Integrated genomics-based approach to identify new therapeutic targets and cancer biomarkers for lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13019-e13019
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Mammalian Cells ◽  
Therapeutic Targets ◽  
Cancer Biomarkers ◽  
Lung Cancer Cells ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Integrated Genomics

e13019 Background: Because the number of lung cancer patients who show good response to standard therapies is still limited, development of new anti-cancer agents with minimum risk of adverse effects and highly sensitive molecular biomarkers is urgently required. Methods: We have been screening novel therapeutic targets and their companion biomarkers for lung cancer as follows; i) To identify up-regulated genes in lung cancers by the gene microarray analysis, ii) To verify the candidate genes for their low expression in normal organs, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering hundreds of lung cancers, and iv) To verify their function for the growth of lung cancer cells by siRNAs. Results: We identified dozens of candidate oncoproteins and selected a serine/threonine kinase LASK2 (lung cancer-associated kinase 2). Immunohistochemical analysis showed that strong LASK2 positivity was an independent prognostic factor for non-small cell lung cancer patients (P < 0.0001). Suppression of LASK2 expression by its siRNAs inhibited proliferation of lung cancer cells. Introduction of LASK2 in mammalian cells also enhanced cellular growth in vitro and in mice model. Induction of LASK2 appeared to increase the levels of phosphorylation of oncogenic signal proteins for lung cancer. The data indicate that LASK2 is a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Integrated genomics-based approach could facilitate the development of new cancer biomarkers as well as therapeutic targets for small molecules, monoclonal antibodies, nucleic acid drugs, and immunotherapies.

Comprehensive cancer genomics-based screening of new therapeutic targets and biomarkers for lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21031-e21031
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Therapeutic Target ◽  
Cancer Genomics ◽  
Cancer Biomarkers ◽  
Lung Cancer Cells ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Target Molecules

e21031 Background: Since the clinical outcome of advanced lung cancer patients is still poor after standard therapies, development of new anti-cancer drugs with minimum risk of adverse effects and cancer biomarkers for precision medicine is urgently required. Methods: We have been screening new therapeutic target molecules and molecular biomarkers for lung cancers as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the target genes for their scarce expression in normal tissues, iii) To validate the clinicopathologic importance of their protein expression by tissue microarray covering 263 lung cancers, and iv) To confirm their function for the growth and/or invasive ability of the lung cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis of lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Comprehensive cancer genomics-based screening could be useful for selection of new cancer biomarkers and molecular targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies.

scholarly journals Long non-coding RNA AFAP1-AS1 accelerates lung cancer cells migration and invasion by interacting with SNIP1 to upregulate c-Myc

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yu Zhong ◽  
Liting Yang ◽  
Fang Xiong ◽  
Yi He ◽  
Yanyan Tang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Lung Cancer Patients ◽  
Lung Cancer Metastasis ◽  
Non Coding Rna ◽  
Long Non Coding Rna

AbstractActin filament associated protein 1 antisense RNA 1 (named AFAP1-AS1) is a long non-coding RNA and overexpressed in many cancers. This study aimed to identify the role and mechanism of AFAP1-AS1 in lung cancer. The AFAP1-AS1 expression was firstly assessed in 187 paraffin-embedded lung cancer and 36 normal lung epithelial tissues by in situ hybridization. The migration and invasion abilities of AFAP1-AS1 were investigated in lung cancer cells. To uncover the molecular mechanism about AFAP1-AS1 function in lung cancer, we screened proteins that interact with AFAP1-AS1 by RNA pull down and the mass spectrometry analyses. AFAP1-AS1 was highly expressed in lung cancer clinical tissues and its expression was positively correlated with lung cancer patients’ poor prognosis. In vivo experiments confirmed that AFAP1-AS1 could promote lung cancer metastasis. AFAP1-AS1 promoted lung cancer cells migration and invasion through interacting with Smad nuclear interacting protein 1 (named SNIP1), which inhibited ubiquitination and degradation of c-Myc protein. Upregulation of c-Myc molecule in turn promoted the expression of ZEB1, ZEB2, and SNAIL gene, which ultimately enhanced epithelial to mesenchymal transition (EMT) and lung cancer metastasis. Understanding the molecular mechanism by which AFAP1-AS1 promotes lung cancer’s migration and invasion may provide novel therapeutic targets for lung cancer patients’ early diagnosis and therapy.

