Abstract
Background:
Cancer remains one of the leading causes of death worldwide, underscoring the need for novel therapies. SH003, an herbal mixture composed of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii, is a traditional Korean medicine formulation with potential to enhance chemotherapy efficacy and reduce toxicity. This study aimed to assess the safety and determine maximum tolerated dose of SH003 in combination with docetaxel in patients with advanced solid tumors, specifically lung and breast cancer.
Methods:
This Phase I, multi-center, open-label, dose-escalation study enrolled patients with advanced lung or breast cancer. Participants received SH003 orally at doses of 2400, 3600, or 4800 mg daily, alongside intravenous docetaxel (75 mg/m²) every 21 days. A 3 + 3 dose-escalation design was employed to determine the maximum tolerated dose. Safety assessments and adverse event monitoring were conducted at each treatment cycle.
Results:
Twelve participants were enrolled. SH003 was well tolerated up to 4800 mg/day, with no dose-limiting toxicities attributed to SH003. The most common adverse events were neutropenia, primarily associated with docetaxel, and mild dermatologic reactions such as eczema, rash acneiform, and pruritus. Preliminary evidence of disease stabilization was observed in several participants.
Conclusion:
The combination of SH003 and docetaxel demonstrated a favorable safety profile, with 4800 mg/day identified as maximum tolerated dose for SH003. These findings support further investigation in Phase II trials to assess therapeutic efficacy.
Background
Cancer remains a major global health challenge, characterized by uncontrolled cell growth and high mortality. It was responsible for approximately 10 million deaths in 2020, highlighting its lethal impact. 1 Projections indicate that by 2040, global cancer cases could reach 28.4 million, a 47% increase from current figures, emphasizing the urgent need for effective treatments. 2 In response, there is growing interest in natural substances, known for their bioactive properties, as potential anticancer agents.3,4
Combination chemotherapy, which involves using multiple drugs to enhance treatment efficacy and reduce resistance, is a cornerstone of current cancer treatment strategies.5,6 Similarly, the integration of herbal medicines with anticancer drugs is being explored for potential synergistic effects.7,8
SH003, a novel herbal mixture comprising Huang-Qi (Astragalus membranaceus Bunge), Dang-Gui (Angelica gigas Nakai), and Gua-Lou-Gen (Trichosanthes Kirilowii Maxim), exemplifies this approach. This mixture, grounded in traditional Korean medicinal theory, features bioactive compounds such as apigenin, cucurbitacin D, decursin, kaempferol, and quercetin, which have shown promising results across various cancer types, including triple-negative breast cancer and non-small cell lung cancer.9,10 These compounds have demonstrated abilities in apoptosis induction, cell cycle regulation, and immune modulation, establishing SH003 as a candidate for combination therapy with chemotherapeutic agents like docetaxel, doxorubicin, and dabrafenib.11 -17
Preclinical studies have demonstrated synergistic anticancer effects of SH003 combined with docetaxel in both non-small cell lung cancer and triple-negative breast cancer. This combination has been shown to inhibit tumor growth by enhancing apoptosis, suppressing EGFR/STAT3 signaling, 15 disrupting pyrimidine nucleotide synthesis, 18 and modulating the tumor immune microenvironment, including increased infiltration of cytotoxic T and NK cells in anti-PD1-resistant models. 19 In triple-negative breast cancer models, SH003 and docetaxel co-treatment synergistically inhibited EGFR and AKT phosphorylation, reduced cell viability, and suppressed tumor growth in xenograft models. 14 These findings support the rationale for evaluating SH003 in combination with docetaxel in clinical trials targeting advanced solid tumors.
SH003 is based on Dangguibohyul-tang, a traditional formula composed of Dang-gui and Huang-Qi that was first documented during the Yuan Dynasty in China in the “Treasured Mirror of the Hygiene (Weishengbogam)” and subsequently referenced in prominent Korean texts such as “Treasured Mirror of Eastern Medicine (Dongeuibogam)” and “Compilation of Formulas and Medicinals (Bangyakhappyeon).” Formulated primarily with herbs known for tonifying blood and qi, it is considered particularly suitable for patient with cancer exhibiting dual deficiency of qi and blood. SH003 has been enhanced by the addition of Gua-Lou-Gen, which is recognized for its abilities to disperse abscesses and nodules, thereby potentially augmenting its anticancer properties.
