bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3044: The novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling
Authors: park kyu jin , Jeon Eun-Ju , Choi Ji-Hye , Lee Kwan-Woo , Lee Kyung-Woo , Park Gun-Woo , Hong Hae-Jin , Hwang In-Chang , Moon Seung-Kee , Koh Yeo-Wook 
Published: September 2020

Abstract
Development of drug resistance is one of the main causes of poor prognosis and therapeutic failure in NSCLC. Mutual synergism between cMET and EGFR is known to promote acquired drug resistance. In NSCLC, cMET gene amplification is reported in 2-4% previously untreated patients and in 5-20% of patients with EGFR mutation and acquired resistance to EGFR TKIs. Because of this crosstalk between cMET and EGFR pathways, dual inhibition of these targets holds promise as a treatment for NSCLC patients, especially those with acquired cMET activation.
CKD-702 is a bispecific antibody designed to dually target cMET and EGFR. It is tetravalent IgG1-like bispecific antibody, in which single-chain variable fragment specific to EGFR is genetically fused to the c-terminus of a conventional IgG1 of a cMET. The antibody binds to extracellular domains of cMET and EGFR with high affinity and inhibits signaling by blocking ligand binding. CKD-702 also induces internalization and degradation of both receptors.
There are various types of cMET activation in NSCLC patients, including point mutations and amplification. An emerging aberrant cMET activation is through a splice site mutation of cMET that leads to skipping of exon 14, inducing prolonged signaling and oncogenic activity. In this study, we carried out genetic analysis of cMET activation in cancer cell line as well as PDX model with or without EGFR mutation, and the efficacy of CKD-702 in each model for NSCLC was determined. CKD-702 showed complete tumor regression as monotherapy in tumor models that have primary/secondary activating EGFR mutations and cMET amplification. Also, CKD-702 resulted in complete tumor regression in models where cMET is activated by either skipping of exon 14 or amplification. Interestingly, unlike other previously developed EGFR-targeting agents, CKD-702 showed limited skin rash in GLP toxicity study.
In summary, CKD-702 is confirmed to inhibit tumors with activated cMET pathway such as cMET amplification and exon 14 skipping as well as with EGFR-activating mutations. This profile of preclinical data supports the clinical trial of CKD-702 as monotherapy in selected lung cancer patients with aberrant cMET and EGFR signaling.
A Phase I study of CKD-702 is planned to initiate in 2020.
Citation Format: kyu jin park, Eun-Ju Jeon, Ji-Hye Choi, Kwan-Woo Lee, Kyung-Woo Lee, Gun-Woo Park, Hae-Jin Hong, In-Chang Hwang, Seung-Kee Moon, Yeo-Wook Koh. The novel bi-specific antibody CKD-702 is a potential agent for NSCLC patients with aberrant cMET and EGFR signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3044.
Abstract 3052: Targeting AXL in PIK3R2-amplified ovarian cancer
Authors: Rao Ling , Mak Victor C. , Zhou Yuan , Zhang Dong , Li Xinran , Lu Yiling , Mills Gordon B. , Cheung Lydia W. 
Published: September 2020

Abstract
The p85 regulatory subunit and its associated p110 catalytic subunit are components of the class IA PI3K that mediates the downstream signal of receptor tyrosine kinases. PIK3R2 (encoding p85β, one of the p85 isoforms) is commonly amplified in ovarian cancer patients. Importantly, high PIK3R2 expression significantly correlated with worse patient survival. Here, we showed that p85β promoted tumorigenic properties of ovarian cancer cells. The protein expression of a receptor tyrosine kinase AXL was positively regulated by p85β. AXL is a member of the TAM receptor family. The regulation was specific to AXL because the other two members (Tyro3 and MERTK) were not altered by p85β. Drug sensitivity assays suggested that inhibition of AXL reduced oncogenic activities of p85β in vitro and in vivo. Together, we propose p85β as a potential therapeutic target in ovarian cancer and therapeutic blockade of AXL signaling may be an effective strategy for ovarian cancer with PIK3R2 amplification.
Citation Format: Ling Rao, Victor C. Mak, Yuan Zhou, Dong Zhang, Xinran Li, Yiling Lu, Gordon B. Mills, Lydia W. Cheung. Targeting AXL in PIK3R2-amplified ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3052.
Abstract 3054: Targeting TGF-β signaling for obesity/insulin resistance-associated hepatocellular carcinoma
Authors: Chen Jian , Su Xiaoping , Rojas Andres , Bresalier Robert S , Stroehlein John R. , Yeung Sai-ching 
Published: September 2020

