bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A107: Cancer invadopodia controlled down-regulated miRNAs in esophageal squamous cell carcinoma
Authors: Kano Masayuki , Matsumoto Yasunori , Matsubara Hisahiro 
Published: May 2016

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers of the gastrointestinal tract. However, molecular indicators of the origin of cellular deregulation in ESCC have not been identiﬁed. MicroRNAs (miRNAs), noncoding RNAs 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in ESCC was performed using the miRNA expression signatures. miRNA signatures from ESCC identified miRNAs that are downregulated in common, and these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion. These miRNAs, which have conserved sequences in the 3'UTR of FSCN1, inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.
FSCN1 is actin bundling protein, which is concerned with cancer invadopodia. Cancer invadopodia is one of the most important phenomenon regarding cancer cell invasion into surrounding tissue. Many kinds of molecules participate invadopodia in the cancer cell. We focused on MMP14 and examined the gene expression of MMP14 in ESCC tissues and patient survival. FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. The relationship between the expressions of miR-133 and MMP14 is strongly negative correlation. miR-145 and miR-133 play a chief role in cancer invasion and metastasis, which control invadopodia associated proteins.
The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.
Citation Format: Masayuki Kano, Yasunori Matsumoto, Hisahiro Matsubara. Cancer invadopodia controlled down-regulated miRNAs in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A107.
Abstract A130: Targeting BMI-1 by the novel BMI-1 inhibitor PTC596 in acute leukemia
Authors: Nishida Yuki , Maeda Aya , Cao Liangxian , Dumble Melissa , Kimura Shinya , Davis Thomas W. , Kojima Kensuke 
Published: May 2016

Abstract
Leukemia stem cells are resistant to chemotherapeutic agents and contribute to disease relapse. BMI-1, a part of polycomb repressive complex 1 (PRC1) is essential for the self-renewal of normal hematopoietic and leukemia stem cells. We have reported that acute myeloid leukemia (AML) patients with higher levels of BMI-1 have worse overall survival and that the translational BMI-1 inhibitor PTC-209 induces apoptosis in patient-derived CD34+CD38low/- AML cells. PTC596 is a second-generation BMI-1 inhibitor that accelerates BMI-1 degradation. Based on preclinical data showing excellent anti-tumor activities against solid cancers, PTC596 is currently in PH1 clinical development. We here investigated preclinical activities of PTC596 against acute leukemias in vitro and in vivo. A total of 6 AML (MOLM-13, OCI-AML3, U-937, MV4-11, MOLM-14 and HL60) and 3 acute lymphoblastic leukemia (ALL) (Reh, NALM6 and MOLT-4) cell lines were exposed to PTC596 for 48 hours. PTC596 exhibited dose- and time-dependent anti-proliferative and cytotoxic (apoptotic) activities. The IC50 values (concentration at which cell growth is inhibited by 50% at 48 hours of exposure) were 30.7 ± 4.1 nM (mean ± SEM) for AML and 37.7 ± 8.0 nM for ALL. The ED50 values (effective concentration inducing 50% killing as measured by Annexin V/PI induction) were 60.3 ± 6.7 nM for AML and 77.8 ± 11.5 nM for ALL. PTC596 induced apoptosis in AML cells irrespective of their p53 status. 72-hour treatment of MOLM-13 and OCI-AML3 cells with 100nM PTC596 reduced total BMI-1 protein levels by 87% and 61%, respectively. Forced overexpression of BMI-1 in K562 cells abrogated PTC596-induced apoptosis (∼ 80% at 50 nM PTC596; P &lt; 0.05). 16-hour treatment of MOLM-13 cells with 200nM PTC596 resulted in reduced levels of non-phosphorylated BMI-1 by 85%, along with increased levels of phosphorylated BMI-1. PTC596 reduced the levels of ubiquitylated histone H2A, which indicates a deactivation of the PRC1 complex function. The anti-leukemia activity of PTC596 was tested in xenograft (K562) and syngeneic (L210) mouse models. PTC596 at a daily dose of 20 mg/kg significantly delayed an enlargement of the implanted tumor of K562 by ∼55%. PTC596 significantly prolonged survival of mice injected with syngeneic L210 leukemia cells (27 versus 37 days; 76% extension of lifespan with a median survival time; P &lt; 0.05). Collectively, BMI-1 inhibition by PTC596 offers a novel therapeutic strategy for acute leukemias.