Building on previous Phase I findings that established the maximum tolerated dose of SH003 as a single agent, 20 this study aims to determine the maximum tolerated dose of SH003 in combination with docetaxel. The results will contribute to understanding the broader applicability of SH003 in enhancing conventional chemotherapy, potentially leading to more effective and less toxic cancer treatments.
Materials and Methods
Study Design
This Phase I clinical trial was a multi-center, open-label, dose-escalation study designed to evaluate the safety of SH003 in combination with docetaxel. It was conducted at Korea University Anam Hospital, Guro Hospital in Seoul, and Ajou University Hospital in Suwon, Republic of Korea. Participants who met the eligibility criteria were enrolled and assigned to one of 3 groups receiving daily doses of 2400, 3600, and 4800 mg of SH003. The selection of 2400 mg as the starting dose was based on prior safety and efficacy evaluations, ensuring an appropriate balance between potential therapeutic effects and safety. 21 Additionally, considering the formulation of SH003, it was determined that doses up to 4800 mg/day would be feasible for administration. These dose levels refer to the amount of active herbal extract in SH003. Each tablet weighs 800 mg and contains 400 mg of active extract and 400 mg of excipients. Accordingly, the highest daily dose of 4800 mg corresponds to 12 tablets. Dose escalation was scheduled twice, following the modified Fibonacci sequence, a widely accepted approach in Phase I clinical trials. The sample size was not fixed in advance, as the study followed a traditional 3 + 3 dose-escalation design. The trial was designed to allow up to 2 dose escalations, with a minimum of 3 and a maximum of 18 participants, depending on the occurrence of dose-limiting toxicities (DLTs) at each dose level. Adverse events of each participant were assessed at each visit during the study period. Detailed study methods and protocols were followed as described in the published protocol paper. 22 This study is also registered with the Korean registry for clinical trials, Clinical Research Information Service (KCT0004770). The study was conducted in accordance with the guidelines of the Declaration of Helsinki and Tokyo for humans, and was approved by the institutional review board of each participating institution (AJIRB-MED-T12-19-479, 2020AN0020, 2022GR0097). Informed consent was obtained from all participants prior to enrollment. No important changes to methods were made after trial commencement. No formal interim analyses were planned or conducted; however, dose-escalation decisions were made based on periodic safety assessments in accordance with the 3 + 3 design.
Intervention
Participants received oral doses of SH003 combined with intravenous docetaxel administered at 75 mg/m2 over 1 hour on the first day of each 21-day cycle. SH003 was administered in tablet form, taken with water 3 times daily after meals. Each 800 mg tablet contained 400 mg of solid extract prepared by 30% ethanol extraction from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii in a 1:1:1 ratio, with the remaining 400 mg consisting of excipients. SH003 was manufactured by Hanpoong Pharm and Foods Co. Ltd. (Jeonju, Republic of Korea) in accordance with Korea Good Manufacturing Practice standards. SH003 was produced in 2 batches during the study period. All batches were stored under ambient conditions in the investigational drug storage units at each clinical trial site. Stability testing had previously confirmed that SH003 remains stable for up to 36 months under room temperature conditions. The subsequent production followed the same quality standards established in the Investigational New Drug approval by the Korean Ministry of Food and Drug Safety, including validation based on the marker compounds decursin and formononetin, as designated in the Korean Herbal Pharmacopoeia.
Participants
Inclusion Criteria
Participants eligible for this study were adults over the age of 19 years, diagnosed with histologically or cytologically confirmed lung or breast cancer, for which no standard curative treatments were effective or available. Eligibility required that participants had not received chemotherapy, radiotherapy, or surgery within the preceding 4 weeks and exhibited no residual toxicity from previous treatments, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with no adverse events graded higher than 1. Additionally, candidates needed to have an Eastern Cooperative Oncology Group performance status of 2 or lower and an estimated life expectancy of at least 12 weeks. Participants were required to have the capability to swallow tablets, measurable lesions as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Specific organ function requirements included a hemoglobin level of at least 8 g/dL, an absolute neutrophil count of 1500/μL or higher, platelet counts over 100 000/μL, total bilirubin and liver enzymes (Aspartate Aminotransferase or Alanine Aminotransferase) within 2.5 times the upper limit of normal (or 5 times if liver metastases were present), and renal function within normal limits or a creatinine clearance of 60 mL/min or higher as calculated by the Cockcroft-Gault equation. Female participants were required to have no potential for pregnancy, either due to age, surgical history, or menopausal status; those of childbearing potential were tested for pregnancy prior to study entry. All participants were mandated to use effective contraception during the trial and for 8 weeks thereafter. Furthermore, they had to demonstrate an understanding of the study procedures and provide written informed consent.
