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Connecting the Dots to Find New Treatments for Breast Cancer
Systems biologists uncovered new ways of cancer cell reprogramming to treat drug-resistant cancers
Scientists at KAIST believe they may have found a way to reverse an aggressive, treatment-resistant type of breast cancer into a less dangerous kind that responds well to treatment. The study involved the use of mathematical models to untangle the complex genetic and molecular interactions that occur in the two types of breast cancer, but could be extended to find ways for treating many others. The study’s findings were published in the journal Cancer Research.
Basal-like tumours are the most aggressive type of breast cancer, with the worst prognosis. Chemotherapy is the only available treatment option, but patients experience high recurrence rates. On the other hand, luminal-A breast cancer responds well to drugs that specifically target a receptor on their cell surfaces, called estrogen receptor alpha (ERα).
KAIST systems biologist Kwang-Hyun Cho and colleagues analyzed the complex molecular and genetic interactions of basal-like and luminal-A breast cancers to find out if there might be a way to switch the former to the latter and give patients a better chance to respond to treatment.
To do this, they accessed large amounts of cancer and patient data to understand which genes and molecules are involved in the two types. They then input this data into a mathematical model that represents genes, proteins and molecules as dots and the interactions between them as lines. The model can be used to conduct simulations and see how interactions change when certain genes are turned on or off.
“There have been a tremendous number of studies trying to find therapeutic targets for treating basal-like breast cancer patients,” says Cho. “But clinical trials have failed due to the complex and dynamic nature of cancer. To overcome this issue, we looked at breast cancer cells as a complex network system and implemented a systems biological approach to unravel the underlying mechanisms that would allow us to reprogram basal-like into luminal-A breast cancer cells.”
Using this approach, followed by experimental validation on real breast cancer cells, the team found that turning off two key gene regulators, called BCL11A and HDAC1/2, switched a basal-like cancer signalling pathway into a different one used by luminal-A cancer cells. The switch reprograms the cancer cells and makes them more responsive to drugs that target ERα receptors. However, further tests will be needed to confirm that this also works in animal models and eventually humans.
“Our study demonstrates that the systems biological approach can be useful for identifying novel therapeutic targets,” says Cho.
The researchers are now expanding its breast cancer network model to include all breast cancer subtypes. Their ultimate aim is to identify more drug targets and to understand the mechanisms that could drive drug-resistant cells to turn into drug-sensitive ones.
This work was supported by the National Research Foundation of Korea, the Ministry of Science and ICT, Electronics and Telecommunications Research Institute, and the KAIST Grand Challenge 30 Project.
-Publication Sea R. Choi, Chae Young Hwang, Jonghoon Lee, and Kwang-Hyun Cho, “Network Analysis Identifies Regulators of Basal-like Breast Cancer Reprogramming and Endocrine TherapyVulnerability,” Cancer Research, November 30. (doi:10.1158/0008-5472.CAN-21-0621)
-ProfileProfessor Kwang-Hyun ChoLaboratory for Systems Biology and Bio-Inspired EngineeringDepartment of Bio and Brain EngineeringKAIST
2021.12.07 View 7023 -
Renault 5 EV and Canoo’s Pickup Truck Win the 2021 FMOTY Awards
KAIST Future Mobility of the Year Awards recognize the most innovative concept cars of the year
The Renault 5 EV from France and a pickup truck from the US startup Canoo won the 2021 Future Mobility of the Year Awards (FMOTY) hosted by the Cho Chun Shik Graduate School of Green Transportation at KAIST. The awards ceremony was held at Renault Samsung Motors in Seoul on November 25.
KAIST began the FMOTY in 2019 to advance future car technology and stimulate growth in the industry. The award recognizes the most innovative ideas for making the most futuristic concept car and improving the technological and social value of the industry.
The awards ceremony was attended by KAIST President Kwang Hyung Lee, the dean of the Cho Chun Shik Graduate School of Green Transportation In Gwun Jang, CEO of Renault Samsung Motors Dominique Signora, and CEO of Canoo Tony Aquila. President Lee said, “The new world order will be impacted by new technology developers who envision the future. Their innovation and creative ideas will open a new world of sustainable future transportation.”
