professor Krešimir Josić at the University of Houston, and Professor Matt Bennett at Rice University has identified how a large community can communicate with each other almost simultaneously even with very short distance signaling. The research was reported at Nature Chemical Biology.
Cells often communicate using signaling molecules, which can travel only a short distance. Nevertheless, the cells can also communicate over large distances to spur collective action. The team revealed a cell communication mechanism that quickly forms a network of local interactions to spur collective action, even in large communities.
The research team used an engineered transcriptional circuit of combined positive and negative feedback loops in E. coli, which can periodically release two types of signaling molecules: activator and repressor. As the signaling molecules travel over a short distance, cells can only talk to their nearest neighbors. However, cell communities synchronize oscillatory gene expression in spatially extended systems as long as the transcriptional circuit contains a positive feedback loop for the activator.
Professor Kim said that analyzing and understanding such high-dimensional dynamics was extremely difficult. He explained, “That’s why we used high-dimensional partial differential equation to describe the system based on the interactions among various types of molecules.” Surprisingly, the mathematical model accurately simulates the synthesis of the signaling molecules in the cell and their spatial diffusion throughout the chamber and their effect on neighboring cells.
The team simplified the high-dimensional system into a one-dimensional orbit, noting that the system repeats periodically. This allowed them to discover that cells can make one voice when they lowered their own voice and listened to the others. “It turns out the positive feedback loop reduces the distance between moving points and finally makes them move all together. That’s why you clap louder when you hear applause from nearby neighbors and everyone eventually claps together at almost the same time,” said Professor Kim.
Professor Kim added, “Math is a powerful as it simplifies complex thing so that we can find an essential underlying property. This finding would not have been possible without the simplification of complex systems using mathematics."
The National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation, the Hamill Foundation, the National Research Foundation of Korea, and the T.J. Park Science Fellowship of POSCO supported the research.
(Figure: Complex molecular interactions among microbial consortia is simplified as interactions among points on a limit cycle (right).)
2019.10.15 View 26455 -
Professor Ki-Jun Yoon selected as the 2019 SUHF Young Investigator
< Professor Ki-Jun Yoon >
Professor Ki-Jun Yoon from the Department of Biological Sciences was named one of four recipients of the 2019 Suh Kyung-Bae Science Foundation (SUHF) Young Investigator Awards.
The SUHF is a non-profit organization established in 2016 and funded by a personal donation of 300 billion KRW in shares from Chairman and CEO Kyung-Bae Suh of the Amorepacific Group. The primary purpose of the foundation is to serve as a platform to nurture and provide comprehensive long-term support for creative and passionate young Korean scientists committed to pursuing research in the field of life sciences. The SUHF selects three to five scientists through an open recruiting process every year, and grants each scientist a maximum of 2.5 billion KRW over a period of up to five years.
Since January this year, the foundation received 83 research proposals from scientists across the nation, especially from those who had less than five years of experience as professors, and selected the four recipients, including Professor Yoon.
Professor Yoon was recognized for his contributions to the advancement of research on how post-transcriptional mechanisms may modulate stem cell properties. His research project involves deciphering the molecular mechanisms controlling RNA metabolism in neural stem cells during normal development, and how alterations in RNA regulatory programs lead to human brain disorders.
< (From left) Professor Joo-Hong Park, Professor Yuree Lee, Chairman and CEO Kyung-Bae Suh, Professor Eunjung Lee, Professor Ki-Jun Yoon, ⓒ Amorepacific Group >
The other awards were given to Professor Joo-Hong Park and Professor Yuree Lee of Seoul National University, and Professor Eunjung Lee of Boston Children's Hospital and Harvard Medical School.
The awards ceremony was held on September 18 at the Amorepacific Headquarters in Seoul.
With these four new awardees, a total of 14 scientists have been named as SUHF Young Investigators to date.
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2019.09.23 View 8768 -
Sungjoon Park Named Google PhD Fellow
PhD candidate Sungjoon Park from the School of Computing was named a 2019 Google PhD Fellow in the field of natural language processing. The Google PhD fellowship program has recognized and supported outstanding graduate students in computer science and related fields since 2009. Park is one of three Korean students chosen as the recipients of Google Fellowships this year. A total of 54 students across the world in 12 fields were awarded this fellowship.
Park’s research on computational psychotherapy using natural language processing (NLP) powered by machine learning earned him this year’s fellowship. He presented of learning distributed representations in Korean and their interpretations during the 2017 Annual Conference of the Association for Computational Linguistics and the 2018 Conference on Empirical Methods in Natural Language Processing. He also applied machine learning-based natural language processing into computational psychotherapy so that a trained machine learning model could categorize client's verbal responses in a counseling dialogue. This was presented at the Annual Conference of the North American Chapter of the Association for Computational Linguistics.