Exclusion Criteria
Excluded from participation were patients undergoing any form of systemic or regional cancer therapy, those with known hypersensitivities to any components of the study drug (including Astragalus membranaceus, Angelica gigas, Trichosanthes kirilowii, and polysorbate 80), and individuals with active infections requiring treatment. Also excluded were patients with a history of HIV infection, uncontrolled cardiovascular diseases, recent major surgery for cerebrovascular disease, pregnant or lactating women, and those with symptomatic metastatic encephalopathy. Additional exclusion criteria included recent participation in other clinical trials, recent organ transplantation, active infections like cytomegalovirus, suspected infection-related fever, substance abuse, or any neurological, medical, psychological, or sociological conditions that could interfere with protocol compliance or interpretation of study results. Patients deemed by the investigator to be inappropriate for the study or incapable of providing consent due to cognitive impairment were also excluded.
Participant Withdrawal Criteria
Participants could be withdrawn from the study due to disease progression despite treatment, occurrence of uncontrolled adverse events, initiation of other cancer treatments, voluntary withdrawal, serious adverse events related to the investigational drug, significant protocol violations, or if the investigator deemed it necessary for the health of the participant. If withdrawal occurred due to consent retraction or a non-drug-related dose-limiting toxicity, additional participants were to be recruited to replace those lost. Any loss incurred by participants as a result of clinical trial involvement was covered by insurance.
Outcome Measurement
The primary outcome measured was the occurrence of DLTs, defined as any Grade 3 or 4 toxicity according to the CTCAE version 5.0. Secondary outcomes included the overall incidence and severity of adverse events. No changes were made to the trial outcomes after the trial commenced.
Outcome Analysis
The trial utilized a traditional 3 + 3 dose-escalation design to determine the maximum tolerated dose (MTD) of SH003 when used in conjunction with docetaxel. If no DLTs occurred, the dose was escalated; if 1 DLT occurred, additional participants were recruited at the current dose. If 2 or more DLTs occurred among participants at any dose level, no further dose escalation was undertaken, and the dose level immediately lower was considered the MTD. Demographic characteristics were summarized using descriptive statistics. Continuous variables such as age, height, and weight were presented as median and range, while categorical variables such as sex and cancer type were shown as counts. Safety data, including adverse events, were categorical and presented as frequencies, based on CTCAE grades. No additional adjusted analyses were performed beyond the predefined dose cohort subgroup analyses.
Data and Safety Monitoring
The quality of trial was overseen by a Contract Research Organization. Data collection was subject to double-entry verification, and any serious adverse events were reported to the institutional review board and the Ministry of Food and Drug Safety. All participants experiencing adverse events were followed up until resolution.
Results
Participants Demographics
This clinical trial began on May 20, 2021, and was completed on March 14, 2023. The characteristics of all participants and each cohort are outlined in Table 1. The study was designed with 3 distinct cohorts, each comprising 4 of the 12 total participants (Figure 1). These cohorts were systematically assigned to escalating daily dosages: 2400 mg for Cohort I, 3600 mg for Cohort II, and 4800 mg for Cohort III. The median age of participants was 61.5 years, ranging from 46 to 80 years. The gender distribution included 4 males and 8 females. The diagnoses were evenly distributed, with 6 participants having breast cancer and 6 having lung cancer. Cohort I received the lowest dosage of 2400 mg/day. This cohort had a median age of 53.5 years. Cohort II was administered a daily dose of 3600 mg with a median age of 59 years. Cohort III, treated with the highest dosage of 4800 mg/day, had the oldest median age at 67 years. Each cohort included participants diagnosed with both breast and lung cancers, representing a range of ages and clinical diagnoses.
Participants Characteristics.
Participants flow.