Abstract
Background: Recently, obesity, insulin resistance/type 2 diabetes mellitus and fatty liver disease, i.e., key components of the metabolic syndrome, have been recognized as risk factors for hepatocellular carcinoma (HCC). Obesity and dysmetabolism serve as drivers of oncogenesis in the setting of abnormal hepatic morphology and physiology, and hepatic steatosis may provide the promoting microenvironment for the development of HCC. Dysregulated signaling in the transforming growth factor (TGF)-β pathway plays a central role in immunomodulation, inflammation, and fibrogenesis in the HCC microenvironment. We used a carcinogen Diethylnitrosamine (DEN)-induced HCC mouse model in genetically obese mice [heterozygous Agouti yellow (Ay/a)] and haplo-knock out of Smad3 (a kinase downstream of type II receptor for TGFβ to study the detailed mechanism by which Smad3-dependent TGF-β signaling regulates obesity-associated dysmetabolism in HCC, and to determine whether inhibition of TGF-β signaling could inhibit obesity-associated HCC.
Methods: Ay/a mice in C57B/L genetic background were bred with Smad3 knockout mouse (Smad3+/−). Obese and insulin-resistant Ay/a mice were treated with DEN (i.p. 25mg/kg) at 14 days of age to induce HCC. Ay/a mice and DEN-induce HCC mice were treated with TGF-β receptor 2 inhibitor (EW7919, 20 mg/kg orally 3 times/week for 8 weeks). We performed RNA sequencing analysis for 40 mouse liver samples from the groups of mice above.
Results: 1. Haplodeficiency of Smad3 significantly decreased obesity Ay/a mouse weight and suppressed fatty liver development. 2. Treatment of TGF-β receptor 2 inhibitor to Ay mice successfully blocked weight gain in Ay/a mice. 3. DEN-induced hepatocarcinogenesis in Ay/a mice occurred significantly earlier than in lean (a/a) C57B/L mice. 4. Inhibition of TGF-β signaling by Smad3 haplodeficiency significantly upregulated lipid catabolic processes and downregulated cytokine-induce leukocyte migration in the fatty livers of Ay/a mice. 5. Inhibition of TGF-β signaling by genetic or pharmacologic inhibitors significantly suppressed HCC development in Ay/a mice.
Conclusion: We demonstrated a specific cancer promoting role of TGF-β in metabolic reprogramming in liver cancer cells, highlighting the TGF-β signaling pathway as a potential therapeutic target in obesity/insulin resistance-associated HCC.
Citation Format: Jian Chen, Xiaoping Su, Andres Rojas, Robert S Bresalier, John R. Stroehlein, Sai-ching Yeung. Targeting TGF-β signaling for obesity/insulin resistance-associated hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3054.
Abstract 3068: The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer
Authors: Noro Rintaro , Omori Miwako , Fukuizumi Aya , Matsuda kuniko , Hirao Mariko , Takahashi Satoshi , Takano Natsuki , Nakamichi Shinji , Sugano Teppei , Miyanaga Akihiko , Minegishi Yuji , Seike Masahiro , Kubota Kaoru , Gemma Akihiko 
Published: September 2020

