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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 11635 -
Blood-Based Multiplexed Diagnostic Sensor Helps to Accurately Detect Alzheimer’s Disease
A research team at KAIST reported clinically accurate multiplexed electrical biosensor for detecting Alzheimer’s disease by measuring its core biomarkers using densely aligned carbon nanotubes.
Alzheimer’s disease is the most prevalent neurodegenerative disorder, affecting one in ten aged over 65 years. Early diagnosis can reduce the risk of suffering the disease by one-third, according to recent reports. However, its early diagnosis remains challenging due to the low accuracy but high cost of diagnosis.
Research team led by Professors Chan Beum Park and Steve Park described an ultrasensitive detection of multiple Alzheimer's disease core biomarker in human plasma. The team have designed the sensor array by employing a densely aligned single-walled carbon nanotube thin films as a transducer.
The representative biomarkers of Alzheimer's disease are beta-amyloid42, beta-amyloid40, total tau protein, phosphorylated tau protein and the concentrations of these biomarkers in human plasma are directly correlated with the pathology of Alzheimer’s disease.
The research team developed a highly sensitive resistive biosensor based on densely aligned carbon nanotubes fabricated by Langmuir-Blodgett method with a low manufacturing cost.
Aligned carbon nanotubes with high density minimizes the tube-to-tube junction resistance compared with randomly distributed carbon nanotubes, which leads to the improvement of sensor sensitivity. To be more specific, this resistive sensor with densely aligned carbon nanotubes exhibits a sensitivity over 100 times higher than that of conventional carbon nanotube-based biosensors.
By measuring the concentrations of four Alzheimer’s disease biomarkers simultaneously Alzheimer patients can be discriminated from health controls with an average sensitivity of 90.0%, a selectivity of 90.0% and an average accuracy of 88.6%.
This work, titled “Clinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma”, were published in Nature Communications on January 8th 2020. The authors include PhD candidate Kayoung Kim and MS candidate Min-Ji Kim.
Professor Steve Park said, “This study was conducted on patients who are already confirmed with Alzheimer’s Disease. For further use in practical setting, it is necessary to test the patients with mild cognitive impairment.” He also emphasized that, “It is essential to establish a nationwide infrastructure, such as mild cognitive impairment cohort study and a dementia cohort study. This would enable the establishment of world-wide research network, and will help various private and public institutions.”
This research was supported by the Ministry of Science and ICT, Human Resource Bank of Chungnam National University Hospital and Chungbuk National University Hospital.
< A schematic diagram of a high-density aligned carbon nanotube-based resistive sensor that distinguishes patients with Alzheimer’s Disease by measuring the concentration of four biomarkers in the blood. >
Profile:
Professor Steve Park
stevepark@kaist.ac.kr
Department of Materials Science and Engineering
http://steveparklab.kaist.ac.kr/
KAIST
Profile:
Professor Chan Beum Park
parkcb at kaist.ac.kr
Department of Materials Science and Engineering
http://biomaterials.kaist.ac.kr/
KAIST
2020.02.07 View 8974 -
A System Controlling Road Active Noise to Hit the Road
The research team led by Professor Youngjin Park of the Department of Mechanical Engineering has developed a road noise active noise control (RANC) system to be commercialized in partnership with Hyundai Motor Group.
On December 11, Hyundai Motor Group announced the successful development of the RANC system, which significantly reduces the road noise flowing into cars. The carmaker has completed the domestic and American patent applications for the location of sensors and the signal selection method, the core technology of RANC.
RANC is a technology for reducing road noise during driving. This system consists of an acceleration sensor, digital signal processor (the control computer to analyze sound signals), microphone, amplifier, and audio system. To make the system as simple as possible, the audio system utilizes the original audio system embedded in the car instead of a separate system.
The acceleration sensor first calculates the vibration from the road into the car. The location of the sensor is important for accurately identifying the vibration path. The research team was able to find the optimal sensor location through a number of tests.
The System Dynamics and Applied Control Laboratory of Professor Park researched ways to significantly reduce road noise with Hyundai Motor Group for four years from 1993 as a G7 national project and published the results in international journals. In 2002, the researchers published an article titled “Noise Quietens Driving” in Nature, where they announced the first success in reducing road noise in actual cars. The achievement did not lead to commercialization, however, due to the lack of auxiliary technologies at the time, digital amplifiers and DSP for cars for example, and pricing issues.