Out of the 46 concept cars revealed at global motor exhibitions between last year and the first quarter of this year, models demonstrating transport technology useful for future society and innovative service were selected in the categories of passenger cars and commercial vehicles.
Sixteen automotive journalists from 11 countries, including the chief editor of Car Magazine in Germany Georg Kacher and editorial director of BBC Top Gear Charlie Turner, participated as judges.
This year’s award for the best concept car for a passenger vehicle went to an electric vehicle, the Renault 5 EV. The compact electric car was highly regarded for its practicality and environmental friendliness. A pickup truck by Canoo, an American EV manufacturing start-up, won the award in the commercial vehicle category. The pickup features an innovative design allowing for a variety of functions topped with a competitive price and it received overwhelming support from the judges.
While Hyundai Motors swept both prizes at the awards last year and demonstrated the potential of Korean concept cars, Canoo’s win in the commercial vehicle section as a young American venture company brought attention to the changing dynamics in the automotive market. This shows that young EV start-ups can compete with existing car companies as the automotive paradigm is shifting from those with internal combustion engines to EVs.
The awards organizers said that the Cho Chun Shik Graduate School of Green Transportation will continue to hold the FMOTY to lead the fast-changing global mobility market. For more information, please visit www.fmoty.org.
2021.11.26 View 5813 -
Study Finds Player-Character Relationships Affected Game Satisfaction in the Last of Us Part II
Research analyzed player experiences with a polarizing game and found differences in how the players related to their characters
The action adventure game ‘The Last of Us’ was a big hit worldwide in 2014. However, its sequel, the Last of Us Part II divided opinions in the game community when it was released in 2020.
A research team from the Games and Life Lab in the Graduate School of Culture Technology at KAIST analyzed why the game players’ reviews were so polarized and found that player-character relationships influenced the game players’ satisfaction. This study, published in Frontiers in Psychology, will help developers of character-driven games foresee how different players will react to their games.
The team under Professor Young Yim Doh conducted in-depth interviews with 12 players from diverse nations, both those satisfied and dissatisfied with the game.
The team found that three elements affected the game players’ satisfaction. First, players’ satisfaction varied according to their tolerance of forced character switches. When a player is forced to switch their controlled figure in the game to another character that is introduced as the antagonist, most players initially had a negative reaction. The feeling of being forced to play in a way they didn’t want reduced their rights as a player. However, later on, some players viewed this character switch as an interesting transition and were more tolerant toward forced game play.
Second, the researchers found that the flexibility of character attachment is related to game satisfaction. Players who were unhappy about the game resisted building a relationship with the new antagonist character. Meanwhile, players who were happy about the game slowly formed an additional relationship with the new character. This led to the player feeling conflicting emotions, which satisfied players considered a meaningful experience of understanding a perspective of someone initially considered the enemy.
Lastly, the satisfaction of the play depended on how much the players could accept a changing character image in the game. Dissatisfied players found inconsistencies in the characters’ behavior and did not accept the new information about the characters. Meanwhile, satisfied players tried to understand and accept the new information and actions.
“Previous research on narrative games focused more on the game design than on the players’ experiences. To understand why reactions to the game were very different across players, we focused our research on differences in the players’ psychological experiences with the game.” said lead author and Master’s candidate Valérie Erb.
Co-author Dr. Seyeon Lee added, “This suggests that there is no one way to satisfy all players in a character-based narrative game. To satisfy a game’s players, it is important to understand the different players in the player base, target the right player group, and manage expectations accordingly.”
This research was supported by the Year 2020 Culture Technology R&D Program by the Ministry of Culture, Sports and Tourism and the Korea Creative Content Agency.
-PublicationErb V, Lee S, and Doh YY (2021) “Player-Character Relationship and Game Satisfaction in Narrative Game: Focus on Player Experience of Character Switch in The Last of Us Part II”
Frontiers in Psychology. 12:709926. (https://doi.org/10.3389/fpsyg.2021.709926)
-ProfileProfessor Young Yim DohGames and Life LabGraduate School of Culture TechnologyKAIST
2021.11.15 View 4682 -
GSI Forum Highlights Global Collaboration Toward a Sustainable Global Economy
The forum stresses global collaboration to make the global value chain more resilient
Speakers at the 5th Global Strategy Institute International Forum on October 28 stressed the importance of global collaboration for rebuilding the global economy and making innovations in national science and technology governance in order to enhance national competitiveness. The forum entitled “Grand Strategic Shift under Global Techno-Geopolitical Paradigm” examined strategies for making the global supply chain more resilient and rebuild the global economy as well as how Korea could advance in the technology race.