Citation Format: Yuki Nishida, Aya Maeda, Liangxian Cao, Melissa Dumble, Shinya Kimura, Thomas W. Davis, Kensuke Kojima. Targeting BMI-1 by the novel BMI-1 inhibitor PTC596 in acute leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A130.
Abstract A144: Restoration of tumor suppressor function by mitochondrially targeting p14 peptide in tumor cells
Authors: Saito Ken , Kondo Eisaku 
Published: May 2016

Abstract
Introduction
Loss of CDKN2A (encoding p16INK4a and p14ARF) gene mainly by epigenetic alternations is associated with an increased susceptibility for development of malignant tumors. We previously reported the loss of the p14ARF function especially on the gefitinib-resistant lung adenocarcinomas (NSCLCs). In the present study, we identified the p14MIS (p14 minimal inhibitory sequence) peptide covering the functional core sequence of p14ARF, which is targeted to the mitochondria in the tumor cells and report its utility in growth suppression of biologically aggressive cancer cells of diverse origins.
Experimental procedures
Human tumor lines of various origins were treated with 10 μM of the p14MIS for 24 h or 48 h. The intracellular localization of p14MIS and growth suppression which is correlated to mitochondrial membrane potential by the p14MIS were examined by MTT assay and inverted fluorescence microscopy which is available to the peptide-treated living tumor cells. For in vivo study, the tumor xenograft mouse models were made by intraperitoneal injection of the human pancreatic adenocarcinoma cell, GFP-expressing BxPC3, and examined the antitumor effect of the peptide. The mice were daily treated with the 300ug/mouse of the p14MIS or with the polyarginine peptide (R9) as a control for a week, respectively. After the sequential treatment of the peptide, the mice of each group were autopsied and evaluated intraperitoneal dissemination (metastasis) of the GFP-expressing tumors.
Results
The p14MIS successfully targeted to the mitochondria and triggered an apoptosis to the various lineage of tumor cells by reduction of their mitochondrial membrane potential. The sensitivity and efficacy of the p14MIS was dependent on the expression level of endogenous mitochondrial ATPAF1 (F1-ATPase assembly protein) and also the magnitude of downregulation of the mitochondrial membrane potential in each tumor line. Moreover, in vivo delivery of the p14MIS to the pancreatic tumor model mice resulted in a 75% reduction in tumor volume compared with those in the control mice.
Conclusions
These results support the biological significance of the tumor suppressor molecule, p14ARF, especially localized at mitochondrias on tumor cells, and the utility of p14MIS peptide as an antitumor biotool against highly aggressive cancers. Although molecular details in tumor cells still remain to be clarified with respect to mitochondrial action of the p14MIS, it a potential of the peptide-based molecular therapy in intractable human malignancies of diverse origins.
Citation Format: Ken Saito, Eisaku Kondo. Restoration of tumor suppressor function by mitochondrially targeting p14 peptide in tumor cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A144.
Abstract A151: Quantitative systems pharmacology approaches accelerate lead generation and optimization of a PD-1 x TIM-3 therapeutic in immuno-oncology
Authors: Apgar Joshua F. , Wong Jamie , Ryan Phennicie Ryan , Briskin Mike , Burke John M. 
Published: May 2016

Abstract
The goal of this collaboration was to provide early quantitative decision making guidance for the project team by developing and interrogating a quantitative systems pharmacology (QSP) model of the co-modulation inhibitory receptors PD-1 and TIM-3 in immuno-oncology. The QSP model was to: (1) provide predictions of the best-in-class profile for a PD-1 and TIM-3 dual antagonist, (2) accelerate project timelines, (3) provide biological insights, and (4) reduce experimental costs.