Since 2013, Professor Park’s research team has participated in one technology transfer and eight university-industry projects. Based on these efforts, the team was able to successfully develop the RANC system with domestic technology in partnership with Hyundai’s NVH Research Lab (Research Fellow, Dr. Gangdeok Lee; Ph.D. in aviation engineering, 1996), Optomech (Founder, Professor Gyeongsu Kim; Ph.D. in mechanical engineering, 1999), ARE (CEO Hyeonseok Kim; Ph.D. in mechanical engineering, 1998), WeAcom, and BurnYoung.
Professor Park’s team led the project by performing theory-based research during the commercialization stage in collaboration with Hyundai Motor Group.
For the commercialization of the RANC system, Hyundai Motor Group is planning to collaborate with the global car audio company Harman to increase the degree of completion and apply the RANC system to the GV 80, the first SUV model of the Genesis brand.
“I am very delighted as an engineer to see the research I worked on from my early days at KAIST be commercialized after 20 years,” noted Professor Park. “I am thrilled to make a contribution to such commercialization with my students in my lab.”
2019.12.27 View 9744 -
KAIST GSAI and SNUBH Join Hands for AI in Healthcare
< Dean Song Chong (left) and Director Chang Wan Oh (right)
at the KAIST GSAI - SNUBH MOU Signing Ceremony >
The Graduate School of AI (GSAI) at KAIST and the Seoul National University Bundang Hospital (SNUBH) signed a memorandum of understanding (MOU) to cooperate in AI education and research in the field of healthcare last month. The two institutions have agreed to collaborate on research and technology development through the implementation of academic and personnel exchange programs.
The GSAI, opened in August 2019 as Korea’s first AI graduate school, has been in the forefront of nurturing top-tier AI specialists in the era of Fourth Industrial Revolution. The school employs a two-track strategy that not only provides students with core AI-related courses on machine learning, data mining, computer vision, and natural language processing, but also a multidisciplinary curriculum incorporating the five key fields of healthcare, autonomous vehicles, manufacturing, security, and emerging technologies. Its faculty members are "the cream of the crop” in their early 40s, achieving world-class performance in their respective fields.
SNUBH opened the Healthcare Innovation Park in 2016, the first hospital-led convergence research complex among Korean medical institutions. It is leading future medical research in five specialized areas: medical devices, healthcare ICT, human genetics, nano-machines, and regenerative medicine.
The Dean of the GSAI, Song Chong, said, “We have set the stage for a cooperative platform for continuous and efficient joint education and research by the two institutions.” He expressed his excitement, saying, “Through this platform and our expertise in AI engineering and medicine, we will lead future AI-based medical technology.”
The Director of the SNUBH Research Division, Chang Wan Oh, stressed that “the mutual cooperation between the two institutions will become a crucial turning point in AI education and research, which is at the core of future healthcare.” He added, “Through a high level of cooperation, we will have the ability to bring about global competitiveness and innovation.”
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2019.12.27 View 7204 -
Professor Junil Choi Receives Stephen O. Rice Prize
< Professor Junil Choi (second from the left) >
Professor Junil Choi from the School of Electrical Engineering received the Stephen O. Rice Prize at the Global Communications Conference (GLOBECOM) hosted by the Institute of Electrical and Electronics Engineers (IEEE) in Hawaii on December 10, 2019.
The Stephen O. Rice Prize is awarded to only one paper of exceptional merit every year. The IEEE Communications Society evaluates all papers published in the IEEE Transactions on Communications journal within the last three years, and marks each paper by aggregating its scores on originality, the number of citations, impact, and peer evaluation.
Professor Choi won the prize for his research on one-bit analog-to-digital converters (ADCs) for multiuser massive multiple-input and multiple-output (MIMO) antenna systems published in 2016. In his paper, Professor Choi proposed a technology that can drastically reduce the power consumption of the multiuser massive MIMO antenna systems, which are the core technology for 5G and future wireless communication. Professor Choi’s paper has been cited more than 230 times in various academic journals and conference papers since its publication, and multiple follow-up studies are actively ongoing.
In 2015, Professor Choi received the IEEE Signal Processing Society Best Paper Award, an award equals to the Stephen O. Rice Prize. He was also selected as the winner of the 15th Haedong Young Engineering Researcher Award presented by the Korean Institute of Communications and Information Sciences (KICS) on December 6, 2019 for his outstanding academic achievements, including 34 international journal publications and 26 US patent registrations.
