Leucine rich repeat kinase 2 (LRRK2) is a highly promising target for Parkinson's disease (PD) that affects millions of people worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of pyrrolopyrimidine-based selective LRRK2 kinase inhibitors. This study was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. A reliable 3D-QSAR model was developed using comparative molecular field analysis (CoMFA) technique. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$) of 0.539 and a non-cross-validated correlation coefficient ($r^2$) of 0.871. Robustness of the model was further evaluated by bootstrapping and progressive scrambling analysis. This work could assist in designing more potent LRRK2 inhibitors.
Immune checkpoint inhibitors (ICIs) have shown remarkable benefit in the treatment of patients with non-small-cell lung cancer (NSCLC) and have emerged as an effective treatment option even in the first-line setting. ICIs can block inhibitory pathways that restrain the immune response against cancer, restoring and sustaining antitumor immunity. Currently, there are 4 PD-1/PD-L1 blocking agents available in clinics, and immunotherapy-based regimen alone or in combination with chemotherapy is now preferred option. Combination trials assessing combination of ICIs with chemotherapy, targeted therapy and other immunotherapy are ongoing. Controversies remain regarding the use of ICIs in targetable oncogene-addicted subpopulations, but their initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the choice. For the majority of patients without targetable driver oncogenes, deciding between therapeutic options can be difficult due to lack of direct cross-comparison studies. There are continuous efforts to find predictive biomarkers to find those who respond better to ICIs. PD-L1 protein expressions by immunohistochemistry and tumor mutational burden have emerged as most well-validated biomarkers in multiple clinical trials. However, there still is a need to improve patient selection, and to establish the most effective concurrent or sequential combination therapies in different NSCLC clinical settings. In this review, we will introduce currently used ICIs in NSCLC and analyze most recent trials, and finally discuss how, when and for whom ICIs can be used to provide promising avenues for lung cancer treatment.
Ahn, Jae-Hee;Lee, Byung-Hyun;Kim, Seong-Eun;Kwon, Bo-Eun;Jeong, Hyunjin;Choi, Jong Rip;Kim, Min Jung;Park, Yong;Kim, Byung Soo;Kim, Dae Hee;Ko, Hyun-Jeong
Biomolecules & Therapeutics
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v.29
no.2
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pp.166-174
/
2021
Multiple myeloma is a malignant cancer of plasma cells. Despite recent progress with immunomodulatory drugs and proteasome inhibitors, it remains an incurable disease that requires other strategies to overcome its recurrence and non-response. Based on the high expression levels of programmed death-ligand 1 (PD-L1) in human multiple myeloma isolated from bone marrow and the murine myeloma cell lines, NS-1 and MOPC-315, we propose PD-L1 molecule as a target of anti-multiple myeloma therapy. We developed a novel anti-PD-L1 antibody containing a murine immunoglobulin G subclass 2a (IgG2a) fragment crystallizable (Fc) domain that can induce antibody-dependent cellular cytotoxicity. The newly developed anti-PD-L1 antibody showed significant antitumor effects against multiple myeloma in mice subcutaneously, intraperitoneally, or intravenously inoculated with NS-1 and MOPC-315 cells. The anti-PD-L1 effects on multiple myeloma may be related to a decrease in the immunosuppressive myeloid-derived suppressor cells (MDSCs), but there were no changes in the splenic MDSCs after combined treatment with lenalidomide and the anti-PD-L1 antibody. Interestingly, the newly developed anti-PD-L1 antibody can induce antibody-dependent cellular cytotoxicity in the myeloma cells, which differs from the existing anti-PD-L1 antibodies. Collectively, we have developed a new anti-PD-L1 antibody that binds to mouse and human PD-L1 and demonstrated the antitumor effects of the antibody in several syngeneic murine myeloma models. Thus, PD-L1 is a promising target to treat multiple myeloma, and the novel anti-PD-L1 antibody may be an effective anti-myeloma drug via antibody-dependent cellular cytotoxicity effects.