Adverse Events
In this clinical trial, various adverse events were recorded across different cohorts (Table 2). In Cohort 1, 1 case of severe tumor pain (Grade ≥ 3) was reported, along with 2 cases of mild edema in the limbs (Grade ≤ 2). Notably, decreases in neutrophil counts were recorded as severe (Grade ≥ 3) in 2 cases each in Cohorts 1 and 2. Cohort 3 showed a high incidence of decreased neutrophil counts with 6 cases recorded among 4 participants: 2 cases were mild (Grade ≤ 2) and 4 cases were severe (Grade ≥ 3). Dyspnea was reported as severe (Grade ≥ 3) in 1 case each in Cohorts 1 and 3. Eczema, which appeared in Cohorts 2 and 3, involved only mild cases (Grade ≤ 2). In Cohort 3, other serious conditions included 1 case of febrile neutropenia and 1 case of significant fatigue, both documented as Grade ≥ 3. Additionally, this cohort experienced mild cases of diarrhea and anorexia, with 2 instances each (Grade ≤ 2), and a mild increase in creatinine noted in 1 case (Grade ≤ 2). No unexpected harms or unintended effects related to SH003 were observed in any cohort.
Toxicity Results.
Dose-Limiting Toxicities and Maximum Tolerated Dose
During the study, while Grade ≥ 3 adverse events (AEs) were observed across all cohorts, these were not classified as DLTs since they were attributed by the investigators to either the effects of docetaxel or the underlying cancer symptoms rather than the experimental drug SH003. Despite the presence of severe AEs, none met the criteria for DLTs as they were not directly linked to SH003. As a result, the MTD of SH003 was established at 4800 mg/day, the highest administered dose, since no SH003-related DLTs were identified. Since safety was confirmed at the highest planned dose, no further dose escalation was necessary, and the trial was completed as planned.
Efficacy Observations
Although the primary focus of this Phase I trial was on safety and determining the MTD, preliminary observations on efficacy were also made using RECIST criteria for tumor evaluations. Tumor responses were assessed in 3 participants per cohort, as 1 participant discontinued the study before evaluation. In Cohort 1 (2400 mg), 2 participants achieved stable disease (SD): 1 with breast cancer and 1 with lung cancer, while 1 had progressive disease (PD). In Cohort 2 (3600 mg), 1 participant with lung cancer showed SD, and 2 had PD. In Cohort 3 (4800 mg), 2 participants achieved SD, both with lung cancer, while 1 had PD. These findings, though exploratory, suggest potential tumor control in some participants, warranting further investigation in subsequent trials to better understand the therapeutic potential of the treatment.
Discussion
This Phase I trial aimed to establish the safety profile and maximum tolerated dose of SH003 in combination with docetaxel in patients with solid tumors. The study successfully determined that the highest administered dose of 4800 mg/day in combination with docetaxel could be tolerated without dose-limiting toxicities attributable to SH003, suggesting a promising safety profile at all tested dosage levels.
Unlike previous studies that evaluated the safety of SH003 monthearpy,20,23 this study is the first to assess its safety and tolerability in combination with docetaxel, a standard chemotherapeutic agent for lung and breast cancer. The rationale for this combination stems from preclinical findings suggesting that SH003 enhances apoptosis and inhibits cancer cell proliferation when used alongside chemotherapeutic agents.14,15 Preclinical studies have also suggested that individual components of SH003 may contribute to its antitumor effects. Among these, decursin (from Angelica gigas) and formononetin (from Astragalus membranaceus) have demonstrated antitumor activity through mechanisms such as apoptosis induction and inhibition of metastasis.24,25 Trichosanthes kirilowii extracts, as well as its active compound cucurbitacin D, have also demonstrated anticancer activity in preclinical studies.26,27 From a traditional medicine perspective, Trichosanthes has been used in formulations addressing mass-like conditions, while Angelica and Astragalus are considered to support systemic recovery. 28 In this phase I study, a fixed dose of docetaxel (75 mg/m²) was used to minimize variability while evaluating the safety profile of SH003. Given the limited sample size, exploring multiple dose levels of docetaxel was not feasible within the scope of this trial. Future studies may evaluate whether SH003 allows for dose reduction of docetaxel without compromising efficacy.