Abstract
Small cell lung cancer (SCLC) is a highly aggressive disease with median survival of &lt;2 years. Most patients respond initially to the topoisomerase inhibitors, resistance rapidly emerges. The purpose is overcoming the resistance of the topoisomerase inhibitors in SCLCs. To identify the key factors for the resistance of the topoisomerase I (SN38) or II (VP-16) inhibitors in SCLCs, we analyzed MTS cell proliferation assay. We identified 8 sensitive cell lines and 2 resistant cell lines. We established 4 resistant cell lines by continuous exposure to increasing concentrations of SN-38 or VP-16 stepwise.
RNA sequencing was performed using the established cell lines to discover novel therapeutic targets associated with the resistance to topoisomerase inhibitors. We found that whenever the drug efflux protein ATP-binding cassette transporter B1 (ABCB1) was associated the with resistance of VP-16, ATP-binding cassette super-family G member 2 (ABCG2) was associated with the resistance of SN-38. The silencing of ABCG2 or ABCB1 in every resistant cell line, could induce synergistic apoptosis of every cell line. Elacridar and tariquidar which are glycoprotein inhibitors, recovered the sensitivity of SN38 or VP-16 in every resistant line, increased expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and promoted G2/M arrest and apoptosis. Furthermore, we are going to analyze the expressions of ABCG2 and ABCB1 in serum before and after the treatment of VP-16 or CPT-11. These results suggested the glycoprotein inhibitors, which phase I study is ongoing, could be a promising therapeutic strategy for the purpose of preventing the resistance of topoisomerase inhibitors in SCLCs.
Citation Format: Rintaro Noro, Miwako Omori, Aya Fukuizumi, kuniko Matsuda, Mariko Hirao, Satoshi Takahashi, Natsuki Takano, Shinji Nakamichi, Teppei Sugano, Akihiko Miyanaga, Yuji Minegishi, Masahiro Seike, Kaoru Kubota, Akihiko Gemma. The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3068.
Abstract 307: KSR1-dependent modulation of the translational landscape in Ras-driven colorectal cancer
Authors: Vieira Heidi , Rao Chaitra , Black Adrian R. , Southekal Siddesh , Mizutani Tomohiro , Guda Babu , Clevers Hans , Black Jennifer D. , Lewis Robert E. 
Published: September 2020

Abstract
KRAS is mutated and activated in an estimated 40% of colon cancers but has proven difficult to target directly due to the lack of drug-binding pockets on the surface of Ras. Thus, identifying effectors that transmit signals from oncogenic Ras is a critical step in targeting vulnerabilities in the tumors of patients with colorectal cancer (CRC). Kinase Suppressor of Ras 1 (KSR1) is a molecular scaffold that coordinates the interaction of effectors in the Raf/MEK/ERK signaling cascade downstream of Ras. KSR1 is necessary for oncogenic transformation of cells expressing mutated Ras but is dispensable for normal cell growth making KSR1 an attractive therapeutic target for Ras-driven colon cancers. In CRC cells, KSR1 and ERK mediate Ras-dependent effects on protein translation, notably driving cap-dependent and cap-independent translation of the Myc oncogene. Depletion of KSR1 or treatment with ERK inhibitor (SCH772984) leads to a decrease in phophorylated 4EBP1 and a decrease in PDCD4, which collectively impair protein translation, notably leading to a decrease in Myc translation. Patient-derived CRC organoids with deletion of APC, p53, and SMAD4, and an activating G12D mutation in KRAS treated with ERK inhibitor show a marked decrease in Myc protein expression, coincident with changes in PDCD4 and 4EBP1 that impair protein translation. These observations indicate that the KSR1-dependent ERK activation observed in CRC cell lines is present in pre-clinical colon tumoroid models. Genome-wide polysome profiling in CRC cell lines HCT116 and HCT15 depleted of KSR1 identified mRNAs that were preferentially translated in a KSR1 and ERK-dependent manner. Several of these mRNAs were previously predicted by our Functional Signature Ontology (FUSION) screen to be critical to CRC viability but dispensable for normal cell growth. GSEA identified functional classes of mRNAs whose translation is KSR1-dependent, including mediators of oncogenic signaling in pathways that regulate mTOR, MAPK, WNT and JAK-STAT. Our data suggest that an essential component of oncogenic Ras-induced and KSR1-dependent signaling is the preferential translation of mRNAs supporting the transformed phenotype of CRC cells.
Citation Format: Heidi Vieira, Chaitra Rao, Adrian R. Black, Siddesh Southekal, Tomohiro Mizutani, Babu Guda, Hans Clevers, Jennifer D. Black, Robert E. Lewis. KSR1-dependent modulation of the translational landscape in Ras-driven colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 307.
Abstract 3083: Selective inhibition of transcription factor BRN2 as a treatment strategy for Small Cell Prostate Cancer
Authors: Thaper Daksh , Munuganti Ravi , Aguda Adeleke , Kim Soojin , Ku Shungyu , Kumar Sahil , Vahid Sepideh , Nouruzi Shaghayegh , Sivak Olena , Ganguli Dwaiyapan , Morrissey Colm , Corey Eva , Beltran Himisha , Zoubeidi Amina 
Published: September 2020