More recently, he has been developing on neural response generation model and the prediction and extraction of complex emotion in text, and computational psychotherapy applications.
2019.09.17 View 8453 -
Distinguished Professor Sukbok Chang Donates His Prize Money
The honoree of the 2019 Korea Best Scientist and Technologist Award, Distinguished Professor Sukbok Chang donated his prize money of one hundred million KRW to the Chemistry Department Scholarship Fund and the Lyu Keun-Chul Sports Complex Management Fund during a donation ceremony last week.
Professor Chang won the award last month in recognition of his pioneering achievements and lifetime contributions to the development of carbon-hydrogen activation strategies, especially for carbon-carbon, carbon-nitrogen, and carbon-oxygen formations. Professor Chang, a world renowned chemist, has been recognized for his highly selective catalytic systems, allowing the controlled defunctionalization of bio-derived platform substrates under mild conditions and opening a new avenue for the utilization of biomass-derived platform chemicals.
“All my achievements are the results of my students’ hard work and dedication. I feel very fortunate to have such talented team members. I want to express my sincere gratitude for such a great research environment that we have worked together in so far,” said Professor Chang at the ceremony.
KAIST President Sung-Chul Shin said, “Not only will Professor Chang’s donation make a significant contribution to the Department of Chemistry, but also to the improvement of the Lyu Keun-Chul Sports Complex’s management, which directly links to the health and welfare of the KAIST community.”
Professor Chang currently holds the position of distinguished professor at KAIST and director of the Center for Catalytic Hydrocarbon Functionalizations in the Institute for Basic Science (IBS). He previously received the Kyung-Ahm Academic Award in 2013 and the Korea Toray Science Award in 2018. All these prize money also went to the school.
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2019.08.26 View 8005 -
Manipulating Brain Cells by Smartphone
Researchers have developed a soft neural implant that can be wirelessly controlled using a smartphone. It is the first wireless neural device capable of indefinitely delivering multiple drugs and multiple colour lights, which neuroscientists believe can speed up efforts to uncover brain diseases such as Parkinson’s, Alzheimer’s, addiction, depression, and pain.
A team under Professor Jae-Woong Jeong from the School of Electrical Engineering at KAIST and his collaborators have invented a device that can control neural circuits using a tiny brain implant controlled by a smartphone. The device, using Lego-like replaceable drug cartridges and powerful, low-energy Bluetooth, can target specific neurons of interest using drugs and light for prolonged periods. This study was published in Nature Biomedical Engineering.
“This novel device is the fruit of advanced electronics design and powerful micro and nanoscale engineering,” explained Professor Jeong. “We are interested in further developing this technology to make a brain implant for clinical applications.”
This technology significantly overshadows the conventional methods used by neuroscientists, which usually involve rigid metal tubes and optical fibers to deliver drugs and light. Apart from limiting the subject’s movement due to bulky equipment, their relatively rigid structure causes lesions in soft brain tissue over time, therefore making them not suitable for long-term implantation. Although some efforts have been made to partly mitigate adverse tissue response by incorporating soft probes and wireless platforms, the previous solutions were limited by their inability to deliver drugs for long periods of time as well as their bulky and complex control setups.
To achieve chronic wireless drug delivery, scientists had to solve the critical challenge of the exhaustion and evaporation of drugs. To combat this, the researchers invented a neural device with a replaceable drug cartridge, which could allow neuroscientists to study the same brain circuits for several months without worrying about running out of drugs.
These ‘plug-n-play’ drug cartridges were assembled into a brain implant for mice with a soft and ultrathin probe (with the thickness of a human hair), which consisted of microfluidic channels and tiny LEDs (smaller than a grain of salt), for unlimited drug doses and light delivery.
Controlled with an elegant and simple user interface on a smartphone, neuroscientists can easily trigger any specific combination or precise sequencing of light and drug delivery in any implanted target animal without the need to be physically inside the laboratory. Using these wireless neural devices, researchers can also easily setup fully automated animal studies where the behaviour of one animal could affect other animals by triggering light and/or drug delivery.
“The wireless neural device enables chronic chemical and optical neuromodulation that has never been achieved before,” said lead author Raza Qazi, a researcher with KAIST and the University of Colorado Boulder.
This work was supported by grants from the National Research Foundation of Korea, US National Institute of Health, National Institute on Drug Abuse, and Mallinckrodt Professorship.
(A neural implant with replaceable drug cartridges and Bluetooth low-energy can target specific neurons .)
(Micro LED controlling using smartphone application)
2019.08.07 View 32034 -
KAIST-Google Partnership for AI Education and Research
Google has agreed to support KAIST students and professors in the fields of AI research and education. President Sung-Chul Shin and Google Korea Country Director John Lee signed the collaboration agreement during a ceremony on July 19 at KAIST.