Various combination therapies are used for cancer treatment. 6 Herbal medicine is also frequently incorporated into cancer management, and research in this area is expanding. Many studies investigating herbal medicine in combination with chemotherapy primarily focus on alleviating treatment-related symptoms and adverse effects.29,30 However, there is increasing interest in evaluating the potential anticancer efficacy of such combinations.7,8 A previous Phase I clinical trial established the safety of SH003 monotherapy at doses up to 4800 mg/day. Additionally, a recent study confirmed the safety of SH003 at doses up to 9600 mg/day. 23 Building on these findings, this study assessed the safety and potential therapeutic effects of SH003 in combination with docetaxel, contributing to the growing body of evidence supporting integrative cancer treatment approaches.
The evaluation of adverse events revealed that while severe adverse events occurred, none were directly linked to SH003 as per the assessments by the investigators. This highlights the potential of SH003 to be administered at high doses without significant drug-related toxicity. While it is acknowledged that the severe adverse events observed in this trial have been attributed primarily to either docetaxel or underlying disease symptoms as assessed by oncology specialists, it is important to recognize that such assessments can be subjective and may represent a potential limitation in interpreting adverse event data. Therefore, it is also relevant to consider the safety data from previous clinical trials where SH003 was administered as a monotherapy. In these trials, even at higher doses than those used in the current combination therapy trial, the incidence of severe (Grade 3 or higher) adverse events was notably lower. 20 This suggests that SH003 may have a favorable safety profile, underscoring the need to differentiate the adverse events of combination therapy from those observed with SH003 alone.
Based on previous studies, frequently reported adverse events associated with SH003 monotherapy included hot flashes, nausea, back pain, fatigue, dyspepsia, anorexia, abdominal pain, diarrhea, constipation, and dizziness. 20 A Grade 3 elevation in Gamma-Glutamyl Transferase was also noted. In this combination trial, several of these events—specifically fatigue, dyspepsia, anorexia, and diarrhea—were again reported. These adverse events are well-documented with docetaxel therapy, it is more likely that they are attributable to docetaxel rather than SH003.
In addition to these overlapping events, several adverse events not previously reported in SH003 monotherapy trials—namely neutrophil count decrease, myalgia, eczema, rash acneiform, pruritus, febrile neutropenia, oral mucositis, laryngeal hemorrhage, and arthralgia—were reported during the combination phase. Most of these events are commonly associated with docetaxel, supporting the interpretation that they are related to the known toxicity profile of this chemotherapeutic agent. A single case of laryngeal hemorrhage was observed. While this is not a typical toxicity associated with docetaxel, isolated mucosal bleeding events have been reported in patients receiving docetaxel therapies. 31 Given its singular occurrence and the complexity of attributing causality in combination treatments, it remains unclear whether this event is related to SH003, docetaxel, or their interaction. Continued observation and further evaluation of such events in future clinical trials will be important for more definitive safety characterization. Although 1 case of febrile neutropenia was observed, no clinical infections—such as pneumonia, urinary tract infection, or sepsis—were reported. Continued monitoring for infection-related events will be necessary in future trials involving SH003 in combination with cytotoxic chemotherapy.
To ensure an accurate assessment of safety and tolerability, participants with uncontrolled comorbidities—particularly cardiovascular conditions—were excluded, and only those with clinically stable baseline status were enrolled.
Interestingly, the overall frequency of some common docetaxel-related adverse events appeared lower than previously reported. For example, neutrophil count decrease, which has been reported in nearly 90% of patients receiving 75 mg/m² docetaxel, was observed at a lower frequency in our cohort. 32 Additionally, no cases of anemia were reported, despite previous data indicating similarly high incidence rates. 32 However, given the small sample size and short treatment duration of this trial, these findings should be interpreted with caution and cannot be considered indicative of a toxicity-sparing effect. Further evaluation in larger, controlled studies will be necessary to determine whether SH003 may contribute to reducing the toxicity profile of docetaxel.
Despite the primary focus of the present study on safety and dosing, preliminary efficacy observations based on RECIST criteria indicate some level of tumor control, as evidenced by stable disease observed in participants across various cohorts. Although stable disease was consistently reported in both the lowest and highest dose cohorts, the similar rates across these groups do not strongly suggest a dose-response relationship. Given this variability in response to SH003, it is essential to conduct a Phase II clinical trial to further investigate its efficacy. Although preliminary efficacy was observed, including stable disease in 55.6% of evaluable patients, these findings should be interpreted with caution. Similar disease control rates have been reported for docetaxel monotherapy in breast and lung cancer (approximately 46%-56%),33,34 suggesting that the observed responses in this study may primarily reflect the known activity of docetaxel. However, considering the small sample size, short treatment duration, and inclusion of only patients with stage IV disease, a potential contribution of SH003 to tumor control cannot be ruled out and warrants further investigation in larger trials.
