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Discovery of an Optimal Drug Combination: Overcoming Resistance to Targeted Drugs for Liver Cancer
A KAIST research team presented a novel method for improving medication treatment for liver cancer using Systems Biology, combining research from information technology and the life sciences. Professor Kwang-Hyun Cho in the Department of Bio and Brain Engineering at KAIST conducted the research in collaboration with Professor Jung-Hwan Yoon in the Department of Internal Medicine at Seoul National University Hospital. This research was published in Hepatology in September 2017 (available online from August 24, 2017).
Liver cancer is the fifth and seventh most common cancer found in men and women throughout the world, which places it second in the cause of cancer deaths. In particular, Korea has 28.4 deaths from liver cancer per 100,000 persons, the highest death rate among OECD countries and twice that of Japan.
Each year in Korea, 16,000 people get liver cancer on average, yet the five-year survival rate stands below 12%. According to the National Cancer Information Center, lung cancer (17,399) took the highest portion of cancer-related deaths, followed by liver cancer (11,311) based on last year data.
Liver cancer is known to carry the highest social cost in comparison to other cancers and it causes the highest fatality in earlier age groups (40s-50s). In that sense, it is necessary to develop a new treatment that mitigates side effects yet elevates the survival rate.
There are ways in which liver cancer can be cured, such as surgery, embolization, and medication treatments; however, the options become limited for curing progressive cancer, a stage in which surgical methods cannot be executed.
Among anticancer medications, Sorafenib, a drug known for enhancing the survival rate of cancer patients, is a unique drug allowed for use as a targeted anticancer medication for progressive liver cancer patients. Its sales reached more than ten billion KRW annually in Korea, but its efficacy works on only about 20% of the treated patients. Also, acquired resistance to Sorafenib is emerging. Additionally, the action mechanism and resistance mechanism of Sorafenib is only vaguely identified.Although Sorafenib only extends the survival rate of terminal cancer patients less than three months on average, it is widely being used because drugs developed by global pharmaceutical companies failed to outperform its effectiveness.
Professor Cho’s research team analyzed the expression changes of genes in cell lines in response to Sorafenib in order to identify the effect and the resistance mechanism of Sorafenib.
As a result, the team discovered the resistance mechanism of Sorafenib using Systems Biology analysis. By combining computer simulations and biological experiments, it was revealed that protein disulfide isomerase (PDI) plays a crucial role in the resistance mechanism of Sorafenib and that its efficacy can be improved significantly by blocking PDI.
The research team used mice in the experiment and discovered the synergic effect of PDI inhibition with Sorafenib for reducing liver cancer cells, known as hepatocellular carcinoma. Also, more PDIs are shown in tissue from patients who possess a resistance to Sorafenib. From these findings, the team could identify the possibility of its clinical applications. The team also confirmed these findings from clinical data through a retrospective cohort study.
“Molecules that play an important role in cell lines are mostly put under complex regulation. For this reason, the existing biological research has a fundamental limitations for discovering its underlying principles,” Professor Cho said. “This research is a representative case of overcoming this limitation of traditional life science research by using a Systems Biology approach, combining IT and life science. It suggests the possibility of developing a new method that overcomes drug resistance with a network analysis of the targeted drug action mechanism of cancer.”
The research was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT.
(Figure 1. Simulation results from cellular experiments using hepatocellular carcinoma)
(Figure 2. Network analysis and computer simulation by using the endoplasmic reticulum (ER) stress network)
(Figure 3. ER stress network model)
2017.08.30 View 12623 -
The Medici Effect: Highly Flexible, Wearable Displays Born in KAIST
(Ph.D. candidate Seungyeop Choi)
How do you feel when technology you saw in a movie is made into reality? Collaboration between the electrical engineering and textile industries has made TVs or smartphone screens displaying on clothing a reality.
A research team led by Professor Kyung Cheol Choi at the School of Electrical Engineering presented wearable displays for various applications including fashion, IT, and healthcare. Integrating OLED (organic light-emitting diode) into fabrics, the team developed the most highly flexible and reliable technology for wearable displays in the world.
Recently, information displays have become increasingly important as they construct the external part of smart devices for the next generation. As world trends are focusing on the Internet of Things (IoTs) and wearable technology, the team drew a lot of attention by making great progress towards commercializing clothing-shaped ‘wearable displays’.