Speakers concurred that technology has become an issue of national security. The global supply chain has been disrupted amid the global pandemic and intense conflict between the U.S. and China. Speakers presented a common solution: global collaboration and innovations in science and technology governance.
KAIST President Kwang Hyung Lee said in his opening remarks that the future ‘world map’ may turn out very differently depending on how we prepare and what we envision for the future. He also stressed the importance of technology sovereignty, adding that only those who can create their own new technology independently will be the future leaders.
Prime Minister Boo Kyum Kim and Vice Minister of Science and ICT Hongtaek Yong delivered congratulatory remarks. Keynote speakers included Professor Scott Stern from the MIT Sloan School of Management, Professor Aaron Chatterji from the Fuqua School of Business at Duke University, Professor Sarah Kreps from the Department of Government at Cornell University, SK Group Chairperson Tae-Won Chey, President Woo Il Lee of the Korean Federation of Science and Technology Societies, Professor Young Kwan Yoon at Seoul National University, President Eun Mee Kim of Ewha Womans University, and President Ieehwan Kim of the University of Science and Technology.
During the first session, Professor Chatterji stressed that how to make supply chains resilience will be the key for making long-term strategy with relevant government policy. He said that AI has become a general purpose technology (GPT) and Korea ranked 4th in AI innovation in the world, but how to translate this innovativeness into national strategic leadership will be a new challenge for Korea. He suggested that Korea strengthen its strategic partnerships with allies such as the U.S. and provide opportunities not only for established players but start-ups and entrepreneurs. Meanwhile, Professor Kreps said that industrial policy should also leverage trust and innovations for building technology alliances with a more longer-term approach, without antagonizing certain groups of nations.
Vice President for Planning and Budget Bowon Kim who joined the forum as a discussant pointed out that in this hyper-connected era, nothing can be manufactured in a single company and country without the global supply chain. “In longer-term policy and strategies, we should embrace China as a global economy partner and include all nations around the world.”
Chairman Chey from SK said that the clear role among universities, industry, and the government doesn’t exist any longer. Now, universities are working hard for the commercialization of technology from their labs. Industry is nurturing the talents inept for future industry, and the government is trying to introduce a more private-sector approach. As such, universities, the government, and industry should embrace all-inclusive approaches encompassing global politics and trade to lead on the global stage.
Meanwhile in the second session, all of the speakers stressed innovation in science and technology governance in order to adopt to the new industrial paradigm. They agreed to make prompt innovations and solid collaborative systems among the government ministries to ensure national competitiveness, especially in the field of science and technology.
President Lee from KOFST said Korea should adopt a first mover strategy and the government should adopt a mission-oriented projects and deregulate more. He pointed out that when mandating more autonomy in decision making, scientists and students can make more creative outcomes.
Professor Yoon at SNU stressed the close alliance with the U.S. in the technology race, but suggested that Korea should also seek ways to help minimize the technology gap between advanced and developing countries. Universities should also be allowed more autonomy in running creative curriculum and academic affairs to in order boost the competitiveness of science and technology.
President Kim from Ewha pointed out the role of education as a public good. In some countries, strengthening science and technology can be accomplished with wider educational opportunities in middle and high schools. President Kim also stressed expanding strategic partnerships. She said Korea should expand its alliances and partnerships, not only with the U.S. but with European countries and other niche countries where certain technologies are superior.
President Kim of UST stressed a new science and technology leadership is required to build technology sovereignty and the government should spearhead the deregulations of the government policy.
This GSI forum was co-hosted by two think-tanks at KAIST, the Korea Policy Center for the Fourth Industrial Revolution (KPC4IR) and the Innovation Strategy and Policy Institute (ISPI).
