bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A010: Development of OVA-expressing immunogenic syngeneic mouse tumor models: CT26-OVA and B16-OVA
Authors: Jin Ying , Wang Phillip Shuzong , Li Zhongliang , An Annie Xiaoyu , Zhou Jiahua , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: March 2020

Abstract
Background: Syngeneic homograft mouse tumor models have been the workhorse for investigating immuno-oncology (I/O) therapeutics. However, there are limited number of such models available, and among them, only a few respond to immune checkpoint inhibitors (ICI). One potential reason for the ICI-insensitivity may be their intrinsic low-/non-immunogenicity. Chicken ovalbumin (OVA) is a protein known to be highly immunogenic, and engineered syngeneic cell line expressing OVA could potentially render the cell more immunogenic, thus providing further tools for I/O research. To this end, we developed immunogenic variants of both colon cancer CT26.WT and melanoma B16-F10 syngeneic tumors by introducing the OVA transgene. Method: CT26.WT and B16-F10 cells were transduced by lentiviral vector (pLVX-EF1a-IRES-PURO) with a chicken ovalbumin coding cDNA and selected in culture in the presence of the antibiotic puromycin. OVA expression was confirmed by Western blotting analysis and the cells denoted as CT26-OVA and B16-OVA. The engineered cells were evaluated for tumorigenicity following subcutaneous (SC) implantation in immune competent mice and for in vivo/in vitro response to anti-PD-1 treatment. Mice bearing CT26-OVA and B16-OVA tumors were treated with anti-PD-1 antibodies (10mg/kg) or vehicle (intraperitoneally (IP) twice weekly for 3 weeks). Tumors were collected at termination and subjected to flow analysis for the frequency of total tumor-infiltrating CD8+T cells and H-2Kb-restricted OVA tetramer (SIINFEKL)-positive cells. Results: OVA-expressing models showed slower SC tumor growth compared to the parental lines, which was probably due to immune-mediated rejection. Both B16-OVA and CT26-OVA produced a higher sensitivity to anti-PD-1 treatment, superior to corresponding untransduced parental models. In addition, adoptive T cell transfer was conducted by isolating CD3+ T cells from the cured mice and subsequent inoculation into recipient mice in order to verify the presence of tumor-specific memory T cells. Conclusion: Our preliminary results indicate that CT26.WT and B16-F10 OVA-expressing engineered syngeneic models had a higher immunogenic profile, which resulted in enhanced response to ICI, thus providing additional models for I/O research.
Citation Format: Ying Jin, Phillip Shuzong Wang, Zhongliang Li, Annie Xiaoyu An, Jiahua Zhou, Henry Qixiang Li, Davy Xuesong Ouyang. Development of OVA-expressing immunogenic syngeneic mouse tumor models: CT26-OVA and B16-OVA [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A010. doi:10.1158/1535-7163.TARG-19-A010
Abstract A020: 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one from Betula platyphylla impairs autophagy and induces apoptosis in lung cancer cells
Authors: Jung Hyun Jin , Kang Ju-Hee , Oh Seung Hyun 
Published: March 2020

Abstract
Aim of the Study: Betula platyphylla (BP) is a representative medicinal herb used in the treatment of various inflammatory diseases in East Asia. The purpose of this study was to identify the active components of BP extracts and examine the cytotoxic effect of constituents through specific biological mechanisms that regulate the chemotherapeutic activity in lung cancer cells. Materials and Methods: We performed MTT assays, colony formation assays, flow cytometry assays, western blot analysis, and used fluorescence microscopy after transfection with plasmids to study the molecular mechanisms and chemotherapeutic effects of BP extracts and its active components. Results: We observed that BP extracts and 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one (BE1), one of the components of BP, effectively decreased the cell viability of several lung cancer cell lines. BE1-treated cells exhibited apoptosis induction and cell cycle arrest at the G2/M phase. Further examination demonstrated that BE1 treatment resulted in suppression of autophagy, as evidenced by increased protein expression levels of both LC3 II and p62/SQSTM1. Interestingly, the pharmacological induction of autophagy with rapamycin remarkably reduced the BE1-induced apoptosis, indicating that apoptosis induced by BE1 was associated with autophagy inhibition. Our data also demonstrated that BE1 exposure activated the p38 pathway resulting in regulation of the pro-apoptotic activity. Conclusion: Taken together, we believe that BE1 is a potential anticancer agent for human lung cancer, which exerts its effect by enhancing apoptosis via regulating autophagy and the p38 pathway.
Citation Format: Hyun Jin Jung, Ju-Hee Kang, Seung Hyun Oh. 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one from Betula platyphylla impairs autophagy and induces apoptosis in lung cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A020. doi:10.1158/1535-7163.TARG-19-A020
Abstract A046: Pre-clinical assessment of neratinib sensitivity and biomarkers of response
Authors: Conlon Neil T , Kooijman Jeffrey J , Zaman Guido JR , Diala Irmina , Lalani Alshad , Crown John , Collins Denis M 
Published: March 2020