The research for realizing displays on clothing gained considerable attention from academia as well as industry when research on luminescence formed in fabrics was introduced in 2011; however, there was no technology for commercializing it due to its surface roughness and flexibility.
Because of this technical limitation, clothing-shaped wearable displays were thought to be unreachable technology. However, the KAIST team recently succeeded in developing the world’s most highly efficient, light-emitting clothes that can be commercialized.
The research team used two different approaches, fabric-type and fiber-type, in order to realize clothing-shaped wearable displays. In 2015, the team successfully laminated a thin planarization sheet thermally onto fabric to form a surface that is compatible with the OLEDs approximately 200 hundred nanometers thick. Also, the team reported their research outcomes on enhancing the reliability of operating fiber-based OLEDs. In 2016, the team introduced a dip-coating method, capable of uniformly depositing layers, to develop polymer light-emitting diodes, which show high luminance even on thin fabric.
Based on the research performance in 2015 and 2016, Ph.D. candidate Seungyeop Choi took the lead in the research team and succeeded in realizing fabric-based OLEDs, showing high luminance and efficiency while maintaining the flexibility of the fabric.
The long-term reliability of this wearable device that has the world’s best electrical and optical characteristics was verified through their self-developed, organic and inorganic encapsulation technology. According to the team, their wearable device facilitates the operation of OLEDs even at a bending radius of 2mm.
According to Choi, “Having wavy structures and empty spaces, fiber plays a significant role in lowering the mechanical stress on the OLEDs.”
“Screen displayed on our daily clothing is no longer a future technology,” said Professor Choi. “Light-emitting clothes will have considerable influence on not only the e-textile industry but also the automobile and healthcare industries.”
Moreover, the research team remarked, “It means a lot to realize clothing-shaped OLEDs that have the world’s best luminance and efficiency. It is the most flexible fabric-based light-emitting device among those reported. Moreover, noting that this research carried out an in-depth analysis of the mechanical characteristics of the clothing-spared, light-emitting device, the research performance will become a guideline for developing the fabric-based electronics industry.”
This research was funded by the Ministry of Trade, Industry and Energy and collaborated with KOLON Glotech, INC. The research performance was published in Scientific Reports in July.
(OLEDs operating in fabrics)
(Current-voltage-luminance and efficiency of the highly flexible, fabric-based OLEDs;Image of OLEDs after repetitive bending tests;Verification of flexibility through mechanical simulation)
2017.08.24 View 16098 -
KAIST Researchers Receive Awards at the 13th Asian Congress on Biotechnology
(From left: Seon Young Park, Dr. So Young Choi, and Yoojin Choi)
Researchers in the laboratory of KAIST Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering swept awards at the 13th Asian Congress on Biotechnology held in Thailand last month. The conference awarded a total of eight prizes in the areas of best research and best poster presentation. This is an exceptional case in which members of one research team received almost half of the awards at an international conference.
Dr. So Young Choi received the Best Research Award, while Ph.D. candidates Yoojin Choi and Seon Young Park each received the Best Poster Presentation Award at the conference held in Khon Kaen, Thailand from July 23 to 27.
The Asian Congress on Biotechnology is an international conference in which scientists and industry experts in Asia and from around the world gather to present recent research findings in the field of biotechnology. At the conference, around 400 researchers in biotechnology from 25 countries, including Korea, gathered to present and discuss various research findings under the theme of “Bioinnovation and Bioeconomy.”
Distinguished Professor Sang Yup Lee attended the conference to give the opening plenary lecture on the topic of ‘Systems Strategies in Biotechnology.’ Professor Lee announced, “I have attended international conferences with students for the last 20 years, but this is the first in which my team received three awards at an international conference that only honors a total of eight awards, three for Best Research and five for Best Presentation.”
Dr. Choi presented research results on poly (lactate-co-glycolate) (PLGA) synthesis through a biological method using micro-organisms and received the Best Research Award. PLGA is a random copolymer of DL-lactic and glycolic acids and is a biopolymer widely used for biomedical applications. PLGA is biodegradable, biocompatible, and nontoxic, and thus has been approved by the US Food and Drug Administration (FDA) for its use in implants, drug delivery, and sutures.
Dr. Choi’s research was deemed to be innovative for synthesizing PLGA from glucose and xylose in cells through metabolic engineering of E.Coli. Dr. Choi received her Ph.D. under the supervision of Distinguished Professor Lee this February and is currently conducting post-doc research.