Abstract
Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges. In particular, a subset of patients who relapse following ARPI therapy their dependence on AR signaling and emerge with neuroendocrine features. These tumors, termed treatment induced small-cell prostate cancer (t-SCPC) or neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapies. Previously, our group identified the neural transcription factor BRN2 as a major clinically relevant driver of SCPC and now report that targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC.Methods/Results: In silico screening of small molecules was conducted on a model of BRN2 which was later validated with the first-in-field crystal structure of BRN2 DNA binding domain. On the basis of the model, several small molecules were identified that showed direct binding to BRN2 and inhibited its activity. Pharmacokinetic studies measured stability and bioavailability of med-chem optimized lead compound (BRN2i) that significantly reduced tumor growth in multiple xenograft models with no measurable side-effects. In silico modeling predicted a 7Å “closing” in the DBD once it was bound to BRN2i, this shift translated to reduced interaction with DNA by chromatin fractionation and ChIP-seq, thus confirming the mode of action for BRN2i is through loss of DNA binding. Loss of BRN2 binding reduced cell proliferation in tSCPC cell line 42DENZR, de novo SCPC cell line NCI-H660 and NEPC organoids as well as downregulated several known targets like EZH2, ASCL1, SOX2 and PEG10. Down-regulation of these target genes was also measured in the xenograft tumors, confirming on target effect in vivo. Moreover, the specificity of BRN2i was validated with CRISPR/Cas9 mediated knockout of BRN2 with downstream mRNA expression and phenotypic changes. Conclusion: The described work aims to lay the pre-clinical foundation for the integration of BRN2 targeted therapies into the treatment landscape to improve survival for patients suffering from small-cell neuroendocrine prostate cancer.
Citation Format: Daksh Thaper, Ravi Munuganti, Adeleke Aguda, Soojin Kim, Shungyu Ku, Sahil Kumar, Sepideh Vahid, Shaghayegh Nouruzi, Olena Sivak, Dwaiyapan Ganguli, Colm Morrissey, Eva Corey, Himisha Beltran, Amina Zoubeidi. Selective inhibition of transcription factor BRN2 as a treatment strategy for Small Cell Prostate Cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3083.
Abstract 3098: Urine-based molecular biomarker signatures for bladder cancer
Authors: Zhao Zhixin , Chang Amy , Xiang Binggang , Xie Feng , Wang Xiaohong , Zhou Kemin , Yu Jianjun , Du Pan , Jia Shidong 
Published: September 2020

Abstract
Introduction: By 2020 the estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. The tremendous success in cell-free DNA (cfDNA) blood test provides a strong rationale for using body fluids such as blood and urine as minimally invasive “liquid biopsies” to identify DNA-based molecular biomarkers in urologic malignancies. Urinary cfDNA as a liquid biopsy holds greater potential for a more sensitive alternative to blood biopsies-based tests for clinical use in GU cancers. Urinary biomarker test offers advantages including the potential for more convenient testing, monitoring, and home use.
Methods: Analytic validation was conducted using urine cfDNA samples containing different SNPs with different titrations. Urine samples were collected from two different groups, including treatment-naïve patients with pathology-confirmed bladder cancer (BLCA) and healthy donors. Both tumor and germline tissues were collected from the BLCA patients.
Results: We report the development, validation, and clinical application of the urine-based next-generation sequencing for integrated genomic cfDNA profiling of bladder cancers, including genomic alterations, tumor mutation burden (TMB) and microsatellite instability (MSI). The analytic sensitivity goes down to 0.5% with 100% analytical specificity. High concordance for mutations between tumor tissue and urinary cfDNA suggests a higher sensitivity alternative for the non-invasive early detection of BLCA. In addition to the NGS-based test, we also developed a Bio-Rad digital PCR assay for orthogonal confirmation of the detected biomarkers such as FGFR3 hotspot mutations.
Conclusions: Our work has demonstrated the promise of using urinary cfDNA for detecting genomic alterations at the early stage of BLCA for biomarker detections.
Citation Format: Zhixin Zhao, Amy Chang, Binggang Xiang, Feng Xie, Xiaohong Wang, Kemin Zhou, Jianjun Yu, Pan Du, Shidong Jia. Urine-based molecular biomarker signatures for bladder cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3098.
Abstract 3099: Ultra-deep next-generation sequencing of selected single genes for detecting circulating tumor DNA in lung cancer patients
Authors: Ottestad Anine Larsen , Emdal Elisabeth F. , Wahl Sissel G. , Grønberg Bjørn Henning , Dai Hong Yan 
Published: September 2020