The QSP model was based on first principles as a system of elementary mass-action, mechanistic PKPD, ordinary differential equations. The model parameters and reactions were based on biophysics, and are interpretable. The model reactions include protein synthesis and elimination, ligand-receptor and drug-target formation and turnover, and drug administration and first order clearance. There were four versions of the model: PD-1 monospecific, TIM-3 monospecific, PD-1 x TIM-3 bispecific and fixed dose combination (FDC) targeting PD-1 and TIM-3. The monospecific models were then benchmarked against published data such that model parameter values were set to known values and unknown parameters were estimated. Once benchmarked, the FDC and bispecific models were analyzed by systematically investigating how tuning the model parameters (e.g., affinity, avidity, dose, half-life, target expression, etc.) impacted target inhibition, and to simulate patient variability.
The model was in good agreement with published clinical data from nivolumab and pembrolizumab, and data from RMT3-23 in the TIM-3 driven mouse model. QSP model analysis predicted: (1) there would be diminishing returns on very tight binding biologics due to Target Mediated Drug Disposition (TMDD) that offsets potency, and (2) there is no advantage between FDC, 2-2 bispecific, and 2-1 bispecific formats, which are predicted to be roughly equivalent. As a result of these analyses, there was a significant reduction in the number of experiments, and acceleration of project timelines by (1) eliminating rounds of affinity maturation, as drug leads were in predicted optimal drug parameter ranges, and (2) eliminating the need to construct and evaluate bi-specific constructs and proceed with FDCs.
Citation Format: Joshua F. Apgar, Jamie Wong, Ryan Ryan Phennicie, Mike Briskin, John M. Burke. Quantitative systems pharmacology approaches accelerate lead generation and optimization of a PD-1 x TIM-3 therapeutic in immuno-oncology. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A151.
Abstract A167: A phase I study of MET TKI SAR125844 in Asian patients (pts) with advanced solid tumors
Authors: Shitara Kohei , Oh Do-Youn , Yokota Tomoya , Kim Tae Won , Doi Toshihiko , Hamauchi Satoshi , Ahn Jin-Hee , Gomez Corinne , Harnois Marzia , Jue Bang Yung 
Published: May 2016

Abstract
Background: SAR125844 (SAR) is a potent and small molecule inhibitor of the MET kinase (IC50 = 4.2nM; Ki = 2.8nM). This phase I study (NCT01657214) was initiated to address the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity in adult Asian pts with advanced solid tumors.
Methods: Eligible pts received SAR by IV infusion every week. Dose escalation proceeded with an adaptive Bayesian method. At the MTD, pts with advanced c-Met amplified solid tumors including gastric cancer (GC) pts were enrolled in an expansion cohort.
Results: As of 30 June 2015, 32 pts have received SAR, 19 pts in the dose escalation phase over 4 dose levels (DL) ranging from 260 to 570 mg/m2 and 13 pts in the MTD expansion cohort including 8 pts with advanced GC. Of the 32 treated pts, median age was 64 years [28-78], 18M/14F, ECOG-PS 0/1/2: 14/16/2 with various solid tumors including 16 GC, 6 colorectal and 4 lung adenocarcinomas. Pts received a median of 4 infusions [2-20]. No dose-limiting toxicity (DLT) was reported nor MTD was reached. Of the 19 pts treated in dose escalation, blood exposure PK parameters (AUC and Cmax) increased in proportion with the dose with a mean clearance of 34 L/h associated with a large volume of distribution (239 L). Dose expansion was opened at 570 mg/m2 for pts with solid tumor and c-Met-gene amplification determined on local FISH assay. The most commonly reported all-causality AE (≥15% of pts) were: nausea, vomiting, decreased appetite, asthenia/fatigue, constipation, pyrexia, abdominal pains, injection site reaction and back pain. 31.3% of pts had grade ≥3 AEs, none were related to study drug. No relevant severe laboratory abnormality was observed. In the dose escalation part in unselected pts, stable disease (SD) was reported in 8 pts at the 4 week assessment. Of the 13 pts treated so far in dose expansion, 2 pts with GC achieved confirmed partial response and 5 pts had SD (4GC and 1sarcoma).
Conclusions: SAR administered as single agent at the dose of 570mg/m2 has a tolerable and manageable safety profile and encouraging anti-tumor activity is seen in pts with c-Met -amplified GC. Accrual of pts with c-Met-gene amplified GC is still ongoing.