Ph.D. candidate Choi presented her research on the use of recombinant E.Coli for the biological synthesis of various nanoparticles and received the Best Poster Presentation award. Choi used recombinant E.Coli-expressing proteins and peptides that adsorb to heavy metals to biologically synthesize diverse metal nanoparticles such as single-nanoparticle including gold and silver, quantum dots, and magnetic nanoparticles for the first time. The synthesized nanoparticles can be used in the fields of bio-imaging, diagnosis, environment, and energy.
Ph.D. candidate Park, who also received the Best Poster Presentation award, synthesized and increased production of astanxanthin, a strong antioxidant found in nature, in E.Coli using metabolic engineering. Astanxanthin is a carotenoid pigment found in salmon and shrimp that widely used in health products and cosmetics.
2017.08.01 View 15647 -
Professor Nam Jin Cho Selected as the Eugene P. Wigner Reactor Physicist Awardee
Professor Nam Jin Cho from the Department of Nuclear & Quantum Engineering was selected as the recipient of the 2017 ‘Eugene P. Wigner Reactor Physicist Award.’ The award, established in 1990 by the American Nuclear Society, honors individuals who have made outstanding contributions to the advancement of the field of reactor physics. The award is named after the late Eugene P. Wigner, a pioneer who helped nurture the nuclear age to technical maturity with his pioneering leadership in reactor design.
Professor Cho was recognized for his outstanding leadership and achievement in the field of nuclear physics, especially with his original research in analytic function expansion nodal methods, coarse-mesh angular dependent rebalance methods, and neutron transport calculations. A fellow of the ANS, Professor Cho is the first awardee from the Asian region.
Professor Cho gave all the credit to his colleagues and students at KAIST who have spared no effort while working together for three decades. “I am very grateful for the unique academic ambience which made this challenging work possible as well as the government’s continuing funding at the National Research Laboratory project.
2017.07.12 View 8147 -
Cooperative Tumor Cell Membrane-Targeted Phototherapy
A KAIST research team led by Professor Ji-Ho Park in the Bio and Brain Engineering Department at KAIST developed a technology for the effective treatment of cancer by delivering synthetic receptors throughout tumor tissue. The study, led by Ph.D. candidate Heegon Kim, was published online in Nature Communications on June 19.
Cancer targeted therapy generally refers to therapy targeting specific molecules that are involved in the growth and generation of cancer. The targeted delivery of therapeutics using targeting agents such as antibodies or nanomaterials has improved the precision and safety of cancer therapy.
However, the paucity and heterogeneity of identified molecular targets within tumors have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes.
To solve this problem, the team constructed a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumor cell membrane-selective localization of synthetic receptors to amplify the subsequent targeting of therapeutics. Here, synthetic and biological nanocomponents refer to liposomes and extracellular vesicles, respectively.
The synthetic receptors are first delivered selectively to tumor cell membranes in the perivascular region using liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the synthetic receptors are transferred to neighboring cells and further spread throughout the tumor tissues where the molecular targets are limited.
Hitchhiking extracellular vesicles for delivery of synthetic receptors was possible since extracellular vesicles, such as exosomes, mediate intercellular communications by transferring various biological components such as lipids, cytosolic proteins, and RNA through a membrane fusion process. They also play a supportive role in promoting tumor progression in that tumor-derived extracellular vesicles deliver oncogenic signals to normal host cells.
The team showed that this tumor cell membrane-targeted delivery of synthetic receptors led to a uniform distribution of synthetic receptors throughout a tumor and subsequently led to enhanced phototherapeutic efficacy of the targeted photosensitizer.
Professor Park said, “The cooperative tumor targeting system is expected to be applied in treating various diseases that are hard to target.”
The research was funded by the Basic Science Research Program through the National Research Foundation funded by the Ministry of Science, ICT & Future Planning, and the National R&D Program for Cancer Control funded by the Ministry for Health and Welfare.
(Ph.D. candidates Hee Gon Kim (left) and Chanhee Oh)
Figure 1. A schematic of a cooperative tumor targeting system via delivery of synthetic receptors.
Figure 2. A confocal microscopic image of a tumor section after cooperative targeting by synthetic receptor delivery. Green and magenta represent vessels and therapeutic agents inside a tumor respectively.