Abstract
Introduction: Neratinib is an irreversible pan-HER inhibitor that has shown clinical activity against HER2-amplified (HER2+) and HER2-mutated cancers. Alteration in HER2 is currently the only biomarker of sensitivity to neratinib. To examine other potential biomarkers of sensitivity, we evaluated neratinib as a single agent in a panel of 108 cancer cell lines from 25 different primary tumour sites. In order to determine possible biomarkers of response, correlation analysis was performed to assess the relationship between genomic alterations or gene expression levels of oncogenes and neratinib response. Methods: Sensitivity to neratinib was assessed in 108 cancer cell lines (Oncolines™) by ATPlite assay after 72-hour treatment. Pearson correlation analysis was carried out between the gene expression profile of 361 relevant cancer genes for 94 of the 108 cell lines (CCLE) and neratinib sensitivity (10logIC50 values). The neratinib gene expression profile was then compared to &gt; 160 reference compound profiles to exclude false positives. The mutation and copy number status of established oncogenes and tumour suppressor genes was sourced from COSMIC cell lines project and CCLE and compared to neratinib IC50 values by ANOVA and t-test. Results: Neratinib had a potent anti-proliferative effect across numerous cancer types, achieving an IC50 value of &lt; 500 nM in 18 of the 108 cell lines; including breast, lung, pancreatic, colorectal, bladder, head and neck, and cervical cancers. Overall, no significant difference was observed between solid and haematological cancers. As expected, ERBB2-amplification, over-expression, and mutation correlated with neratinib response. However, sensitivity was also significantly correlated with EGFR mutations/ amplification/over-expression, amplification of MRPS28 (p=5.2 x 10-5), mutations in BRCA2 (p=0.02) and FBXW7 (p=0.008), and with both CNVs and mutations in SMAD4 (p=0.007) and PTEN (p=0.02). Gene expression of ERBB2 and RAC1, which can be activated downstream of HER2, positively correlated to neratinib response compared to reference compounds. Conclusions: Neratinib displayed broad-spectrum pre-clinical efficacy across numerous cancer types outside of HER2+ breast cancer. This study identified several novel markers of response to neratinib, which warrant further validation.
Citation Format: Neil T Conlon, Jeffrey J Kooijman, Guido JR Zaman, Irmina Diala, Alshad Lalani, John Crown, Denis M Collins. Pre-clinical assessment of neratinib sensitivity and biomarkers of response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A046. doi:10.1158/1535-7163.TARG-19-A046
Abstract A053: Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma
Authors: Beom Seung-Hoon , Park Sejung , Kwon Woo Sun , Shin Sang Joon , Kim Soo-Youl , Cho Nam Hoon , Rha Sun Young 
Published: March 2020