Systematic approach for development of new immunotherapeutics for lung cancers through cancer genomics analysis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3092-3092
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Clinical Studies ◽  
Critical Role ◽  
Phase I Clinical Trials ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
High Immunogenicity

3092 Background: Oncoantigens are defined to be proteins that are very specifically expressed in cancer cells and that have the oncogenic activity and high immunogenicity, and are considered to be promising targets for immunotherapy such as therapeutic cancer vaccines. Methods: We have established a strategy as follows to identify new oncoantigens; i) screening of highly transactivated genes in the majority of 120 lung cancers using cDNA microarray representing 27,648 genes coupled with enrichment of tumor cells by laser microdissection, ii) verification of no expression of each candidate gene in normal tissues by northern-blot analysis, iii) validation of the clinicopathological significance of its high level of expression with tissue microarray containing 300 lung cancers, iv) verification of a critical role of each gene in the growth or invasiveness of cancer cells by RNAi and cell growth/invasion assays, v) screening of the epitope peptides recognized by HLA-A*0201- or A*2402-restricted cytotoxic T lymphocyte (CTL). We conducted phase I clinical trials of these therapeutic peptide vaccines for lung cancer patients. Results: We identified 35 oncoantigens and screened dozens of 10-amino-acid peptides, each of which corresponded to a part of TTK, LY6K, IMP-3, CDCA1, KIF20A, CDC45L, and FOXM1, and was a candidate to be presented on the surface of HLA-A*0201 or HLA-A*2402 that induced in vitro CTL response. Phase I clinical studies indicated that five epitope peptides could strongly induce the CTL activity in cancer patients. For example, we conducted a phase I study for HLA-A*2402-positive, advanced non-small cell lung cancer patients who failed to standard therapy, using the combination of 1, 2 or 3 mg/body of each peptides from LY6K, CDCA1, and KIF20A mixed with adjuvant once a week. This cancer vaccine therapy demonstrated tolerability and had very high immunogenicity of even 1 mg/body dose to induce antigen-specific CTLs in cancer patients. Conclusions: Through systematic genomics-based approach and clinical study, we have identified five epitope peptides, which could induce CTLs very effectively in cancer patients, and therefore it warrants further clinical studies. Clinical trial information: NCT01069575.

scholarly journals Capilliposide C from Lysimachia capillipes Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Kan Wu ◽  
Xueqin Chen ◽  
Jianguo Feng ◽  
Shirong Zhang ◽  
Yasi Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Lung Cancer Cells ◽  
Rna Seq ◽  
Lung Cancer Cell ◽  
Lung Cancer Patients ◽  
Damage Repair

AimsRadiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. Lysimachia capillipes capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms.MethodsNon-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells in vivo.ResultsCompared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both in vitro and in vivo and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients.ConclusionsTreatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.

scholarly journals Therapeutic effects of statins against lung adenocarcinoma via p53 mutant-mediated apoptosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Cheng-Wei Chou ◽  
Ching-Heng Lin ◽  
Tzu-Hung Hsiao ◽  
Chia-Chien Lo ◽  
Chih-Ying Hsieh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Early Stage ◽  
Lung Cancer Cells ◽  
Research Database ◽  
Early Stage Lung Cancer ◽  
Lung Cancer Patients ◽  
Statin Use ◽  
Stage Lung Cancer