2017.07.07 View 11678 -
Reform of Universities Key in the Wake of the 4th Industrial Revolution
(President Shin makes a keynote speech at the Times Higher Education Research Excellence Summit held in Taiwan on July 4.)
KAIST President Sung-Chul Shin stressed that innovations in education, research, and technology commercialization of universities are critical for responding to the transformations that the Fourth Industrial Revolution will bring about.
In his keynote speech at the Times Higher Education Research Excellence Summit held in Taiwan on July 4, he cited connectivity, superintelligence, and convergence in science and technology as three components the Fourth Industrial Revolution will pierce, saying the speed and breadth of the transformation will be beyond our imagination. He also presented megatrends in science and technology in the years to come and how KAIST is addressing the challenges and opportunities.
“It is imperative to foster creative young talents fluent in convergence, collaboration, and communication skills in the new era. To this end, we need to focus on whole brain education by enhancing basic education in science and engineering plus humanities and social studies,” he stressed. He also presented a Non-Departmental Education Track, which KAIST plans to implement from next semester. The track, designed to prepare students for the new industrial era, will focus on whole brain education including entrepreneurship and leadership education during the undergraduate period.
He also emphasized an effective new teaching methodology. “We need to develop various new teaching methods. The paradigm should shift from lecturer-centered to student-centered. KAIST is revising our curriculum to facilitate team-based, project-based learning and flipped learning,” he explained.
President Shin also pointed out that the educational goals for the next generation should be to sustain the value of people’s own thoughtfulness, wisdom, emotion, and caring against the advent of a new tribe of AI, dubbed Robo Sapiens. “Those traits add undeniable educational value that we should continue to pursue even in the era of Robo Sapiens,” he added.
As for research innovation, he emphasized inter- and multi-disciplinary collaborative research. “Especially, in addressing pressing global issues and big science, international collaboration will be very effective and crucial,” he said.
At the summit, convergence research projects currently underway at KAIST using emerging technologies such as the smart mobile healthcare project, Dr, M; the humanoid robot, HUBO; and AI drone swarms drew lots of attention from the participants, even receiving proposals to join the projects as collaborators.
In the new era, according to Shin, technology commercialization at universities will emerge as a hub of R&DB. Citing that KAIST has long been a draw for startups, he noted that KAIST has also set a high value on entrepreneurship education including social entrepreneurship and startups.
He continued, “The Korean government is making every effort to harness the challenges and opportunities of the Fourth Industrial Revolution by creating a new economic growth engine. For the success of the government initiative, universities should also respond to make innovations commensurate with the changing needs and challenges. KAIST will take the lead in this new initiative for making a new future.”
2017.07.06 View 8153 -
KAIST Professors Sweep the Best Science and Technology Award
(Distinguished Professors Sang Yup Lee (left) and Kyu-Young Whang)
Distinguished Professors Sang Yup Lee from the Department of Chemical and Biomolecular Engineering and Kyu-Young Whang of the College of Computing were selected as the winners of the "2017 Korea Best Science and Technology Award" by the Ministry of Science, ICT and Future Planning (MSIP) and the Korea Federation of Science and Technology Societies.
The award, which was established in 2003, is the highest honor bestowed to the two most outstanding scientists in Korea annually. This is the first time that KAIST faculty members have swept the award since its founding.
Distinguished Professor Lee is renowned for his pioneering studies of system metabolic engineering, which produces useful chemicals by utilizing microorganisms. Professor Lee has developed a number of globally-recognized original technologies such as gasoline production using micro-organisms, a bio-butanol production process, microbes for producing nylon and plastic raw materials, and making native-like spider silk produced in metabolically engineering bacterium which is stronger than steel but finer than human hair.
System metabolism engineering was also selected as one of the top 10 promising technologies in the world in 2016 by the World Economic Forum. Selected as one of the world’s top 20 applied bioscientists in 2014 by Nature Biotechnology, he has many ‘first’ titles in his academic and research careers. He was the first Asian to win the James Bailey Award (2016) and Marvin Johnson Award (2012), the first Korean elected to both the US National Academy of Science (NAS) and the National Academy of Engineering (NAE) this year. He is the dean of KAIST institutes, a multi and interdisciplinary research institute at KAIST. He serves as co-chair of the Global Council on Biotechnology and as a member of the Global Future Council on the Fourth Industrial Revolution at the World Economic Forum.