Abstract
Background: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinical significance in patients with metastatic clear cell RCCs (ccRCCs). Methods: We analyzed 206 metastatic ccRCC patients who received the first-line vascular endothelial growth factor (VEGF) targeted therapy including sunitinib (n = 33), pazopanib (n = 120), and sorafenib (n = 53) between 2006 and 2016. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to membranous staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). Results: TG2 staining intensity was negative in 20.9% of ccRCC (n = 43), 1+ in 46.6% (n = 96), 2+ in 9.71% (n = 20), and 3+ in 22.8% (n = 47). The survival analysis showed a significant association between stronger TG2 expression (≥ 2+) and worse progression-free survival (PFS) (P = 0.032) in the 1st line VEGF-targeted therapy. On multivariate analysis including previous nephrectomy, number of metastatic organs, and International Metastatic RCC Database Consortium Risk Score, stronger TG2 expression was a significant independent predictive indicator for poor PFS (P = 0.004). Conclusions: Our study is the first to demonstrate the significance of TG2 expression on clinical outcome in metastatic ccRCCs. TG2 expression was a significant negative predictive marker for PFS in 1st line VEGF-targeted therapy and targeting TG2 may be a new therapeutic approach to metastatic ccRCC.
Citation Format: Seung-Hoon Beom, Sejung Park, Woo Sun Kwon, Sang Joon Shin, Soo-Youl Kim, Nam Hoon Cho, Sun Young Rha. Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A053. doi:10.1158/1535-7163.TARG-19-A053
Abstract A054: Extracellular vesicles modulate glioblastoma intratumor heterogeneity and treatment resistance
Authors: Schweiger Markus W , Tabet Elie , Li Mao , Tian Tian , Zinter Max , Fleming Renata , Carvalho Litia A , Saad Michael J , Tannous Bakhos A 
Published: March 2020

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor and despite optimal treatment, long-term survival remains uncommon. GBM can be roughly divided into three different molecular subtypes, each varying in aggressiveness and treatment resistance. Interestingly, recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stem-like cells undergo transition into the more aggressive mesenchymal (MES) subtype leading to therapeutic resistance. Extracellular vesicles (EVs) are membranous structures secreted by nearly every cell and have been shown to play a key role in GBM progression by acting as multifunctional signaling complexes. Here we show that EVs derived from MES cells educate PN cells to increase stemness, cell proliferation, tumor aggressiveness, and therapeutic resistance by modulating mesenchymal transition through NF-κB activation. Our findings could potentially help to explore new treatment strategies for GBM and indicate that EVs may also play a role in the mesenchymal transition of different tumor types.
Citation Format: Markus W Schweiger, Elie Tabet, Mao Li, Tian Tian, Max Zinter, Renata Fleming, Litia A Carvalho, Michael J Saad, Bakhos A Tannous. Extracellular vesicles modulate glioblastoma intratumor heterogeneity and treatment resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A054. doi:10.1158/1535-7163.TARG-19-A054
Abstract A069: Mechanisms governing the transcriptional regulation of the liver-specific transporter OATP1B3 in prostate cancer
Authors: Barbier Roberto H , McCrea Edel M , Strope Jonathan D , Huang Phoebe A , Sissung Tristan M , Price Douglas K , Chau Cindy H , Figg William D 
Published: March 2020

Abstract
Background: The testosterone uptake transporter OATP1B3 is expressed de novo in prostate tumors and SLCO1B3 gene (encoding OATP1B3) variants are associated with clinical outcomes in patients with prostate cancer receiving androgen deprivation therapy (ADT) and in castration-resistant disease. These findings support the role of OATP1B3 as a major physiologic contributor to androgen distribution and a contributor to resistance to ADT. We have previously shown CBP/p300-mediated SLCO1B3 expression; however, specific transcriptional regulation of de novo expression remains to be elucidated. We characterized the SLCO1B3 promoter in order to better understand the regulatory mechanisms that govern its expression in prostate cancer. Methods: Functional analysis of the SLCO1B3 promoter was conducted using 5’ deletion mutagenesis. Transcriptional activity of the SLCO1B3 gene was measured using the SLCO1B3 promoter-luciferase reporter plasmids, transient transfections and luciferase reporter assays. Promoter activity was modulated by co-transfection with the p300 expression plasmid or treatment with various p300 inhibitor compounds (chetomin, HATi II, or C646). Results: We detected different transcriptional profiles across multiple prostate cancer cells (22Rv1, LNCaP, PC3) and identified a conserved domain responsible for SLCO1B3 transcriptional activity. Variable transcriptional changes in response to p300 inhibitor treatments were observed in both the conserved domain plasmid and the full-length reporter with the HATi II compound showing a consistent 2 to 3-fold increase in luciferase activity. Putative transcription factor binding sites are being evaluated by site-directed mutagenesis to determine potential regulatory elements involved in transcriptional activity of the gene. Conclusions: Our data suggest that several multi-protein transcription factor complexes assemble at distinct regulatory elements in the SLCO1B3 promoter, driving tissue-specific expression of OATP1B3 in prostate cancer. Understanding the underlying regulatory mechanisms of OATP1B3 expression and the transporter’s role in prostate cancer progression will aid in its development as a potential therapeutic target.
Citation Format: Roberto H Barbier, Edel M McCrea, Jonathan D Strope, Phoebe A Huang, Tristan M Sissung, Douglas K Price, Cindy H Chau, William D Figg. Mechanisms governing the transcriptional regulation of the liver-specific transporter OATP1B3 in prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A069. doi:10.1158/1535-7163.TARG-19-A069
Abstract A081: Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion
Authors: Alewine Christine , Ahmad Mehwish Iqra , Peer Cody J , Steinberg Seth , Figg William D , Hassan Raffit , Pastan Ira 
Published: March 2020