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2019.12.23 View 9030 -
Professor Sung Yong Kim Elected as the Chair of PICES MONITOR
< Professor Sung Yong Kim >
Professor Sung Yong Kim from the Department of Mechanical Engineering was elected as the chair of the Technical Committee on Monitoring (MONITOR) of the North Pacific Marine Science Organization (PICES).
PICES is an intergovernmental marine science organization that was established in 1992 through a collaboration between six North Pacific nations including South Korea, Russia, the United States, Japan, China, and Canada to exchange and discuss research on the Pacific waters. Its headquarters is located in Canada and the organization consists of seven affiliated maritime science and marine technology committees.
Professor Kim was elected as the chair of the technical committee that focuses on monitoring and will be part of the Science Board as an ex-officio member. His term will last three years from November 2019.
Professor Kim was recognized for his academic excellence, expertise, and leadership among oceanographers both domestically and internationally.
Professor Kim will also participate as an academia civilian committee member of the Maritime and Fisheries Science and Technology Committee under the Korean Ministry of Oceans and Fisheries for two years from December 18, 2019.
He stated, “I will give my full efforts to broaden Korean oceanography research by participating in maritime leadership positions at home and abroad, and help South Korea become a maritime powerhouse.”
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2019.12.22 View 7608 -
New Liquid Metal Wearable Pressure Sensor Created for Health Monitoring Applications
Soft pressure sensors have received significant research attention in a variety of fields, including soft robotics, electronic skin, and wearable electronics. Wearable soft pressure sensors have great potential for the real-time health monitoring and for the early diagnosis of diseases.
A KAIST research team led by Professor Inkyu Park from the Department of Mechanical Engineering developed a highly sensitive wearable pressure sensor for health monitoring applications. This work was reported in Advanced Healthcare Materials on November 21 as a front cover article.
This technology is capable of sensitive, precise, and continuous measurement of physiological and physical signals and shows great potential for health monitoring applications and the early diagnosis of diseases.
A soft pressure sensor is required to have high compliance, high sensitivity, low cost, long-term performance stability, and environmental stability in order to be employed for continuous health monitoring. Conventional solid-state soft pressure sensors using functional materials including carbon nanotubes and graphene have showed great sensing performance. However, these sensors suffer from limited stretchability, signal drifting, and long-term instability due to the distance between the stretchable substrate and the functional materials.
To overcome these issues, liquid-state electronics using liquid metal have been introduced for various wearable applications. Of these materials, Galinstan, a eutectic metal alloy of gallium, indium, and tin, has great mechanical and electrical properties that can be employed in wearable applications. But today’s liquid metal-based pressure sensors have low-pressure sensitivity, limiting their applicability for health monitoring devices.
The research team developed a 3D-printed rigid microbump array-integrated, liquid metal-based soft pressure sensor. With the help of 3D printing, the integration of a rigid microbump array and the master mold for a liquid metal microchannel could be achieved simultaneously, reducing the complexity of the manufacturing process. Through the integration of the rigid microbump and the microchannel, the new pressure sensor has an extremely low detection limit and enhanced pressure sensitivity compared to previously reported liquid metal-based pressure sensors. The proposed sensor also has a negligible signal drift over 10,000 cycles of pressure, bending, and stretching and exhibited excellent stability when subjected to various environmental conditions.
These performance outcomes make it an excellent sensor for various health monitoring devices. First, the research team demonstrated a wearable wristband device that can continuously monitor one’s pulse during exercise and be employed in a noninvasive cuffless BP monitoring system based on PTT calculations. Then, they introduced a wireless wearable heel pressure monitoring system that integrates three 3D-BLiPS with a wireless communication module.
Professor Park said, “It was possible to measure health indicators including pulse and blood pressure continuously as well as pressure of body parts using our proposed soft pressure sensor. We expect it to be used in health care applications, such as the prevention and the monitoring of the pressure-driven diseases such as pressure ulcers in the near future. There will be more opportunities for future research including a whole-body pressure monitoring system related to other physical parameters.”
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT.
