bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5435: Molecular subclasses of human hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition
Authors: Schmidt Benjamin , Wei Lan , DePeralta Danielle K. , Hoshida Yujin , Lanuti Michael , Tanabe Kenneth K. , Fuchs Bryan C. 
Published: May 2015

Abstract
Background: A recent gene expression classification of hepatocellular carcinoma (HCC) includes two poor survival subclasses, termed S1 and S2. S1 cells are more locally invasive, while S2 cells express E-cadherin and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between the S1 and S2 gene signatures, this study investigated whether molecular subclasses of HCC could predict sensitivity to FGFR inhibition. Methods: The effects of AZD4547 and BGJ398, two small molecule inhibitors of FGFR1-4, were assessed in four S1 and five S2 human HCC cell lines. Western blotting was performed for FGFR1-4 and phosphorylated p42/44 as a marker of MAPK signaling. Small interfering RNA (siRNA) transfection was used to assess the effects of individual FGFR knockdown. Results: Cell proliferation was inhibited at least two-fold more in S2 than in S1 cell lines at all doses tested above 1 uM of BGJ398 and AZD4547 (p&lt;0.002). BGJ398 also decreased MAPK signaling in S2 but not in S1 cell lines. In xenografts from the S2 cell line HuH-7, BGJ398 reduced tumor volume by 70% over 14 days and this effect was associated with decreased MAPK signaling and a 36% decline in the number of Ki67 positive cells. BGJ398 had no effect on xenografts from the S1 cell line SK-Hep. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 59 ± 12% in all five S2 cell lines (p&lt;0.00001), a significantly greater decrease than seen with knockdown of FGFR1, FGFR2 or FGFR3. FGFR4 knockdown also decreased MAPK signaling in S2 cell lines. Conclusions: The S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of S2 cells. This classification system may help identify those patients who are most likely to benefit from inhibition of the FGFR pathway.
Citation Format: Benjamin Schmidt, Lan Wei, Danielle K. DePeralta, Yujin Hoshida, Michael Lanuti, Kenneth K. Tanabe, Bryan C. Fuchs. Molecular subclasses of human hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5435. doi:10.1158/1538-7445.AM2014-5435
Abstract 5438: Resistance to β1 integrin inhibition in HER2 amplified cancers is mediated by HER3
Authors: Park Catherine C. , Amin Dhara , Zhang Hui , Moasser Mark 
Published: May 2015

Abstract
Our previous work focused on investigating β1 integrin as a target for BC, alone and with radiation therapy. It is well recognized that there is significant cross talk between the EGFR family of receptors and β1 integrin signaling, and a relative resistance of HER2+ BC to β1 integrin inhibitory agents. In 2006, we published our findings that β1 integrin inhibition enhanced the effect of trastuzumab in HER2+ BC. Subsequently, others and we reported that β1 integrin inhibition enhanced the cytostatic effect of multiple HER2-targeted therapies in HER2+ BC. However, the nature of cross talk between β1 integrins and HER2, and the role of β1 integrin in HER2+BC resistance remains unknown. In addition, HER2+BCs have higher rates of local recurrence after radiotherapy, consistent with previous work showing relative radioresistance in HER2+BC. The most potent mitogenic HER2 signaling in HER2+BC occurs upon heterodimerization with HER3. We hypothesized that HER3 could mediate significant resistance to β1 integrin targeting in HER2+BC.
To test this, we correlated β1 integrin and HER3 expression levels in SKBR3 cells over several time points using WB. Inhibitions of β1 integrin activity or shRNA knockdown of HER3 lead to upregulation of HER3 and β1 integrin, respectively. To test whether HER3 knockdown enhanced β1 integrin inhibition, we estimated proliferation by quantitating Ki-67 expression in SKBR3 cells in response to treatment. β1 integrin inhibition lead to a ∼50% reduction in Ki-67 positive cells (48%-22%), which was further enhanced by 50% with HER3 knockdown (12%), p&lt;0.05. In addition, HER3 knockdown enhanced the cytostatic effect of ionizing radiation (IR) by ∼50% (32% to 14%), p&lt;0.05. Enhanced cytostasis was correlated with a significant down modulation of p-HER2 and p-473 Akt on WB. In conclusion, our data indicate that HER3 plays a role in mediating resistance to β1 integrin inhibition in HER2+BC. Further mechanistic and in vivo validation are on going.
Citation Format: Catherine C. Park, Dhara Amin, Hui Zhang, Mark Moasser. Resistance to β1 integrin inhibition in HER2 amplified cancers is mediated by HER3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5438. doi:10.1158/1538-7445.AM2014-5438
Abstract 544: Recurrent DICER1 hotspot mutations in endometrial cancer and their impact on microRNA biogenesis
Authors: Chen Jiamin , Wang Yemin , McConechy Melissa , Anglesio Michael , Senz Janine , Yang Winnie , Rosner Jamie , Chu Andy , Cheng Grace , Morin Gregg , Huntsman David 
Published: May 2015