Sponsored by Sanofi; NCT01657214
Citation Format: Kohei Shitara, Do-Youn Oh, Tomoya Yokota, Tae Won Kim, Toshihiko Doi, Satoshi Hamauchi, Jin-Hee Ahn, Corinne Gomez, Marzia Harnois, Yung Jue Bang. A phase I study of MET TKI SAR125844 in Asian patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A167.
Abstract A168: Discovery of exquisitely selective MerTK inhibitors
Authors: Yoon Taeyoung , Sheen Joon-Ho , Park Seong Jin , Kim Jin Kwan , Kim Hadong , Kim Eun-Jung , Kwon Munjin , Lee Hyung Ki , Lee Okyung , Jeong Youngjee , Ryu Ki Moon , Jang Miyeon , Hwang Jae-Sung 
Published: May 2016

Abstract
MerTK is a receptor tyrosine kinase most prominently expressed in myeloid cells and known for its role in phagocytosis of early apoptotic cells and concomitant establishment of tolerogenic microenvironment. Hence, MerTK is thought to play a significant role in cancer immune evasion as, for example, a defining component of M2c-type tumor-associated macrophages (TAMs). Moreover, it has also been increasingly recognized that MerTK is overexpressed in a variety of malignant tumor cells, promoting the cancer cell survival, invasion, and treatment resistance. As such, it is anticipated that the cancer cell intrinsic and extrinsic effects might conspire to make MerTK a highly promising target for anticancer therapy. We describe herein an exquisitely selective series of MerTK inhibitors. A lead compound, XL1547, exhibited an IC50 of 1 nM against MerTK in an enzyme assay, with a greater than 300-fold selectivity over closely related AXL kinase (IC50 = 350 nM). In fact, MerTK was the only enzyme that was inhibited by XL1547 (&gt; 99% at 100 nM) in the panel of 386 kinases (Reaction Biology Corp.; all others &lt; 35%). X-ray crystal structure revealed a unique binding mode where the compound exploits a large back pocket next to the gatekeeper residue (known as a Type 1.5 binder). XL1547 potently inhibited autophosphorylation as well as the viability of engineered BaF3(CD8:MerTK) cells (GI50 = 230 nM) with little toxicity. Extensive medicinal chemistry efforts yielded a more advanced compound SA3686 with at least 10-fold improvement in potency. More importantly, it displayed a pharmacokinetic profile suitable for oral dosing. Indeed, SA3686 was highly efficacious in vivo in an allograft tumor model of subcutaneously implanted Ba/F3(CD8:MerTK) cells. [SA3686 is being tested in multiple other in vivo models at the time of abstract submission]. In summary, we have identified an essentially mono-selective MerTK inhibitor series that will help delineate the biology of MerTK-specific inhibition and hopefully validate the translational potential of MerTK as a therapeutic target for human diseases including cancer.
Citation Format: Taeyoung Yoon, Joon-Ho Sheen, Seong Jin Park, Jin Kwan Kim, Hadong Kim, Eun-Jung Kim, Munjin Kwon, Hyung Ki Lee, Okyung Lee, Youngjee Jeong, Ki Moon Ryu, Miyeon Jang, Jae-Sung Hwang. Discovery of exquisitely selective MerTK inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A168.