2021.10.28 View 7034 -
Prof. Changho Suh Named the 2021 James L. Massey Awardee
Professor Changho Suh from the School of Electrical Engineering was named the recipient of the 2021 James L.Massey Award. The award recognizes outstanding achievement in research and teaching by young scholars in the information theory community. The award is named in honor of James L. Massey, who was an internationally acclaimed pioneer in digital communications and revered teacher and mentor to communications engineers.
Professor Suh is a recipient of numerous awards, including the 2021 James L. Massey Research & Teaching Award for Young Scholars from the IEEE Information Theory Society, the 2019 AFOSR Grant, the 2019 Google Education Grant, the 2018 IEIE/IEEE Joint Award, the 2015 IEIE Haedong Young Engineer Award, the 2013 IEEE Communications Society Stephen O. Rice Prize, the 2011 David J. Sakrison Memorial Prize (the best dissertation award in UC Berkeley EECS), the 2009 IEEE ISIT Best Student Paper Award, the 2020 LINKGENESIS Best Teacher Award (the campus-wide Grand Prize in Teaching), and the four Departmental Teaching Awards (2013, 2019, 2020, 2021).
Dr. Suh is an IEEE Information Theory Society Distinguished Lecturer, the General Chair of the Inaugural IEEE East Asian School of Information Theory, and a Member of the Young Korean Academy of Science and Technology. He is also an Associate Editor of Machine Learning for the IEEE Transactions on Information Theory, the Editor for the IEEE Information Theory Newsletter, a Column Editor for IEEE BITS the Information Theory Magazine, an Area Chair of NeurIPS 2021, and on the Senior Program Committee of IJCAI 2019–2021.
2021.07.27 View 6473 -
Professor Jung Receives the Hansong Science Award
Professor Yousung Jung of the Department of Chemical and Biomolecular Engineering has been selected as the recipient of the 5th Hansong Science Award in Chemistry. The award recognizes young and mid-career scholars who made outstanding achievement in physics, chemistry, and life sciences. Recipients receive 50 million KRW in prize money.
Professor Jung was recognized for finding a new way to predict synthesis potentials when designing data-based materials and molecules through AI-powered inverse technology. Conventionally, new material discovery mainly relied on a method where the new materials were proposed by an expert’s intuition or experimental trial, then synthesized to measure the properties of the material before it was used. However, this method took a lot of time, which resulted in an inefficient discovery process.
Professor Jung’s AI reverse design technology is reported to be more efficient for discovering new materials by finding crystal structures with desired properties using data and AI algorithms.
"AI reverse design technology can accelerate the development of new materials and new drugs," Professor Jung said. "It can be used as an algorithm for future autonomous laboratories implemented by robots, algorithms, and data without human intervention," he added.
2021.07.13 View 5502 -
Professor Heung-Sun Sim the MSIT Scientist of July
Professor Heung-Sun Sim from the Department of Physics was selected as the Scientist of July by the Ministry of Science and ICT. Professor Sim was recognized for his research of the Kondo effect, which opened a novel way to engineer spin screening and entanglement by directly observing a quantum phenomenon known as a Kondo screening cloud. His research revealed that the cloud can mediate interactions between distant spins confined in quantum dots, which is a necessary protocol for semiconductor spin-based quantum information processing. This phenomenon is essentially a cloud that masks magnetic impurities in a material. It was known to exist but its spatial extension had never been observed, creating controversy over whether such an extension actually existed. The research was reported in Nature in March 2020. With this award, Professor Sim received 10 million KRW in prize money.
2021.07.12 View 5931 -
Repurposed Drugs Present New Strategy for Treating COVID-19
Virtual screening of 6,218 drugs and cell-based assays identifies best therapeutic medication candidates
A joint research group from KAIST and Institut Pasteur Korea has identified repurposed drugs for COVID-19 treatment through virtual screening and cell-based assays. The research team suggested the strategy for virtual screening with greatly reduced false positives by incorporating pre-docking filtering based on shape similarity and post-docking filtering based on interaction similarity. This strategy will help develop therapeutic medications for COVID-19 and other antiviral diseases more rapidly. This study was reported at the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
Researchers screened 6,218 drugs from a collection of FDA-approved drugs or those under clinical trial and identified 38 potential repurposed drugs for COVID-19 with this strategy. Among them, seven compounds inhibited SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, showed anti-SARS-CoV-2 activity in human lung cells, Calu-3.