AbstractThe p53 gene is an important tumour suppressor gene. Mutant p53 genes account for about half of all lung cancer cases. There is increasing evidence for the anti-tumour effects of statins via inhibition of the mevalonate pathway. We retrospectively investigated the correlation between statin use and lung cancer prognosis using the Taiwanese National Health Insurance Research Database, mainly focusing on early-stage lung cancer. This study reports the protective effects of statin use in early-stage lung cancer patients regardless of chemotherapy. Statin treatments reduced the 5-year mortality (odds ratio, 0.43; P < 0.001) in this population-based study. Significantly higher levels of cellular apoptosis, inhibited cell growth, and regulated lipid raft content were observed in mutant p53 lung cancer cells treated with simvastatin. Further, simvastatin increased the caspase-dependent apoptotic pathway, promotes mutant p53 protein degradation, and decreased motile activity in lung cancer cells with p53 missense mutations. These data suggest that statin use in selected lung cancer patients may have clinical benefits.

Updated Review and Perspective on 20S Proteasome Inhibitors in the Treatment of Lung Cancer

2020 ◽  
Vol 20 (6) ◽  
pp. 392-409
Author(s):  
Sagar O. Rohondia ◽  
Zainab Sabry Othman Ahmed ◽  
Q. Ping Dou
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Chemotherapeutic Agents ◽  
Lung Cancer Cells ◽  
20S Proteasome ◽  
Lung Cancer Patients

: Lung cancer is the leading cause of cancer-related deaths worldwide. Most lung cancer patients are diagnosed at advanced stages and may benefit from pembrolizumab (anti-PD-1 antibody), cytotoxic chemotherapy and other adjuvant therapies. Despite the availability of various therapies, the response and survival rates have been low. Therefore, the study of different targets for the treatment of lung cancer has been one of the major focuses of cancer research. : The ubiquitin proteasome system (UPS) is a crucial regulator of cell homeostasis and plays an essential role in the growth and development of all cells. The UPS is dysregulated in human cancer cells including lung cancer cells. Therefore, targeting UPS is potentially a selective, effective treatment for lung cancer. Bortezomib, a 20S proteasome inhibitor that is clinically approved for the management of multiple myeloma, has been studied in various preclinical and clinical models of lung cancer. : Most preclinical studies have shown that a 20S proteasome inhibitor alone and its combination with other chemotherapeutic agents induce apoptosis in non-small cell lung cancer cell lines and animal models. Owing to the impressive preclinical results, many clinical trials were initiated using 20S proteasome inhibitors either as monotherapy or in combination with other conventional lung cancer therapies. Many combinational therapies of 20S PIs with conventional chemotherapy were shown to be well tolerated in clinical trials. However, there have not been any consistent data showing the beneficial effects of such proteasome inhibitor-based therapies. Low clinical efficacy of 20S PIs in lung cancer patients may be due to low drug penetration, the status of 20S proteasomes, oncogene expressions and the inherited or acquired resistance. Potential mechanisms of PI resistance or low or no clinical activity in lung cancer cells might include alteration of apoptotic proteins, overexpression or alteration of β5 subunit, or upregulation of heat shock proteins. Various cutting-edge strategies to counter this resistance or improve 20S PIs’ efficacy in lung cancer cells have been reviewed which include novel combination therapies, new drug delivery systems, development of more potent PIs, and targeting different sites of the UPS. A better understanding of PI resistance mechanisms in lung cancer cells can help improve current clinical treatment strategies and clinical outcomes.