< Figure 1. The front cover image of Advanced Healthcare Materials, Volume 8, Issue 22. >
< Figure 2. Highly sensitive liquid metal-based soft pressure sensor integrated with 3D-printed microbump array. >
< Figure 3. High pressure sensitivity and reliable sensing performances of the proposed sensor and wireless heel pressure monitoring application. >
-ProfileProfessor Inkyu ParkMicro/Nano Transducers Laboratoryhttp://mintlab1.kaist.ac.kr/
Department of Mechanical EngineeringKAIST
2019.12.20 View 11923 -
Team Geumo Wins Consecutive Victories in K-Cyber Security Challenge
< Professor Sang Kil Cha >
< Masters Candidate Kangsu Kim and Researcher Corentin Soulet >
Team Geumo, led by Professor Sang Kil Cha from the Graduate School of Information Security, won the K-Cyber Security Challenge in the AI-based automatic vulnerability detection division for two consecutive years in 2018 and 2019.
The K-Cyber Security Challenge is an inter-machine hacking competition. Participants develop and operate AI-based systems that are capable of independently identifying software vulnerabilities and gaining operating rights through hacking. The K-Cyber Security Challenge, inspired by the US Cyber Grand Challenge launched by the Defense Advanced Research Projects Agency (DARPA), is hosted by the Ministry of Science and ICT and organized by the Korea Internet and Security Agency.
Researcher Corentin Soulet of the School of Computing and master’s student Kangsu Kim of the Graduate School of Information Security teamed up for the competition. Professor Cha, who has led the research on software and systems security since his days at Carnegie Mellon University, succeeded in establishing a world-class system using domestic technology.
In a recent collaboration with the Cyber Security Research Center, Professor Cha achieved a ten-fold increase in the speed of binary analysis engines, a key component of AI-based hacking systems. For this accomplishment, he received the Best Paper Award at the 2019 Network and Distributed System Security Workshop on Binary Analysis Research (NDSS BAR).
Kangsu Kim said, "It is a great honor to win the competition two years in a row. I will continue to work hard and apply my knowledge to serve society.”
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2019.12.20 View 8008 -
New IEEE Fellow, Professor Jong Chul Ye
Professor Jong Chul Ye from the Department of Bio and Brain Engineering was named a new fellow of the Institute of Electrical and Electronics Engineers (IEEE). IEEE announced this on December 1 in recognition of Professor Ye’s contributions to the development of signal processing and artificial intelligence (AI) technology in the field of biomedical imaging.
As the world’s largest society in the electrical and electronics field, IEEE names the top 0.1% of their members as fellows based on their research achievements.Professor Ye has published more than 100 research papers in world-leading journals in the biomedical imaging field, including those affiliated with IEEE.
He also gave a keynote talk at the yearly conference of the International Society for Magnetic Resonance Imaging (ISMRM) on medical AI technology. In addition, Professor Ye has been appointed to serve as the next chair of the Computational Imaging Technical Committee of the IEEE Signal Processing Society, and the chair of the IEEE Symposium on Biomedical Imaging (ISBI) 2020 to be held in April in Iowa, USA.
Professor Ye said, “The importance of AI technology is developing in the biomedical imaging field. I feel proud that my contributions have been internationally recognized and allowed me to be named an IEEE fellow.”
2019.12.18 View 7851 -
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 6540 -
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 11242 -
KAIST Alumnus NYU Professor Supports Female AI Researchers
A KAIST alumnus and an associate professor at New York University (NYU), Dr. Kyunghyun Cho donated 3,000 USD to the KAIST Graduate School of AI to support female AI researchers.
Professor Cho spoke as a guest lecturer at the 2019 Samsung AI Forum on November 4 and received 3,000 USD as an honorarium. He donated this honorarium to the KAIST Graduate School of AI with a special request to support the school’s female PhD students attending the 2020 International Conference on Learning Representations (ICLR), where he serves as a program co-chair.
Professor Cho received his BS degree from KAIST’s School of Computing in 2009 and is now serving as an associate professor at NYU’s Computer Science Department and Center for Data Science. His research mainly covers machine learning and natural language processing.
Professor Cho said that he decided to make this donation because “In Korea and even in the US, women in science, technology, engineering, and mathematics (STEM) lack opportunities and environments that allow them to excel.”
Professor Song Chong, the Head of the KAIST Graduate School of AI, responded, “We are so grateful for Professor Kyunghyun Cho’s contribution and we will also use funds from the school in addition to the donation to support our female PhD students who will attend the ICLR.”
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2019.11.15 View 7257