In recent years, remarkable progress has been made in the molecular profiling of gastric cancer. This progress has led to the development of various molecular classifications to uncover subtype-specific dependencies that can be targeted for therapeutic interventions. Human epidermal growth factor receptor 2 (HER2) is a crucial biomarker for advanced gastric cancer. The recent promising results of novel approaches, including combination therapies or newer potent agents such as antibody-drug conjugates, have once again brought attention to anti-HER2 targeted treatments. In HER2-negative diseases, the combination of cytotoxic chemotherapy and programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors has become the established standard of care in first-line settings. In the context of gastric cancer, potential biomarkers such as PD-L1 expression, Epstein-Barr virus, microsatellite instability, and tumor mutational burden are being considered for immunotherapy. Recently, promising results have been reported in studies on anti-Claudin18.2 and fibroblast growth factor receptor 2 treatments. Currently, many ongoing trials are aimed at identifying potential targets using novel approaches. Further investigations will be conducted to enhance the progress of these therapies, addressing challenges such as primary and acquired resistance, tumor heterogeneity, and clonal evolution. We believe that these efforts will improve patient prognoses. Herein, we discuss the current evidence of potential targets for systemic treatment, clinical considerations, and future perspectives.
Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12-15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.
Jang, Eun Jeong;Kim, Heejeong;Baek, Seung Eun;Jeon, Eun Yeong;Kim, Ji Won;Kim, Ju Yeon;Kim, Chi Dae
The Korean Journal of Physiology and Pharmacology
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v.26
no.5
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pp.389-396
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2022
The increased expression of receptors for advanced glycation end-product (RAGE) is known as a key player in the progression of vascular remodeling. However, the precise signal pathways regulating RAGE expression in vascular smooth muscle cells (VSMCs) in the injured vasculatures are unclear. Given the importance of mitogen-activated protein kinase (MAPK) signaling in cell proliferation, we investigated the importance of MAPK signaling in high-mobility group box 1 (HMGB1)-induced RAGE expression in VSMCs. In HMGB1 (100 ng/ml)-stimulated human VSMCs, the expression of RAGE mRNA and protein was increased in association with an increase in AGE-induced VSMC proliferation. The HMGB1-induced RAGE expression was attenuated in cells pretreated with inhibitors for ERK (PD98059, 10 μM) and p38 MAPK (SB203580, 10 μM) as well as in cells deficient in ERK and p38 MAPK using siRNAs, but not in cells deficient of JNK signaling. In cells stimulated with HMGB1, the phosphorylation of ERK, JNK, and p38 MAPK was increased. This increase in ERK and p38 MAPK phosphorylation was inhibited by p38 MAPK and ERK inhibitors, respectively, but not by JNK inhibitor. Moreover, AGE-induced VSMC proliferation in HMGB1-stimulated cells was attenuated in cells treated with ERK and p38 MAPK inhibitors. Taken together, our results indicate that ERK and p38 MAPK signaling are involved in RAGE expression in HMGB1-stimulated VSMCs. Thus, the ERK/p38 MAPK-RAGE signaling axis in VSMCs was suggested as a potential therapeutic target for vascular remodeling in the injured vasculatures.
Cancer stem cells (CSCs), which are primarily responsible for metastasis and recurrence, have self-renewal, differentiation, therapeutic resistance, and tumor formation abilities. Numerous studies have demonstrated the signaling pathways essential for the acquisition and maintenance of CSC characteristics, such as WNT/${\beta}$-catenin, Hedgehog, Notch, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), Bone morphogenetic protein (BMP), and TGF-${\beta}$ signals. However, few therapeutic strategies have been developed that can selectively eliminate CSCs. Recently, neutralizing antibodies against Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1), immune checkpoint inhibitors (ICIs), have shown promising outcomes in clinical trials of melanoma, lung cancer, and pancreatic cancer, as well as in hematologic malignancies. ICIs are considered to outperform conventional anticancer drugs by maintaining long-lasting anti-cancer effects, with less severe side effects. Several studies reported that ICIs successfully blocked CSC properties in head and neck squamous carcinomas, melanomas, and breast cancer. Together, these findings suggest that novel and effective anticancer therapeutic modalities using ICIs for selective elimination of CSCs may be developed in the near future. In this review, we highlight the origin and characteristics of CSCs, together with critical signaling pathways. We also describe progress in ICI-mediated anticancer treatment to date and present perspectives on the development of CSC-targeting ICIs.