Distinguished Professor Whang, the first recipient in the field of computer science in this award, has been recognized for his lifetime achievement and contributions to the development of the software industry and the spreading of information culture. He has taken a pioneering role in presenting novel theories and innovative technologies in the field of database systems such as probabilistic aggregation, multidimensional indexing, query, and database and information retrieval. The Odysseus database management system Professor Hwang developed has been applied in many diverse fields of industry, while promoting the domestic software industry and its technical independence.
Professor Hwang is a fellow at the American Computer Society (ACM) and life fellow at IEEE. Professor Whang received the ACM SIGMOD Contributions Award in 2014 for his work promoting database research worldwide, the PAKDD Distinguished Contributions Award in 2014, and the DASFAA Outstanding Contributions Award in 2011 for his contributions to database and data mining research in the Asia-Pacific region. He is also the recipient of the prestigious Korea (presidential) Engineering Award in 2012.
2017.07.03 View 12039 -
Professor Poong Hyun Seong Selected as Fellow of the ANS
Professor Poong Hyun Seong of the Department of Nuclear and Quantum Engineering was selected as a fellow of the American Nuclear Society.
The selection was announced at their annual meeting held in San Francisco on June 12, in recognition of Professor Seong's contributions to the field of nuclear instrumentation, control andhuman factors engineering.
Founded in 1954, the American Nuclear Society selects scholars who have made outstanding achievements and contributions to the development of the nuclear engineering field each year.
Professor Seong's researches in the field of nuclear instrumentation, control and human factors engineering have contributed to the safe operation of nuclear power plants, to the development of systems to maintain nuclear power plants safely in the event of emergency and to the enhancement of effective response capabilities of nuclear power plant operators. His researches significantly contributed to the safety improvement of nuclear power plants and have been recognized worldwide.
Professor Seong said, "Korea has emerged as a nuclear powerhouse. I think not only my academic career but our national reputation in the field of nuclear research has been well recognized by our global peers.” Professor Seong has served as president of the Korean Nuclear Society, editor in chief of Nuclear Engineering and Technology, and as a commissioner of the Korean Nuclear Safety Commission. He is currently working as a commissioner of the Korean Atomic Energy Commission.
2017.06.29 View 8533 -
The Embassy Day Builds the Global Presence of KAIST
(Photo caption: Diplomats and KAIST faculty pose at the Embassy Day KAIST hosted on June 23.)
KAIST is stepping up its initiative for building global competitiveness. The Embassy Day hosted on June 23 will be a stepping stone to diversify its channels for promoting the global presence of KAIST. KAIST invited the foreign diplomatic corps from Seoul to share their successful journey to emerge as the world-class university. The event featured KAIST’s research highlights, academic experiences, and global environment through presentations by faculty and students.
KAIST President Sung-Chul Shin said in his welcoming speech that he hopes for brains from around the world to come to KAIST and believes this event will serve as an opportunity to spread the global reputation of KAIST more widely. President Shin, who took office in March, ambitiously hosted this event for the first time, saying, “We didn’t expect this big of a response from the diplomats. The presence of this leading group of diplomats reflects how KAIST’s reputation has blossomed.”
Nearly 100 diplomats from 65 countries attended the event held at the Grand Hyatt Seoul. Among the participants were ambassadors from 33 countries including Australian Amb. James Choi, Canadian Amb. Eric Walsh, and German Amb. Stephan Auer, reflecting the growing interest in the advancements in science and technology education and innovation in KAIST.
The entire leadership team of KAIST turned out for the event including Provost O-Ok Park, Associate Vice President of the International Office Jay Hyung Lee, and Dean of Admissions Hayong Shin to provide an update on KAIST activities as well as admission policies, and make a new network with the foreign envoys.
At the event, KAIST presented some of its latest research highlights that are gaining international acclaim. Professor Jun-ho Oh, director at the Humanoid Robot Research Center talked on the short history of the development of the KAIST humanoid robot, HUBO, which won the DARPA Robotics Challenge (DRC) in 2015. Distinguished Professor Sang-Yup Lee, dean of the KAIST Institute, which is the center of multidisciplinary research projects in KAIST, made a presentation on advances in metabolic engineering. In addition, Professor David Helfman of the Department of Biological Science shared his research on breast cancer and metastasis.