Abstract A172: Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in FGF19-expressing hepatocellular carcinoma
Authors: Futami Takashi , Okada Hidetsugu , Kihara Rumi , Kawase Tatsuya , Nakayama Ayako , Suzuki Tomoyuki , Kameda Minoru , Shindoh Nobuaki , Terasaka Tadashi , Hirano Masaaki , Kuromitsu Sadao 
Published: May 2016

Abstract
Background: Fibroblast growth factor (FGF) / FGF receptor (FGFR) gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers. Recently, FGF19 overexpression was observed in approximately 50% of hepatocellular carcinoma (HCC) patients. The FGF19-FGFR4 signaling has been implicated in the development of HCCs in mice. FGFR4 kinase inhibitors are expected to be a targeted therapy for FGF19-expressing HCC. A phase I clinical trial of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, is ongoing (NCT02038673). Method: We tested selectivity of ASP5878 among 128 kinases and sensitivity of ASP5878 on cell proliferation of HCC cell lines. Activation of FRS2 and ERK, downstream molecules of FGFR signaling, and PARP cleavage in FGF19 expressing HCC cell lines were evaluated with Western blotting. In vivo antitumor effects of ASP5878 were examined in HCC subcutaneous xenograft and orthotopic inoculation mouse models. Finally, plasma levels of FGF19 were measured after dosing ASP5878. Results: Among 128 kinases, only 9 kinases including FGFR1-4 and FGFR3/4 mutations were inhibited more than 50% by ASP5878 (200 nmol/L). The IC50 values of ASP5878 against FGFR1, 2, 3 and 4 kinases were 0.47, 0.60, 0.74 and 3.5 nmol/L, respectively. ASP5878 inhibited cell proliferation of HCC cell lines with FGF19 overexpression. IC50 values were 8.5, 27, and 21 nmol/L in Hep3B2.1-7, HuH-7 and JHH-7, respectively. ASP5878 inhibited activation of downstream signaling molecules, FRS2 and ERK, and induced apoptosis in Hep3B2.1-7 cells. Oral dosing of ASP5878 at 3 mg/kg induced sustained tumor regression in the Hep3B2.1-7 subcutaneous xenograft model, which was poorly responsive to sorafenib. In an HuH-7 orthotopic inoculation mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival. In addition, oral dosing of ASP5878 reduced plasma levels of FGF19 in the HuH-7 subcutaneous xenograft model.Conclusion: These results suggest that ASP5878 is a potentially effective therapeutic agent for FGF19-expressing HCC.
Citation Format: Takashi Futami, Hidetsugu Okada, Rumi Kihara, Tatsuya Kawase, Ayako Nakayama, Tomoyuki Suzuki, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu. Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in FGF19-expressing hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A172.
Abstract A25: Predictive biomarkers for bevacizumab response in recurrent glioblastoma patients
Authors: Urup Thomas , Michaelsen Signe Regner , Olsen Lars Rønn , Toft Anders , Christensen Ib Jarle , Grunnet Kirsten , Broholm Helle , Kosteljanetz Michael , Issazadeh-Navikas Shohreh , Poulsen Hans Skovgaard , Lassen Ulriik 
Published: May 2016

Abstract
BACKGROUND: Bevacizumab (BEV) plus chemotherapy has shown high response rates in recurrent glioblastoma (GBM) and patients who achieve response have an improved overall survival as well as quality of life. Recent retrospective analysis of the randomized phase III trial, AVAglio, indicate that patients with the proneural GBM subtype have a survival benefit when treated with BEV in combination with standard treatment. However, no validated biomarkers able to predict BEV response have been identified and the biology reflecting a clinical BEV response is poorly understood. The primary objective of this study was to evaluate the predictive and prognostic value of GBM subtypes in recurrent GBM patients treated with BEV therapy. The secondary objective was to identify biomarkers able to predict response to BEV therapy in recurrent GBM patients. METHODS: A total of 90 recurrent GBM patients treated with BEV combination treatment according to a previously published treatment protocol were included. Inclusion criteria: BEV plus irinotecan treatment in the period between May 2005-2011; available GBM tissue (according to WHO); response evaluable (RANO). RNA from tumor tissue was analyzed by the NanoString platform covering 800 genes. Raw data was assigned to molecular subtypes for each of the samples using the PAMR classifier model, previously trained on the AVAglio dataset. In order to identify novel candidate biomarkers able to predict response, differentially expressed genes (fold-change difference &gt; 1.5) between patients responding versus progressing on BEV were identified using a t-test. Biomarkers significantly (P&lt;0.05) associated with response in multivariate logistic regression analysis adjusted for recently validated clinical prognostic factors were selected for the final predictive model. RESULTS: Molecular subtypes were not associated with response or overall survival. However, two novel independent predictive biomarkers (gene1 down-regulated and gene2 up-regulated in responders) of BEV response and overall survival were identified. Results will be presented.
Citation Format: Thomas Urup, Signe Regner Michaelsen, Lars Rønn Olsen, Anders Toft, Ib Jarle Christensen, Kirsten Grunnet, Helle Broholm, Michael Kosteljanetz, Shohreh Issazadeh-Navikas, Hans Skovgaard Poulsen, Ulriik Lassen. Predictive biomarkers for bevacizumab response in recurrent glioblastoma patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A25.