Drug repurposing is a practical strategy for developing antiviral drugs in a short period of time, especially during a global pandemic. In many instances, drug repurposing starts with the virtual screening of approved drugs. However, the actual hit rate of virtual screening is low and most of the predicted drug candidates are false positives.
The research group developed effective filtering algorithms before and after the docking simulations to improve the hit rates. In the pre-docking filtering process, compounds with similar shapes to the known active compounds for each target protein were selected and used for docking simulations. In the post-docking filtering process, the chemicals identified through their docking simulations were evaluated considering the docking energy and the similarity of the protein-ligand interactions with the known active compounds.
The experimental results showed that the virtual screening strategy reached a high hit rate of 18.4%, leading to the identification of seven potential drugs out of the 38 drugs initially selected.
“We plan to conduct further preclinical trials for optimizing drug concentrations as one of the three candidates didn’t resolve the toxicity issues in preclinical trials,” said Woo Dae Jang, one of the researchers from KAIST.
“The most important part of this research is that we developed a platform technology that can rapidly identify novel compounds for COVID-19 treatment. If we use this technology, we will be able to quickly respond to new infectious diseases as well as variants of the coronavirus,” said Distinguished Professor Sang Yup Lee.
This work was supported by the KAIST Mobile Clinic Module Project funded by the Ministry of Science and ICT (MSIT) and the National Research Foundation of Korea (NRF). The National Culture Collection for Pathogens in Korea provided the SARS-CoV-2 (NCCP43326).
-PublicationWoo Dae Jang, Sangeun Jeon, Seungtaek Kim, and Sang Yup Lee. Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay. Proc. Natl. Acad. Sci. U.S.A. (https://doi/org/10.1073/pnas.2024302118)
-ProfileDistinguished Professor Sang Yup LeeMetabolic &Biomolecular Engineering National Research Laboratoryhttp://mbel.kaist.ac.kr
Department of Chemical and Biomolecular EngineeringKAIST
2021.07.08 View 10692 -
Wearable Device to Monitor Sweat in Real Time
An on-skin platform for the wireless monitoring of flow rate, cumulative loss, and temperature of sweat in real time
An electronic patch can monitor your sweating and check your health status. Even more, the soft microfluidic device that adheres to the surface of the skin, captures, stores, and performs biomarker analysis of sweat as it is released through the eccrine glands.
This wearable and wireless electronic device developed by Professor Kyeongha Kwon and her collaborators is a digital and wireless platform that could help track the so-called ‘filling process’ of sweat without having to visually examine the device. The platform was integrated with microfluidic systems to analyze the sweat’s components.
To monitor the sweat release rate in real time, the researchers created a ‘thermal flow sensing module.’ They designed a sophisticated microfluidic channel to allow the collected sweat to flow through a narrow passage and a heat source was placed on the outer surface of the channel to induce a heat exchange between the sweat and the heated channel.
As a result, the researchers could develop a wireless electronic patch that can measure the temperature difference in a specific location upstream and downstream of the heat source with an electronic circuit and convert it into a digital signal to measure the sweat release rate in real time. The patch accurately measured the perspiration rate in the range of 0-5 microliters/minute (μl/min), which was considered physiologically significant. The sensor can measure the flow of sweat directly and then use the information it collected to quantify total sweat loss. Moreover, the device features advanced microfluidic systems and colorimetric chemical reagents to gather pH measurements and determine the concentration of chloride, creatinine, and glucose in a user's sweat.
Professor Kwon said that these indicators could be used to diagnose various diseases related with sweating such as cystic fibrosis, diabetes, kidney dysfunction, and metabolic alkalosis. “As the sweat flowing in the microfluidic channel is completely separated from the electronic circuit, the new patch overcame the shortcomings of existing flow rate measuring devices, which were vulnerable to corrosion and aging,” she explained.
The patch can be easily attached to the skin with flexible circuit board printing technology and silicone sealing technology. It has an additional sensor that detects changes in skin temperature. Using a smartphone app, a user can check the data measured by the wearable patch in real time.
Professor Kwon added, “This patch can be widely used for personal hydration strategies, the detection of dehydration symptoms, and other health management purposes. It can also be used in a systematic drug delivery system, such as for measuring the blood flow rate in blood vessels near the skin’s surface or measuring a drug’s release rate in real time to calculate the exact dosage.”