Lee, Hyo Jin;Lee, Ok Sang;Jung, Sun Hoi;Park, Mi Sook;Lim, Sung Cil
Korean Journal of Clinical Pharmacy
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v.23
no.1
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pp.33-41
/
2013
Background: Prevalence of depression comorbid with neurologic disorders such as Alzheimer' disease (AD), Parkinson's disease (PD) and vascular dementia (VD) is higher than that of primary depression. Antidepressant medications, suggested by many researches for depression comorbid with neurologic disorders such as AD, PD and VD, are mainly selective serotonin reuptake inhibitors (SSRI). Objective: The primary objective of this study is the evaluation of antidepressant drug therapy for AD, PD and VD. Method: This study was a retrospective study based on medical records, carried out for 3 years and 6 months (Jan. 2007~Jul. 2010). Patients, diagnosed as comorbid depression through Beck Depression Inventory (BDI), Cornell Depression Scale (CDS), Geriatric Depression Scale (GDS) among neurologic out-patients of Chungnam National University Hospital because of AD, PD and VD, were selected. The results were evaluated by efficacy and safety of antidepressant drug therapy. Results: In result, the prescribing rates of antidepressants were 30%, 55% and 40% for each AD, PD and VD. Depression cure rates of patients receiving antidepressants vs patients not receiving antidepressants were 40% vs 39%, 33% vs 23% and 38% vs 30% for AD, PD and VD. The frequencies of prescriptoin of SSRI were 21%, 11% and 27% for each AD, PD and VD. The frequencies of prescriptoin of benzodiazepine (BZD) was 61%, 82% and 61% for each AD, PD and VD. The ratio of single BZD prescription was more than that of combination prescription of antidepressants. Tricyclic antidepressants (TCA) were rarely prescribed. The rate of patients with BZD-related side effects was 54%. The most frequent side effects of BZD were dizziness (30%), drowsiness (21%) and headache (16%). Side effects of SSRI were rare. Conclusion: In conclusion, the frequencies of prescription of antidepressants were not common for AD, PD and VD. There was little difference in depression cure rate between patient receiving antidepressants and not receiving. Even though SSRI has to be the highest priority of usage, the frequencies of prescription of SSRI were lower than those of BZD. Additional researches and efforts are required to improve antidepressant drug therapy for neurologic disorders such as AD, PD and VD.
Purpose: This study aimed to evaluate the efficacy and safety of neoadjuvant programmed cell death-1 (PD-1) inhibitors plus apatinib and chemotherapy (PAC) in patients with locally advanced gastric cancer (LAGC). Materials and Methods: Seventy-three patients with resectable LAGC were enrolled and named the PAC group (n=39) or apatinib plus chemotherapy (AC) group (n=34) based on the treatment they chose. Neoadjuvant therapy was administered in a 21-day cycle for 3 consecutive cycles, after which surgery was performed. Results: The PAC group exhibited a higher objective response rate than the AC group (74.4% vs. 58.8%, P=0.159). Moreover, the PAC group showed a numerically better response profile than the AC group (P=0.081). Strikingly, progression-free survival (PFS) (P=0.019) and overall survival (OS) (P=0.049) were prolonged, whereas disease-free survival (DFS) tended to be longer in the PAC group than in the AC group (P=0.056). Briefly, the 3-year PFS, DFS, and OS rates were 76.1%, 76.1%, and 86.7% in the PAC group and 46.9%, 49.9%, and 70.3% in the AC group, respectively. Furthermore, PAC (vs. AC) treatment (hazard ratio=0.286, P=0.034) was independently associated with prolonged PFS in multivariate Cox regression analyses. The incidence of adverse events did not differ between the two groups (all P>0.05), where leukopenia, anemia, hypertension, and other adverse events were commonly observed in the PAC group. Conclusions: Neoadjuvant PAC therapy may achieve a preferable pathological response, delayed progression, and prolonged survival compared to AC therapy with a similar safety profile in patients with LAGC; however, further validation is warranted.
Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.
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