Foreign students and faculty shared their experiences on becoming part of the KAIST community during the testimonial session. In particular, the story of Professor Jean-Charles Bazin of the Graduate School of Culture Technology was quite moving. Originally from France, Professor Bazin talked about his unique career path, starting as an exchange student at KAIST before settling down as a faculty member here. He cited the high caliber group of faculty as one of the reasons he completed his Ph.D. at KAIST. “Most of the faculty members are from top institutions in the US, Europe, and around the world, so they have very resourceful contacts with distinguished researchers and scholars abroad. That helped me make up my mind to choose KAIST,” he said.
Currently, 179 foreign faculty and researchers from over 31 countries, representing 8.7% of the total faculty, are working at KAIST. Also, 710 foreign students from 86 countries, representing about 8% of the total students, are now studying at KAIST.
President Shin continued, “In this complex global era, brains follow the best path to where they can reach their potential. KAIST is now gaining tremendous strength by becoming a magnet for talents from around the world. We would like to recruit these brains to create new knowledge with a global impact. Then we will become true global university with supremacy in research and education.
President Shin said KAIST is gearing up for another round of innovation initiatives in education, convergence research, technology commercialization, future strategies, and globalization. He emphasized that globalization of the campus is a must for building up our global competitiveness.
(Photo caption from the top: President Shin greets participant. Professor Oh explains the functions of the HUBO. Professor Helfman presents on his research of breast cancer and metastasis. KAIST a capella group showcases singing skills at the event. Participants meet and greet at the Embassy Day.)
2017.06.23 View 10652 -
KAIST to Participate in the Summer Davos Forum
KAIST will participate in the 2017 Summer Davos Forum in Dalian, China from June 27 to 29. The Summer Davos Forum with the official title “Annual Meeting of New Champions” is an annual international meeting co-hosted by China and the World Economic Forum (WEF) to address global issues which has been held since 2007.
Focusing on this year’s theme ‘Achieving Inclusive Growth in the Fourth Industrial Revolution,’ science and technology experts from 90 different countries will participate in various sessions to present on and discuss pending global innovative issues. KAIST is to be the only Korean university to run ‘IdeasLab,’ in which researchers will introduce current research trends and discuss ideas with global leaders. This is the sixth year for KAIST to run IdeasLab.
This year’s IdeasLab has the theme ‘Materials of the Future,’ and will include presentations and discussions on materials developed at KAIST which could lead the Fourth Industrial Revolution. President Sung-Chul Shin, the chairman of the session, will first introduce the current status of KAIST and IdeasLab, followed by a presentation of cutting-edge integrated research findings by KAIST professors.
President Shin will also participate in various sessions organized by the Global University Leaders Forum (GULF) as discussion leader. President Shin is the only Korean member of GULF, a community comprised of the presidents of the world’s top 27 universities. Other members include the presidents of the University of Oxford and the University of Cambridge in the U.K., MIT, Harvard, Stanford, and Columbia Universities in the US, and the University of Tokyo in Japan.
Further, President Shin will participate in a strategy session for inclusive growth in the era of the Fourth Industrial Revolution and a meeting with the WEF directors.
The Dean of KAIST Institutes, Distinguished Professor Sang Yup Lee from the Chemical and Biomolecular Engineering Department, who has been invited to the Davos Forum and Summer Davos Forum for the last 15 years, is to present in the ‘Future of Life: Medicine’ session to introduce advancements in traditional medicine through systems biology such as his research on microbiomes (gut microbes).
Professor Lee, as the chair of the Global Future Council on Biotechnology at the WEF, and committee member of the Annual Meeting of the Global Future Councils on the Fourth Industrial Revolution, is to participate in various bio-sessions and the Fourth Industrial Revolution banquet session to lead the discussions.
President Shin said, “KAIST has been sharing global research findings with global leaders through IdeasLab at the Davos Forum for the past six years and it has always been well received.” He continued, “The forum will be the place for in-depth discussion on the technological changes that accompany the Fourth Industrial Revolution and human-centered development plan, as well as introducing innovative research and integrated research findings from KAIST.”
This year’s speakers include Li Keqiang, the current Premier of the State Council of China; Guo Ping, the rotating C.E.O. of Huawei; and Ya-Qin Zhang, the President of Baidu, a company leading technological innovation in various fields such as robotics and autonomous vehicles. Two thousand distinguished guests in politics, administration, finance, and academia from 90 countries are to participate in the meeting.
