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Clinical Targeted Next-Generation Sequencing Panels for Detection of Somatic Variants in Gliomas
신혜미,Jason K. Sa,배준설,구하림,진선휘,조희진,최승원,경종민,김자연,서윤지,정제균,Nayoung K.D. Kim,손대순,정종석,이태섭,공두식,최정원,설호준,이정일,서연림,박웅양,남도현 대한암학회 2020 Cancer Research and Treatment Vol.52 No.1
Purpose Targeted next-generation sequencing (NGS) panels for solid tumors have been useful in clinical framework for accurate tumor diagnosis and identifying essential molecular aberrations. However, most cancer panels have been designed to address a wide spectrum of pan-cancer models, lacking integral prognostic markers that are highly specific to gliomas. Materials and Methods To address such challenges, we have developed a glioma-specific NGS panel, termed “GliomaSCAN,” that is capable of capturing single nucleotide variations and insertion/deletion, copy number variation, and selected promoter mutations and structural variations that cover a subset of intron regions in 232 essential glioma-associated genes. We confirmed clinical concordance rate using pairwise comparison of the identified variants from whole exome sequencing (WES), immunohistochemical analysis, and fluorescence in situ hybridization. Results Our panel demonstrated high sensitivity in detecting potential genomic variants that were present in the standard materials. To ensure the accuracy of our targeted sequencing panel, we compared our targeted panel to WES. The comparison results demonstrated a high correlation. Furthermore, we evaluated clinical utility of our panel in 46 glioma patients to assess the detection capacity of potential actionable mutations. Thirty-two patients harbored at least one recurrent somatic mutation in clinically actionable gene. Conclusion We have established a glioma-specific cancer panel. GliomaSCAN highly excelled in capturing somatic variations in terms of both sensitivity and specificity and provided potential clinical implication in facilitating genome-based clinical trials. Our results could provide conceptual advance towards improving the response of genomically guided molecularly targeted therapy in glioma patients.
Spatiotemporal genomic architecture informs precision oncology in glioblastoma
Lee, Jin-Ku,Wang, Jiguang,Sa, Jason K,Ladewig, Erik,Lee, Hae-Ock,Lee, In-Hee,Kang, Hyun Ju,Rosenbloom, Daniel S,Camara, Pablo G,Liu, Zhaoqi,van Nieuwenhuizen, Patrick,Jung, Sang Won,Choi, Seung Won,Ki Nature Pub. Co 2017 Nature genetics Vol.49 No.4
<P>Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies1-5. However, this proposition is complicated by spatial and temporal heterogeneity6-14. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones. Chemical screening of patient-derived glioma cells (PDCs) shows that therapeutic response is associated with genetic similarity, and multifocal tumors that are enriched with PIK3CA mutations have a heterogeneous drug-response pattern. We show that targeting truncal events is more efficacious than targeting private events in reducing the tumor burden. In summary, this work demonstrates that evolutionary inference from integrated genomic analysis in multisector biopsies can inform targeted therapeutic interventions for patients with GBM.</P>
Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy
Lee, Jin-Ku,Liu, Zhaoqi,Sa, Jason K.,Shin, Sang,Wang, Jiguang,Bordyuh, Mykola,Cho, Hee Jin,Elliott, Oliver,Chu, Timothy,Choi, Seung Won,Rosenbloom, Daniel I. S.,Lee, In-Hee,Shin, Yong Jae,Kang, Hyun J Nature Pub. Co 2018 Nature genetics Vol.50 No.10
Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain
Park, Hyunkyu,Kim, Donggeon,Kim, Eunmi,Sa, Jason K.,Lee, Hee Won,Yu, Suji,Oh, Jiwon,Kim, Seok-Hyung,Yoon, Yeup,Nam, Do-Hyun MDPI AG 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.9
<P>Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth.</P>
A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma
Barnes, J. Matthew,Kaushik, Shelly,Bainer, Russell O.,Sa, Jason K.,Woods, Elliot C.,Kai, FuiBoon,Przybyla, Laralynne,Lee, Mijeong,Lee, Hye Won,Tung, Jason C.,Maller, Ori,Barrett, Alexander S.,Lu, Kan Nature Publishing Group 2018 Nature cell biology Vol.20 No.10
Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress Glioblastoma Tumor Growth
Lee, Jaehyun,Shin, Yong Jae,Lee, Kyoungmin,Cho, Hee Jin,Sa, Jason K.,Lee, Sang-Yun,Kim, Seok-Hyung,Lee, Jeongwu,Yoon, Yeup,Nam, Do-Hyun 대한암학회 2018 Cancer Research and Treatment Vol.50 No.3
<P><B>Purpose</B></P><P>Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression.</P><P><B>Materials and Methods</B></P><P>We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze <I>SEMA3A</I> mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody <I>in vivo</I>.</P><P><B>Results</B></P><P>By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line <I>in vitro</I>. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment.</P><P><B>Conclusion</B></P><P>In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.</P>
Park, Hyunkyu,Kim, Donggeon,Son, Eunju,Shin, Sunhwa,Sa, Jason K.,Kim, Seok-Hyung,Yoon, Yeup,Nam, Do-Hyun Elsevier 2017 Biochemical and biophysical research communication Vol.494 No.1
<P><B>Abstract</B></P> <P>The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c-Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong <I>in vivo</I> antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. <I>Ex vivo</I> fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We developed a novel human and mouse cross-reactive antibody, IRCR201. </LI> <LI> IRCR201 inhibits HGF/c-Met pathway through c-Met degradation. </LI> <LI> IRCR201 interferes with crosstalk between c-Met and other RTKs. </LI> <LI> IRCR201 is highly tumor-specific and has a stable pharmacokinetic profile. </LI> <LI> IRCR201 provides exceptional anti-tumoral activity in a GBM xenograft model. </LI> </UL> </P>
Yin, Jinlong,Oh, Young Taek,Kim, Jeong-Yub,Kim, Sung Soo,Choi, Eunji,Kim, Tae Hoon,Hong, Jun Hee,Chang, Nakho,Cho, Hee Jin,Sa, Jason K.,Kim, Jeong Cheol,Kwon, Hyung Joon,Park, Saewhan,Lin, Weiwei,Naka American Association for Cancer Research 2017 Cancer research Vol.77 No.18
<P>Inhibition of a cellular enzyme that blocks the conversion from nonmesenchymal to mesenchymal forms of glioblastoma may prevent recurrence and resistance to radiation therapy, the latter of which continues to pose a major clinical challenge.</P><P>Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. <I>Cancer Res; 77(18); 4973–84. ©2017 AACR</I>.</P>