Integrated genomics-based discovery of new druggable kinases as a therapeutic target and cancer biomarker for lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23144-e23144
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Genomics ◽  
False Positive Rate ◽  
Cellular Growth ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Nsclc Patients

e23144 Background: Since the number of lung cancer patients responding well to current standard therapies is still small, further development of new anti-cancer agents with minimum risk of adverse effect and highly sensitive cancer biomarkers is eagerly awaited. Methods: We have been developing new molecular therapies targeting oncoproteins with their biomarkers; i) To identify up-regulated genes in 120 lung cancers by the gene expression microarray representing 27,648 genes, ii) To verify the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 407 non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNA and antibody assays, and v) To measure their serum protein levels by ELISA in 343 lung cancer patients. Results: We identified 50 druggable oncoproteins and selected a LSERT (lung cancer-specific receptor tyrosine kinase). Strong LSERT protein expression was associated with poor prognosis for NSCLC patients (P < 0.0001; N = 407) as confirmed by multivariate analysis. We established an ELISA to measure serum LSERT (a cleaved form of its extracellular domain) and found that the proportion of serum LSERT-positive cases was 149 (56.4%) of 264 NSCLC and 35 (44.3%) of 79 SCLC patients, while only 6 (4.7%) of 127 healthy volunteers were falsely diagnosed. A combined ELISA for both LSERT and CEA classified 77.2% of the NSCLC patients as positive, and the use of both LSERT and ProGRP increased sensitivity in the detection of SCLCs up to 77.5%, while the false positive rate was 7 - 8%. Oncogenic LSERT activity was suppressed by treatment of lung cancer cells with anti-LSERT antibody or siRNA. Induction of LSERT increased the cellular growth and invasion by directly phosphorylating oncogenic driver kinase proteins for lung cancer and enhancing their downstream signaling of MAPK, AKT, and STAT3. Conclusions: Integrated cancer genomics might facilitate the development of diagnostic and prognostic biomarkers as well as therapeutic targets for small molecules, monoclonal antibodies, nucleic acid drugs, and cancer vaccines.

scholarly journals NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

2016 ◽  
Vol 113 (18) ◽  
pp. E2526-E2535 ◽  
Author(s):  
Ching-Feng Chiu ◽  
Yi-Wen Chang ◽  
Kuang-Tai Kuo ◽  
Yu-Shiuan Shen ◽  
Chien-Ying Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Egfr Mutation ◽  
Lung Cancer Cells ◽  
Cancer Stemness ◽  
Lung Cancer Patients ◽  
Gefitinib Resistance ◽  
Egfr Tki ◽  
Egfr Tkis

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3′UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

scholarly journals Cyclovirobuxine D Induced-Mitophagy through the p65/BNIP3/LC3 Axis Potentiates Its Apoptosis-Inducing Effects in Lung Cancer Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5820
Author(s):  
Cheng Zeng ◽  
Tingting Zou ◽  
Junyan Qu ◽  
Xu Chen ◽  
Suping Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Transcriptional Repression ◽  
Therapeutic Strategy ◽  
Ectopic Expression ◽  
Lung Cancer Cells ◽  
Lung Cancer Patients ◽  
Cellular Context ◽  
Subcutaneous Xenograft ◽  
Buxus Microphylla

Mitophagy plays a pro-survival or pro-death role that is cellular-context- and stress-condition-dependent. In this study, we revealed that cyclovirobuxine D (CVB-D), a natural compound derived from Buxus microphylla, was able to provoke mitophagy in lung cancer cells. CVB-D-induced mitophagy potentiates apoptosis by promoting mitochondrial dysfunction. Mechanistically, CVB-D initiates mitophagy by enhancing the expression of the mitophagy receptor BNIP3 and strengthening its interaction with LC3 to provoke mitophagy. Our results further showed that p65, a transcriptional suppressor of BNIP3, is downregulated upon CVB-D treatment. The ectopic expression of p65 inhibits BNIP3 expression, while its knockdown significantly abolishes its transcriptional repression on BNIP3 upon CVB-D treatment. Importantly, nude mice bearing subcutaneous xenograft tumors presented retarded growth upon CVB-D treatment. Overall, we demonstrated that CVB-D treatment can provoke mitophagy and further revealed that the p65/BNIP3/LC3 axis is one potential mechanism involved in CVB-D-induced mitophagy in lung cancer cells, thus providing an effective antitumor therapeutic strategy for the treatment of lung cancer patients

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