Abstract
Alternation in genes associated with microRNA (miRNA) biogenesis pathway may lead to miRNA dysregulation, and is implicated in a variety of human malignancies. Previously our group identified recurrent somatic “hotspot” mutations (E1705, D1709, D1810, E1813) in a critical miRNA-processing gene, DICER1, in rare sex cord-stromal tumors. During miRNA biogenesis, the two RNase III domains of DICER1 form an intramolecular dimer, which leads to the cleavage of the precursor miRNA (pre-miRNA) hairpin and generate mature 5p and 3p miRNAs from 5’ and 3’ arms of the precursor hairpin respectively. Studies have shown that the hotspot mutations in the RNase IIIb metal binding domain could impair DICER1's ability to generate mature 5p miRNAs, leading to global loss of 5p miRNAs.
Recently, in collaboration with The Cancer Genome Atlas (TCGA), we identified DICER1 hotspot mutations in a small subset of endometrial cancer from TCGA cohort (6/248) as well as our own tumor bank (6/307), suggesting disruption of DICER1 is implicated in a common malignancy. We also found an additional recurrent mutation G1809R and demonstrated that it has similar detrimental effects on miRNA biogenesis as hotspot mutations through deep sequencing and realtime PCR. Using Illumina Miseq targeted resequencing and Sanger sequencing, we observed biallelic DICER1 mutations in RNase IIIb domain in some but not all cases. miRNA deep sequencing confirmed that 5p miRNAs are decreased in both cell line models and endometrial tumors with hotspot mutations. Bioinformatic analysis of RNA sequencing profiles from TCGA dataset predicted hotspot DICER1 mutations to have greater functional impact than non-hotspot DICER1 mutations on gene expression. The oncogenic properties of DICER1 hotspot mutations are currently under investigation.
Citation Format: Jiamin Chen, Yemin Wang, Melissa McConechy, Michael Anglesio, Janine Senz, Winnie Yang, Jamie Rosner, Andy Chu, Grace Cheng, Gregg Morin, David Huntsman. Recurrent DICER1 hotspot mutations in endometrial cancer and their impact on microRNA biogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 544. doi:10.1158/1538-7445.AM2014-544
Abstract 5448: PTK7 as a potential therapeutic target in ovarian cancer
Authors: Ding Zhihu , Lennon Amanda , Perron Keli , Harper David , Su Hui , Wolfram Meredith , Murtie Joshua , Licht Stuart , Pinckney Jason , Simonds-Mannes Helene , Bishop Kimberly , Gavigan Julie-Ann , Bangari Dinesh , Magnay Maureen , Weber William , Reczek David , Brondyk William , Drewett Vicky , Trombe Marc , Hoffmann Dietmar , Baffa Raffaele , Silver Serena , Richon Victoria , Winter Christopher , Reddy Venkat , Gregory Richard C. 
Published: May 2015

Abstract
The identification of proteins that selectively discriminate between tumor cells and normal adult cells allows for the specific targeting of diseased cells with antibody therapeutics. One such recently identified protein, PTK7, is an onco-fetal membrane protein which exhibits limited expression and function in adults. PTK7 was identified as a member of the RTK super family but lacks a functional kinase domain. Normally, PTK7 is expressed early in development and its loss is associated with severe defects in neural tube closure and sensory hair cell bundle formation. Functionally, little is known about the signaling involving PTK7, but it has been linked to both the canonical and noncanonical WNT pathways. Recently, PTK7 expression has been shown to be upregulated in a number of cancers including: ovarian, melanoma, leukemia, lung, pancreatic, colon, renal and breast. In vitro and in vivo studies support a role in regulating angiogenesis, invasion & survival. To further validate PTK7 as a potential cancer target that may be required for tumor maintenance and progression, we analyzed the expression of PTK7 in normal and tumor samples, and validated an in vitro and in vivo role of PTK7 on cell growth in ovarian cancer cell lines using both genetic tools and polyclonal antibodies. Silencing PTK7 with stably expressed inducible shRNAs is shown to inhibit the growth of ovarian cancer cell lines in vitro and to lead to delayed tumor growth upon PTK7 knockdown in murine tumor xenograft models. Further supporting the role of PTK7 as a potential antibody target, polyclonal antibodies to PTK7 are shown to inhibit the growth of SKOV3 and OVCAR8 cells in vitro. Although 4 human antibodies derived from phage display failed to inhibit in vitro cell growth, these results suggest that functionally blocking PTK7 may lead to the inhibition of ovarian tumor growth and is a potential target for antibody therapies.
Citation Format: Zhihu Ding, Amanda Lennon, Keli Perron, David Harper, Hui Su, Meredith Wolfram, Joshua Murtie, Stuart Licht, Jason Pinckney, Helene Simonds-Mannes, Kimberly Bishop, Julie-Ann Gavigan, Dinesh Bangari, Maureen Magnay, William Weber, David Reczek, William Brondyk, Vicky Drewett, Marc Trombe, Dietmar Hoffmann, Raffaele Baffa, Serena Silver, Victoria Richon, Christopher Winter, Venkat Reddy, Richard C. Gregory. PTK7 as a potential therapeutic target in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5448. doi:10.1158/1538-7445.AM2014-5448
Abstract 545: Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability
Authors: Kim Min Sung , Choi Youn Jin , Gwak Min , Oh Hyerim , Choi Mi Ryoung , Hwang Sun Yong , Yoo Nam Jin , Lee Sug Hyung 
Published: May 2015