-PublicationKyeongha Kwon, Jong Uk Kim, John A. Rogers, et al. “An on-skin platform for wireless monitoring of flow rate, cumulative loss and temperature of sweat in real time.” Nature Electronics (doi.org/10.1038/s41928-021-00556-2)
-ProfileProfessor Kyeongha KwonSchool of Electrical EngineeringKAIST
2021.06.25 View 8074 -
Defining the Hund Physics Landscape of Two-Orbital Systems
Researchers identify exotic metals in unexpected quantum systems
Electrons are ubiquitous among atoms, subatomic tokens of energy that can independently change how a system behaves—but they also can change each other. An international research collaboration found that collectively measuring electrons revealed unique and unanticipated findings. The researchers published their results on May 17 in Physical Review Letters.
“It is not feasible to obtain the solution just by tracing the behavior of each individual electron,” said paper author Myung Joon Han, professor of physics at KAIST. “Instead, one should describe or track all the entangled electrons at once. This requires a clever way of treating this entanglement.”
Professor Han and the researchers used a recently developed “many-particle” theory to account for the entangled nature of electrons in solids, which approximates how electrons locally interact with one another to predict their global activity.
Through this approach, the researchers examined systems with two orbitals — the space in which electrons can inhabit. They found that the electrons locked into parallel arrangements within atom sites in solids. This phenomenon, known as Hund’s coupling, results in a Hund’s metal. This metallic phase, which can give rise to such properties as superconductivity, was thought only to exist in three-orbital systems.
“Our finding overturns a conventional viewpoint that at least three orbitals are needed for Hund’s metallicity to emerge,” Professor Han said, noting that two-orbital systems have not been a focus of attention for many physicists. “In addition to this finding of a Hund’s metal, we identified various metallic regimes that can naturally occur in generic, correlated electron materials.”
The researchers found four different correlated metals. One stems from the proximity to a Mott insulator, a state of a solid material that should be conductive but actually prevents conduction due to how the electrons interact. The other three metals form as electrons align their magnetic moments — or phases of producing a magnetic field — at various distances from the Mott insulator. Beyond identifying the metal phases, the researchers also suggested classification criteria to define each metal phase in other systems.
“This research will help scientists better characterize and understand the deeper nature of so-called ‘strongly correlated materials,’ in which the standard theory of solids breaks down due to the presence of strong Coulomb interactions between electrons,” Professor Han said, referring to the force with which the electrons attract or repel each other. These interactions are not typically present in solid materials but appear in materials with metallic phases.
The revelation of metals in two-orbital systems and the ability to determine whole system electron behavior could lead to even more discoveries, according to Professor Han.
“This will ultimately enable us to manipulate and control a variety of electron correlation phenomena,” Professor Han said.
Co-authors include Siheon Ryee from KAIST and Sangkook Choi from the Condensed Matter Physics and Materials Science Department, Brookhaven National Laboratory in the United States. Korea’s National Research Foundation and the U.S. Department of Energy’s (DOE) Office of Science, Basic Energy Sciences, supported this work.
-PublicationSiheon Ryee, Myung Joon Han, and SangKook Choi, 2021.Hund Physics Landscape of Two-Orbital Systems, Physical Review Letters, DOI: 10.1103/PhysRevLett.126.206401
-ProfileProfessor Myung Joon HanDepartment of PhysicsCollege of Natural ScienceKAIST
2021.06.17 View 7012 -
Identification of How Chemotherapy Drug Works Could Deliver Personalized Cancer Treatment
The chemotherapy drug decitabine is commonly used to treat patients with blood cancers, but its response rate is somewhat low. Researchers have now identified why this is the case, opening the door to more personalized cancer therapies for those with these types of cancers, and perhaps further afield.
Researchers have identified the genetic and molecular mechanisms within cells that make the chemotherapy drug decitabine—used to treat patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) —work for some patients but not others. The findings should assist clinicians in developing more patient-specific treatment strategies.
The findings were published in the Proceedings of the National Academies of Science on March 30.