In this Phase I trial, lung cancer patients demonstrated a higher rate of stable disease compared to breast cancer patients. Specifically, 4 out of 5 participants who achieved stable disease had lung cancer. Given these findings, a Phase II trial focusing on lung cancer may be warranted to further evaluate the therapeutic potential of SH003 in this subgroup. This targeted approach may help identify tumor-specific response patterns. Furthermore, recent preclinical studies have demonstrated that the combination of SH003 and docetaxel induces cancer cell death in non-small cell lung cancer by inhibiting pyrimidine nucleotide biosynthesis and causing DNA damage. 18 Future research should continue to explore these mechanisms and consider the genetic characteristics of cancer cells, such as TP53 status, to optimize treatment strategies and therapeutic efficacy. Additionally, considering the synergistic effects observed with other chemotherapeutic agents in preclinical studies, such as dabrafenib, paclitaxel, and doxorubicin, combination therapies with these agents should also be explored.16,17,35 There is also promising evidence that SH003 can alleviate chemotherapy-induced neuropathic pain, including that induced by paclitaxel and docetaxel, suggesting potential benefits in improving the management of chemotherapy side effects.36,37 Therefore, future research should also investigate the potential of SH003 to improve chemotherapy-induced side effects.
The primary limitations of this study include its small sample size and short duration, which may affect the generalizability of the results. The small sample size was primarily due to the 3 + 3 dose-escalation design, which is standard in Phase I trials for assessing safety and determining the MTD. Additionally, the selection of 4800 mg as the highest dose, based on prior safety data and formulation considerations, contributed the limited number of participants. Future Phase II trials will require a larger sample size to better evaluate the efficacy of SH003 in combination with docetaxel. Another limitation of this study is the inherent subjectivity in evaluating the causes of adverse events, as these assessments were based on clinical judgment, introducing a degree of uncertainty. This underscores the challenges of accurately attributing adverse effects within a multi-drug regimen. However, these subjective evaluations are supported by results from previous clinical trials where SH003 was administered as a monotherapy, and similar safety profiles were observed. This consistency between studies helps validate the subjective assessments made in the current trial, although the difficulty in discerning the specific impacts of SH003 from those associated with combination therapy complicates the analysis. To address these challenges, future research should incorporate more objective measures or biomarkers that could definitively characterize the pharmacodynamic interactions and effects of SH003. Such measures could reduce reliance on subjective evaluations and provide a clearer understanding of the true impact of drug.
To our knowledge, this study is the first in the Republic of Korea to determine the safe dosage range of an herbal medicine formulation in combination with chemotherapy. This pioneering effort lays the foundation for further integration of traditional and modern oncology, addressing a significant gap in cancer treatment research in the region. The findings of this study contribute to the growing body of evidence supporting the use of complementary therapies alongside conventional cancer treatments and highlight the need for continued exploration in future clinical trials.
Conclusion
Overall, this Phase I trial provides valuable insights into the safety and potential efficacy of SH003, setting the stage for further clinical development. Continued research is essential to fully determine the therapeutic value of SH003 in the treatment of solid tumors, with future studies ideally designed to clarify the efficacy and refine the safety profile observed in this initial exploration.
Footnotes
Acknowledgements
None.
Ethical Considerations
This study was approved by the institutional review board of Ajou University Hospital (AJIRB-MED-T12-19-479), Korea University Anam Hospital (2020AN0020), and Korea University Guro Hospital (2022GR0097).
Consent to Participate
Informed consent was obtained from all participants prior to enrollment.
Author Contributions
CC and S-GK conceptualized the study. CC, KHP, and S-GK developed the methodology. SYK, SYL, and KHP carried out the investigation. CC and HK wrote the original draft of the manuscript. CC, HK, and S-GK reviewed and edited the manuscript. All authors reviewed and approved the final manuscript.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Research Foundation of Korea Grant funded by the Korea Government (No. RS-2020-NR049559). The funder had no role in design, management, analysis, and publication of the study.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.