Abstract
Cohesin is a protein complex that regulates chromatid cohesion and plays a role in preventing aneuploidy and maintaining chromosomal stability. SGOL1 encodes a cohesin protector, and PDS5B encodes a regulatory cohesion factor. Both SGOL1 and PDS5B are considered putative tumor suppressor genes. The aim of this study was to explore whether SGOL1 and PDS5B genes are mutated and expressionally altered in gastric and colorectal cancers. A genome database indicated that both genes possessed mononucleotide repeats in coding sequences, which could be mutation targets in cancers with microsatellite instability. We analyzed mutations in 91 gastric cancers and 100 colorectal cancers with high microsatellite instability or stable/low microsatellite instability by single-strand conformation polymorphism analysis and DNA sequencing. We also analyzed SGOL1 and PDS5B expression by immunohistochemistry. Overall, we found 21 SGOL1 frameshift mutations in 21 cases and 18 PDS5B frameshift mutations in 16 cases. SGOL1 and PDS5B frameshift mutations were detected in 26.6% and 20.3%, respectively, of high microsatellite instability but not in stable/low microsatellite instability (0/112). By immunohistochemistry, losses of SGOL1 and PDS5B were identified in 19% to 47% of the gastric and colorectal cancers irrespective of microsatellite instability status. The losses were more common in those with frameshift mutations or high microsatellite instability than those without mutations or high microsatellite instability. The data indicate that frameshift mutations of SGOL1 and PDS5B and the loss of their expression may be a feature of gastric and colorectal cancers with high microsatellite instability. In addition, the data suggest that these alterations might contribute to cancer pathogenesis by deregulating cohesin-related functions.
Citation Format: Min Sung Kim, Youn Jin Choi, Min Gwak, Hyerim Oh, Mi Ryoung Choi, Sun Yong Hwang, Nam Jin Yoo, Sug Hyung Lee. Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 545. doi:10.1158/1538-7445.AM2014-545
Abstract 5463: ICG-001 induces cell cycle arrest to inhibit in vitro and in vivo pancreatic cancer growth
Authors: Arensman Michael D. , Lay Anna R. , Dawson David W. 
Published: May 2015

Abstract
Wnt/β-catenin signaling is an important mediator of pancreatic ductal adenocarcinoma (PDAC) initiation and progression, warranting its exploration as a target of therapeutic intervention. Wnt modulators with acceptable in vivo bioavailability and efficacy as Wnt/β-catenin transcriptional inhibitors have only recently become available and include the small molecule compound ICG-001. Discovered in a library screen for inhibitors of Wnt/β-catenin reporter activity, ICG-001 interacts with cyclic AMP-response element-binding protein (CBP) to block its function as a co-transcriptional activator of β-catenin/TCF-mediated transcription. ICG-001 inhibits both in vitro and in vivo colon cancer growth and has demonstrated efficacy in a variety of other in vivo Wnt-driven disease models. Having recently shown subsets of PDAC tumors are dependent on increased levels of Wnt ligand-dependent autocrine signaling, we addressed the efficacy and function of ICG-001 on in vitro and in vivo PDAC growth. As a single agent, ICG-001 significantly inhibited anchorage-dependent and -independent growth of PDAC cell lines in vitro and increased survival in an orthotopic xenograft model of PDAC (HR=0.207, 95%CI: 0.079-0.543, P=0.001). ICG-001 also synergized with gemcitabine to inhibit anchorage-dependent growth in vitro and improve survival in the orthotopic xenograft model (HR= 0.074, 95%CI: 0.026, 0.212, P&lt;0.001). Mechanistically, ICG-001 treatment did not significantly increase apoptosis in PDAC cell lines, but instead dramatically inhibited cell cycle progression via G1 arrest. Although ICG-001 inhibited β-catenin/TCF-mediated transcription as measured by luciferase-based reporter assays and endogenous target gene expression, these changes occurred at concentrations above those seen to induce G1 cell cycle arrest, suggesting ICG-001 growth inhibitory effects may be unrelated to its specific effects as a Wnt pathway inhibitor. Gene expression microarray analysis revealed ICG-001 treatment alters the expression of known Wnt target genes, as well as a much larger number of genes involved in DNA replication and cell cycle control. In conclusion, this study indicates ICG-001 is a promising small-molecule therapeutic for pancreatic adenocarcinoma and identifies numerous target genes whose altered expression provide insights into mechanism of action and candidate biomarkers for following therapeutic response.
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Citation Format: Michael D. Arensman, Anna R. Lay, David W. Dawson. ICG-001 induces cell cycle arrest to inhibit in vitro and in vivo pancreatic cancer growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5463. doi:10.1158/1538-7445.AM2014-5463
Abstract 5476: Simultaneous targeting of multiple cancer-related pathways in HPV-positive head and neck cancer with demethylating agents
Authors: Biktasova Asel , Gubanova Evgenia , Zou Mi , Yarbrough Wendell G. , Issaeva Natalia 
Published: May 2015