2017.06.21 View 9717 -
Mutations Unveiled that Predispose Lung Cancer Cells to Refractory Histologic Transformation
Cancer pedigree analysis reveals the mutations in RB1 and TP53 genes play a key role in treatment-resistant, cancer cell-type transformation during EGFR inhibitor therapy for lung cancers.
Research led by Korean medical scientists has discovered that a specific type of drug resistance mechanism to EGFR inhibitor therapy in lung cancer is predisposed by mutations in two canonical cancer-related genes: RB1 and TP53. Published in Journal of Clinical Oncology on May 12, the study also found those mutations can be detectable in patients' tumors at the point of clinical diagnosis. Therefore, it can be used as strong markers in clinic for predicting poor outcome for the targeted treatment for lung adenocarcinoma.
Lung adenocarcinoma is the most common type of lung cancer, and about 15% of patients in Western countries and 50% of patients in Asian countries have mutations in the EGFR gene, which is critical for the development of lung cancer. Patients with lung adenocarcinoma harboring the EGFR mutation show favorable responses to EGFR inhibitors such as erlotinib (Tarceva) or gefitinib (Iressa), but ultimately relapse with drug-resistant tumors. Since the initial report in 2006, it has been known that in about 5~15% of patients, the lung adenocarcinoma cells undergo a mysterious transformation into a very different cancer cell type called “small cell lung cancer,” a much more aggressive lung cancer subtype, common in cigarette smokers.
To find out the genetic basis of this process, the researchers compared the genome sequences of multiple cancer tissues acquired during the treatment courses of patients whose tumors underwent small-cell transformation. They reconstructed the cancer cell pedigree by comparing mutations between cancer tissues, and identified that RB1 and TP53 genes are completely inactivated by mutations already in their lung adenocarcinoma tissues.
"We tried to compare the somatic mutational profile of pre-EGFR inhibitor treatment lung adenocarcinomas and post-treatment small cell carcinomas and to reconstruct the pedigrees of the cancer evolution in each patient. Strikingly, both copies of RB1 and TP53 genes were already inactivated at the stage of lung adenocarcinomas in all sequenced cases," said Dr. Jake June-Koo Lee, the first author from KAIST.
They further pursued the clinical implications of RB1 and TP53 inactivation by investigating 75 EGFR-mutated lung adenocarcinoma tissues from patients who received EGFR inhibitor therapy, including patients with small-cell transformation. In this analysis, the lung adenocarcinomas with a complete inactivation of both RB1 and TP53 genes tended to have a 43-times greater risk of transformation into small cell lung cancer during their EGFR inhibitor treatment courses.
Dr. Young Seok Ju, the co-last author from KAIST, explained, "This study shows the power of entire genome analyses to better understand the mechanisms underlying mysterious phenomenon encountered in clinic. Upon accurate bioinformatics, we are finding cancer-specific somatic mutations from the whole-genomes of patients’ cancer cells. These mutations allow us to track the evolution of cancer cells throughout the extraordinary clinical course of a special set of lung cancers."
The complete inactivation of both RB1 and TP53 tumor suppressor genes is found in a minor (<10%) subset of lung adenocarcinoma. This study suggests that the clinical course against targeted therapy is endogenously different for the cancers in the subgroup, and specific drug-resistance mechanisms are predisposed by the two genetic mutations. Indeed, RB1 and TP53 double inactivation is a genetic hallmark of primary small cell lung cancer, observed in nearly all cases.
"We are actively investigating patient tumor tissues to develop optimal surveillance plans and treatment options for patients with lung adenocarcinomas more prone to small-cell transformation," said Dr. Tae Min Kim, the co-last author from Seoul National University Hospital.
The researchers are implementing their findings into lung cancer clinics by screening the RB1 and TP53 mutational status in lung adenocarcinoma patients receiving EGFR inhibitor treatment, and following their treatment courses to develop a treatment strategy for those patients.
This research (doi.org/10.1200/JCO.2016.71.9096) was funded by the National Research Foundation of Korea (NRF-2013H1A2A1032691 to J.-K.L., NRF-2014R1A2A2A05003665 to Y.T.K.); Korea Institute of Science and Technology Information (K-16-L03-C02-S02 to J.L.); and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which was funded by the Ministry of Health and Welfare (HI14C1234 to T.M.K., HI16C2387 to Y.S.J.)