Abstract
Purpose: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Previous Phase 1 clinical testing of a 30-minute LMB-100 infusion format identified dose-limiting toxicity (DLT) of capillary leak syndrome (CLS) and a serum half-life of ~60 minutes. Pre-clinical data suggested that extending infusion time could improve anti-tumor efficacy by increasing tumor cell duration of exposure to LMB-100. The primary objective of this study was to determine the safety and tolerability of administering LMB-100 over a longer infusion time. We hypothesized that reduced CMAX would result in decreased severity of off-target toxicities like CLS without decreasing anti-tumor activity. Patients and Methods: Patients (n = 15) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; mesothelioma, colon adenocarcinoma, ampullary carcinoma) treated on 3 dose levels received long infusion (24-48 hours) LMB-100 (65 or 100 mcg/kg/day) with or without a loading dose (40 mcg/kg over 30 minutes) for up to 2 cycles. Safety and tolerability, pharmacokinetics, immunogenicity and anti-tumor activity were assessed. Results: DLT of proteinuria (grade 3) was observed in 1 of 6 patients receiving 100 mcg/kg/day over 48 hours with pre-load. Three of 6 patients at this dose level developed significant CLS (&gt;5 kg weight gain from fluid edema) that was not dose-limiting. No CLS was observed in the 6 patients who received 100 mcg/kg over 24 hours on days 1 and 4 with pre-load. Increased immunogenicity was observed with the long infusion compared to standard administration format: 8 of 9 patients receiving 2nd cycle treatment had undetectable plasma LMB-100 concentration during this cycle that was associated with the development of high titer anti-LMB-100 antibodies. Progressive disease was observed in 11 of 12 evaluable patients, and none of 8 evaluable patients with pancreatic adenocarcinoma had a clinically significant decline in CA 19-9 tumor marker. Conclusions: Long infusion format of delivery for LMB-100 can reduce CLS but increases immunogenicity. No anti-tumor activity was observed.
Citation Format: Christine Alewine, Mehwish Iqra Ahmad, Cody J Peer, Seth Steinberg, William D Figg, Raffit Hassan, Ira Pastan. Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A081. doi:10.1158/1535-7163.TARG-19-A081
Abstract A104: Nanoformulations of PARP and CDK inhibitors for cancer therapy
Authors: Singh Bijay , Yang Shicheng , Baldwin Paige , Ven Anne van de , Sridhar Srinivas 
Published: March 2020

Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors have been majorly utilized in cancers with BRCA1/2 mutations that have deficiencies in the homologous recombination (HR) DNA repair pathway. Traditionally, PARP inhibitors have been administered through oral route in the clinic but they have resulted in poor bioavailability, low tumor accumulation and high systemic toxicity. Moreover, tumors develop resistance to PARP inhibitors necessitating the development of strategies to re-sensitize these resistant tumors. To overcome these limitations, nanoparticle drug formulation has demonstrated a great potential to increase the drug concentration and accumulation at tumor sites with low systemic toxicities. Here we report the development of several nanoformulations of PARP inhibitors and observe their efficacies by systemic administration to treat various cancer diseases. We used two FDA approved PARP inhibitors (Olaparib or Talazoparib) for nanoformulations of NanoOlaparib and NanoTalazoparib, decorated with EpCAM or EGFR antibody, and tested on breast, ovarian, prostate and lung cancer with or without irradiation. In HR deficient models, the nanoformulations showed significant inhibition of tumor cell growth in vitro and in vivo. Above all, combination of PARP inhibitor with irradiation resulted in greater efficacy in lung and prostate cancer models. To overcome PARP inhibitor resistance, we formulated nanoparticles, NanoDinaciclib of cyclin-dependent kinase 12 (CDK12) inhibitor (dinaciclib) and used in combination with nanoformulation of PARP inhibitor to arrest the tumor growth in animal model. Our current research reveals that the use of CDK12 inhibitor in PARP resistant tumors further arrests tumor growth compared with monotherapy alone. Further studies will help clarify to achieve clear understanding of the mechanism of action CDK12 inhibitor to determine the best way to use PARP inhibitors beyond HR deficiency.
Citation Format: Bijay Singh, Shicheng Yang, Paige Baldwin, Anne van de Ven, Srinivas Sridhar. Nanoformulations of PARP and CDK inhibitors for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A104. doi:10.1158/1535-7163.TARG-19-A104
Abstract A106: A peptide based on transmembrane domain of S1PR4 as a tumor cell growth inhibitor
Authors: Yoshida Tetsuhiko , Tanaka Kenichi , Asakawa Shuichi , Sawada Makoto , Hasegawa Yoshinori , Nakase Ikuhiko , Kobayashi Nahoko Bailey 
Published: March 2020

Abstract
Background: Many anti-tumor agents are used in chemotherapy for cancers. However, they also have serious side effects because they express similar growth inhibitory activity in normal cells. Meanwhile, the development of molecular target drugs inhibiting biomolecules relating to tumor growth, invasion, and metastasis has been proceeding with the goal of selectively attacking cancer cells. It has been revealed that the proliferation of cancer stem cells involved in redevelopment, invasion, and metastasis is promoted by sphingosine-1-phosphate (S1P). We focused on the transmembrane domains of sphingosine 1 phosphate receptor 4 (S1PR4), and hypothesized that peptides which utilized these domains would exhibit a selective anti-tumor effect in cancer cells. We designed peptides based on the transmembrane domains of S1PR4 and evaluated whether the peptides showed tumor cell growth inhibitory activity against various kinds of human tumor cells. Material and methods: We chemically synthesized conjugation peptides of the human S1PR4 transmembrane domain sequences and a cell-penetrating peptide HIV TAT. The peptides were evaluated for growth inhibitory activity against human melanoma, non-small cell lung cancer (NSCLC),kidney cancer by WST assay. Results: The peptide based on the S1PR4 transmembrane domain 2 exhibited the strongest anti-tumor activity in the synthesized peptides based on the domain from 1 to 7. The result was that more than 95% of the tumor cells were inhibited in cells treated with a concentration of 25μM for 48 hours. Conclusions: We demonstrated a novel strategy for discovering an anti-tumor molecule by focusing on transmembrane domains of proteins involved in the proliferation of cancer cells. In particular, the peptide based on the transmembrane domain 2 of S1PR4 exhibits remarkable anti-tumor activity against human melanoma, NSCLC, kidney cancer which suggests that the peptide could be a candidate for a new anti-tumor agent. COI: I/we (in case of co-authors) have no potential conflict of interest to disclose
Citation Format: Tetsuhiko Yoshida, Kenichi Tanaka, Shuichi Asakawa, Makoto Sawada, Yoshinori Hasegawa, Ikuhiko Nakase, Nahoko Bailey Kobayashi. A peptide based on transmembrane domain of S1PR4 as a tumor cell growth inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A106. doi:10.1158/1535-7163.TARG-19-A106