The chemotherapy drug decitabine, also known by its brand name Dacogen, works by modifying our DNA that in turn switches on genes that stop the cancer cells from growing and replicating. However, decitabine’s response rate is somewhat low (showing improvement in just 30-35% of patients), which leaves something of a mystery as to why it works well for some patients but not for others. To find out why this happens, researchers from the KAIST investigated the molecular mediators that are involved with regulating the effects of the drug.
Decitabine works to activate the production of endogenous retroviruses (ERVs), which in turn induces an immune response. ERVs are viruses that long ago inserted dormant copies of themselves into the human genome. Decitabine in essence, ‘reactivates’ these viral elements and produces double-stranded RNAs (dsRNAs) that the immune system views as a foreign body.
“However, the mechanisms involved in this process, in particular how production and transport of these ERV dsRNAs were regulated within the cell were understudied,” said corresponding author Yoosik Kim, professor in the Department of Chemical and Biomolecular Engineering at KAIST.
“So to explain why decitabine works in some patients but not others, we investigated what these molecular mechanisms were,” added Kim.
To do so, the researchers used image-based RNA interference (RNAi) screening. This is a relatively new technique in which specific sequences within a genome are knocked out of action or “downregulated.” Large-scale screening, which can be performed in cultured cells or within live organisms, works to investigate the function of different genes. The KAIST researchers collaborated with the Institut Pasteur Korea to analyze the effect of downregulating genes that recognize ERV dsRNAs and could be involved in the cellular response to decitabine.
From these initial screening results, they performed an even more detailed downregulation screening analysis. Through the screening, they were able to identify two particular gene sequences involved in the production of an RNA-binding protein called Staufen1 and the production of a strand of RNA that does not in turn produce any proteins called TINCR that play a key regulatory role in response to the drug. Staufen1 binds directly to dsRNAs and stabilizes them in concert with the TINCR.
If a patient is not producing sufficient Staufen1 and TINCR, then the dsRNA viral mimics quickly degrade before the immune system can spot them. And, crucially for cancer therapy, this means that patients with lower expression (activation) of these sequences will show inferior response to decitabine. Indeed, the researchers confirmed that MDS/AML patients with low Staufen1 and TINCR expression did not benefit from decitabine therapy.
“We can now isolate patients who will not benefit from the therapy and direct them to a different type of therapy,” said first author Yongsuk Ku. “This serves as an important step toward developing a patient-specific treatment cancer strategy.”
As the researchers used patient samples taken from bone marrow, the next step will be to try to develop a testing method that can identify the problem from just blood samples, which are much easier to acquire from patients.
The team plans to investigate if the analysis can be extended to patients with solid tumors in addition to those with blood cancers.
-Profile
Professor Yoosik Kim
https://qcbio.kaist.ac.kr/
Department of Chemical and Biomolecular Engineering
KAIST
-Publication
Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs, PNAS
2021.05.24 View 8313 -
Prof. Sang Yup Lee Elected as a Foreign Member of the Royal Society
Vice President for Research Distinguished Professor Sang Yup Lee was elected as a foreign member of the Royal Society in the UK. On May 6, the Society announced the list of distinguished new 52 fellows and 10 foreign members who achieved exceptional contributions to science. Professor Lee and Professor V. Narry Kim from Seoul National University are the first foreign members ever elected from Korea.
The Royal Society, established in 1660, is one of the most prestigious national science academies and a fellowship of 1,600 of the world’s most eminent scientists. From Newton to Darwin, Einstein, Hawking, and beyond, pioneers and paragons in their fields are elected by their peers. To date, there are 280 Nobel prize winners among the fellows.
Distinguished Professor Lee from the Department of Chemical and Biomolecular Engineering at KAIST is one of the Highly Cited Researchers (HCRs) who pioneered systems metabolic engineering and developed various micro-organisms for producing a wide range of fuels, chemicals, materials, and natural compounds.
His seminal scholarship and research career have already been recognized worldwide. He is the first Korean ever elected into the National Academy of Inventors (NAI) in the US and one of 13 scholars elected as an International Member of both the National Academy of Sciences (NAS) and the National Academy of Engineering (NAE) in the US. With this fellowship, he added one more accolade of being the first non-US and British Commonwealth scientist elected into the three most prestigious science academies: the NAS, the NAE, and the Royal Society.
2021.05.07 View 8987