Under the agreement, Google will fund the Google AI-Focused Research Awards Program, the PhD Fellowship Program, and Student Travel Grants for KAIST. In addition, Google will continue to provide more academic and career building opportunities for students, including Google internship programs.
KAIST and Google has been collaborating for years. Professor Steven Whang at the School of Electrical Engineering and Professor Sung Ju Hwang at the School of Computing won the AI-Focused Award in 2018 and conduct their researches on "Improving Generalization and Reliability of Any Deep Neural Networks" and "Automatic and Acitionable Model Analysis for TFX," respectively. Outstanding PhD students have been recognized through the PhD Fellowship Program. However, this new collaboration agreement will focus on research, academic development, and technological innovation in AI.
Google plans to support research in the fields of deep learning, cloud machine learning, and voice technologies. Google will fund the development of two educational programs based on Google open source technology each year for two years that will be used in the new AI Graduate School opening for the fall semester.
John Lee of Google Korea said, “This partnership lays a solid foundation for deeper collaboration.” President Shin added, “This partnership will not only advance Korea’s global competitiveness in AI-powered industries but also contribute to the global community by nurturing talents in this most extensive discipline.”
2019.07.22 View 8116 -
Three Professors Receive Han Sung Science Awards
Three KAIST professors swept the 2nd Han Sung Science Awards. Professor Bum-Ki Min from the Departments of Mechanical Engineering and Physics, Professor Sun-Kyu Han from the Department of Chemistry, and Professor Seung-Jae Lee from the Department of Biological Sciences won all three awards presented by the Han Sung Scholarship Foundation, which recognizes promising mid-career scientists in the fields of physics, chemistry, and biological sciences. The awards ceremony will take place on August 16 in Hwaseong.
Professor Min was declared as the winner of the physics field in recognition of his outstanding research activities including searching for new application areas for metamaterials and investigating their unexplored functionalities. The metamaterials with a high index of refraction developed by Professor Min’s research team have caught the attention of scientists worldwide, as they can help develop high-resolution imaging systems and ultra-small, hyper-sensitive optical devices.
The chemistry field winner, Professor Han, is the youngest awardee so far at 36 years of age. He is often described as one of the most promising next-generation Korean scientists in the field of the total synthesis of complex natural products. Given the fact that this field takes very long-term research, he is making unprecedented research achievements. He is focusing on convergent and flexible synthetic approaches that enable access to not only a single target but various natural products with structural and biosynthetic relevance as well as unnatural products with higher biological potency.
Professor Lee was recognized for his contributions to the advancement of biological sciences, especially in aging research. Professor Lee’s team is taking a novel approach by further investigating complex interactions between genetic and environmental factors that affect aging, and identifying genes that mediate the effects. The team has been conducting large-scale gene discovery efforts by employing RNA sequencing analysis, RNAi screening, and chemical mutagenesis screening. They are striving to determine the functional significance of candidate genes obtained from these experiments and mechanistically characterize these genes.
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2019.07.03 View 9320 -
"It’s a Blessing": Lawyer Couple Donates 82 Acres of Land
Korea Abraham Lincoln Society Founder Kwak Sung-hyun and International IP Alternative Dispute Resolution Center (IIPAC) Chairman Kim Cheol-ho have committed to donate a large tract of land to KAIST during a ceremony on July 3. The couple will donate about 82 acres of land located in Seongnam City, Gyeonggi Province. The value of the property is estimated at over 10 billion won.
Kim, a lawyer who taught at the Moon Soul Graduate School of Future Strategy from 2009 to 2014, said, “It is a real blessing to make a gift to KAIST."
The property is a part of family inheritance that has been passed down for generations. “We’ve thought about the right way to give back to society from a long-term perspective. KAIST will be the best place to honor my father’s generosity and spirit to help young students,” Kwak said at the ceremony.
Kwak’s late father who was also a lawyer was a big landowner in Seongnam City back in the 1970s. But he also had to buy nearby parcels of land because he could not refuse the local farmers asking him to buy their land when they urgently needed to sell their property to pay their children’s college tuition fees. So, he bought the land, paying more than double the asking price.
The couple finalized their donation plan after having a meeting with President Sung-Chul Shin earlier this year. President Shin personally guided them on a campus tour and presented his vision to make KAIST a world-class university.
“We were quite moved by President Shin and the faculty members’ passion and hard work. And we really wanted to help KAIST be the real top university in the world by educating young talents needed for the new era,” Kim said.
President Shin said the university will use the land to establish a new campus for entrepreneurship that combines education, research, and technology commercialization so that it can become an advance base in the Fourth Industrial Revolution era.
2019.07.03 View 4915