Abstract
Purpose
Circulating tumor DNA (ctDNA) can potentially be used to monitor cancer treatment response. In this study, we developed and used a sensitive and selective ultra-deep next-generation sequencing (NGS) approach for detection of ctDNA in lung cancer patients.
Method
Most studies use fixed gene panels for detection of ctDNA by NGS. Deep sequencing of large target regions is expensive and generates a myriad of variants, which are difficult to interpret. For the purpose of using ctDNA for monitoring, we try to overcome these challenges by sequencing only selected regions where mutations were previously found in the tumor. This method is more sensitive and cost-efficient.
In this study, we included about 80 lung cancer patients. Tumor DNA was sequenced with a large gene panel and somatic mutations were identified in each tumor. We then defined the target region according to the tumor mutations and selected primers for constructing NGS libraries. Since the coverage region is small it enables ultra-deep sequencing of several samples simultaneously.
We evaluated the lower limit of detection for this method by sequencing a series of artificially constructed samples with known mutant allele frequencies (MAFs). DNA from peripheral blood leucocytes was sequenced in parallel with plasma DNA to exclude variants from clonal hematopoiesis.
Preliminary results
Using 40 ng as input DNA, which contains approximately 12,000 haploid genomes, we detected mutations down to 0.02% MAF. This corresponds to about 6 mutated copies per mL plasma. Currently, we are applying this method on patient plasma DNA samples.
Conclusion
We have developed a sensitive method for ctDNA detection, and we will present the results of the lung cancer patient samples.
Citation Format: Anine Larsen Ottestad, Elisabeth F. Emdal, Sissel G. Wahl, Bjørn Henning Grønberg, Hong Yan Dai. Ultra-deep next-generation sequencing of selected single genes for detecting circulating tumor DNA in lung cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3099.
Abstract 3108: Combined cfDNA and cfRNA NGS testing for cancer patient care
Authors: Huang Yong , Zhang Yue , Xiang Binggang , Zhao Zhixin , Wang Xiaohong , Xie Feng , Moktari Reza , Zhou Kemin , Du Pan , Jia Shidong , Yu Jianjun 
Published: September 2020

Abstract
Background: NGS based liquid biopsy has its unique advantage in cancer patient care/monitoring as it allows repeated testing of a spectrum of target sites at multiple time points. However, cfDNA assays usually can only cover focused genomic regions. In order to monitor dynamic fusion and alternative splicing variants, we developed and validated a cfRNA assay which can be used in combination with cfDNA assays to get clear snapshots of mutation landscapes in cancer patients. Here we introduce our application of the combined cfDNA and cfRNA approach to cancer patient care.
Method: A single tube of blood is taken from cancer patients, which is used to extract both cfDNA and cfRNA. Predicine proprietary cfDNA and cfRNA NGS assays and analysis pipelines are used to detect SNV/INDEL, CNV as well as fusion and alternative RNA splicing variants from cancer samples, collected at multiple time points from patients during or after treatment.
Results: The cfDNA+cfRNA combined approach allows the cross-validation of results from both methods, which greatly elevated the confidence level of our testing results. For example, a case in which EML4-ALK fusion was detected at cfDNA level but only with fairly low allele frequency was confidently confirmed, as EML4-ALK fusion was also detected at cfRNA level. On the other hand, the cfDNA+cfRNA combined approach allows us to study the broad mutation landscape from both cfDNA and cfRNA levels. For example, for a cohort of prostate samples, the changes of AR alternative splicing forms and the cfDNA mutation landscape can be observed from the same tube of blood samples. In general, the cfDNA+cfRNA combined approach provides a more complete molecular biomarker profiles and extract more information that can be used to instruct cancer patient care.
Citation Format: Yong Huang, Yue Zhang, Binggang Xiang, Zhixin Zhao, Xiaohong Wang, Feng Xie, Reza Moktari, Kemin Zhou, Pan Du, Shidong Jia, Jianjun Yu. Combined cfDNA and cfRNA NGS testing for cancer patient care [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3108.