Figure. Phylogeny analysis of serially-acquired tumors
A. Phylogeny trees of sequenced cases (LC1−LC4) are reconstructed from the WGS data. Conceptual illustrations are depicted with grey color. Circles indicate major clones of the tumors. The length of each branch is proportional to the number of mutations that occurred in the branch. Mutations of cancer-related genes in each branch are indicated with arrows. The time points of relevant treatments are summarized below the trees.
B. Mutations of RB1 and TP53 in two early LADCs (LC1b and LC4a) are visualized using Integrative Genomics Viewer (left panel). Allele-specific copy number analysis shows loss of heterozygosity of chromosomes 13 and 17 in both early LADCs and EGFR TKI-resistant SCLCs (right panel).
C. Clonal evolution of LC1 is described with clinical history and tumor volumes. The horizontal axis represents the time from the diagnosis (0), and the vertical axis indicates the volume of tumors calculated from the computed tomography images.
Abbreviations: LADC, lung adenocarcinoma; SCLC, small cell lung cancer
2017.06.07 View 9225 -
Bio-based p-Xylene Oxidation into Terephthalic Acid by Engineered E.coli
KAIST researchers have established an efficient biocatalytic system to produce terephthalic acid (TPA) from p-xylene (pX). It will allow this industrially important bulk chemical to be made available in a more environmentally-friendly manner.
The research team developed metabolically engineered Escherichia coli (E.coli) to biologically transform pX into TPA, a chemical necessary in the manufacturing of polyethylene terephthalate (PET). This biocatalysis system represents a greener and more efficient alternative to the traditional chemical methods for TPA production. This research, headed by Distinguished Professor Sang Yup Lee, was published in Nature Communications on May 31.
The research team utilized a metabolic engineering and synthetic biology approach to develop a recombinant microorganism that can oxidize pX into TPA using microbial fermentation. TPA is a globally important chemical commodity for manufacturing PET. It can be applied to manufacture plastic bottles, clothing fibers, films, and many other products. Currently, TPA is produced from pX oxidation through an industrially well-known chemical process (with a typical TPA yield of over 95 mol%), which shows, however, such drawbacks as intensive energy requirements at high temperatures and pressure, usage of heavy metal catalysts, and the unavoidable byproduct formation of 4-carboxybenzaldehyde.
The research team designed and constructed a synthetic metabolic pathway by incorporating the upper xylene degradation pathway of Pseudomonas putida F1 and the lower p-toluene sulfonate pathway of Comamonas testosteroni T-2, which successfully produced TPA from pX in small-scale cultures, with the formation of p-toluate (pTA) as the major byproduct. The team further optimized the pathway gene expression levels by using a synthetic biology toolkit, which gave the final engineered E. coli strain showing increased TPA production and the complete elimination of the byproduct.
Using this best-performing strain, the team designed an elegant two-phase (aqueous/organic) fermentation system for TPA production on a larger scale, where pX was supplied in the organic phase. Through a number of optimization steps, the team ultimately achieved production of 13.3 g TPA from 8.8 g pX, which represented an extraordinary yield of 97 mol%.
The team has developed a microbial biotechnology application which is reportedly the first successful example of the bio-based production of TPA from pX by the microbial fermentation of engineered E. coli. This bio-based TPA technology presents several advantages such as ambient reaction temperature and pressure, no use of heavy metals or other toxic chemicals, the removable of byproduct formation, and it is 100% environmentally compatible.
Professor Lee said, “We presented promising biotechnology for producing large amounts of the commodity chemical TPA, which is used for PET manufacturing, through metabolically engineered gut bacterium. Our research is meaningful in that it demonstrates the feasibility of the biotechnological production of bulk chemicals, and if reproducible when up-scaled, it will represent a breakthrough in hydrocarbon bioconversions.”
Ph.D. candidate Zi Wei Luo is the first author of this research (DOI:10.1038/ncomms15689).The research was supported by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) of the Ministry of Science, ICT & Future Planning through the National Research Foundation of Korea.
Figure: Biotransformation of pX into TPA by engineered E. coli.
This schematic diagram shows the overall conceptualization of how metabolically engineered E. coli produced TPA from pX. The engineered E. coli was developed through reconstituting a synthetic metabolic pathway for pX conversion to TPA and optimized for increased TPA yield and byproduct elimination. Two-phase partitioning fermentation system was developed for demonstrating the feasibility of large-scale production of TPA from pX using the engineered E. coli strains, where pX was supplied in the organic phase and TPA was produced in the aqueous phase.
2017.06.05 View 12428