Abstract
Head and neck cancer is the 6th most common cancer worldwide with the vast majority being squamous cell carcinoma (SCC). The human papillomavirus (HPV) has recently been shown to be the etiologic agent in approximately 60% of head and neck SCC (HNSCC) arising from the oropharynx. Patients with HPV-positive HNSCC are clinically distinct from those with HPV-negative cancer being younger, and having decreased exposure to the established risk factors for HNSCC of tobacco and alcohol. Although HPV-positive HNSCC patients have higher cure rates compared to HPV-negative HNSCC, lifelong side effects of treatment are severe, and upon recurrence, treatment options and survival are limited. Therefore, new therapies with better side effect profiles that can also offer therapeutic options for patients with recurrent HPV-associated HNSCC are needed.
Recently, we found that HPV-positive head and neck cancer cell lines and primary cells were more sensitive than HPV-negative cells to the demethylating agent 5-azacytidine. Importantly, even low doses of 5-azacytidine delayed HPV-positive tumor growth in mouse xenograft model. Cancer-related pathways that we found to be altered in HPV-positive, but not in HPV-negative head and neck cancer cells, upon demethylation included: 1) restoration of tumor suppressor p53 levels and associated apoptotic activity; 2) activation of cytotoxic type I interferon response; and, 3) downregulation of matrix metalloproteinase (MMP1 and MMP10 ) expression.
Demethylation as a therapy for HPV-associated HNSCC is particularly interesting, since simultaneous targeting of multiple molecular pathways that are important for cancer development and progression, may increase efficacy and reduce acquisition of resistance. Based on our data, a small clinical trial with 5-azacytide on patients with HNSC C was initiated at Yale Cancer Center.
Citation Format: Asel Biktasova, Evgenia Gubanova, Mi Zou, Wendell G. Yarbrough, Natalia Issaeva. Simultaneous targeting of multiple cancer-related pathways in HPV-positive head and neck cancer with demethylating agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5476. doi:10.1158/1538-7445.AM2014-5476
Abstract 5477: mTOR inhibitors protect from apoptosis in B-ALL cells treated with chemotherapeutic drugs
Authors: Vo Thanh-Trang , Fruman David A. 
Published: May 2015

Abstract
B-cell acute lymphocytic leukemia (B-ALL) is the most common pediatric cancer. Although most children can be cured by combination chemotherapy, 10-20% are refractory or have early relapses. These high-risk B-ALLs include Philadelphia chromosome (Ph+) and Ph-like with activated tyrosine kinases that drive elevated signaling through the PI3K/AKT/mTOR pathway. High mTOR signaling correlates with poor prognosis. These findings have raised interest in targeting mTOR in B-ALL and other leukemias. Novel inhibitors of the PI3K/AKT/mTOR pathway are in clinical development, but little is known about how these agents modulate responses to the standard of care in B-ALL. Here we have tested inhibitors of various nodes in the PI3K/AKT/mTOR pathway on B-ALL cells in combination with chemotherapeutic drugs. The data show that PI3K inhibition sensitizes B-ALL cell lines to chemotherapy but, surprisingly, mTOR inhibition induces resistance to several drugs. This chemotherapy resistance is observed when using rapamycin as well as active-site mTOR inhibitors (MLN0128 and AZD8055). The degree of drug resistance conferred by mTOR inhibition varies with different chemotherapeutic agents. mTOR inhibition best protects cells from killing by methotrexate and is least protective when combined with daunorubicin. In Ph+ cell lines, dasatinib also confers resistance to methotrexate that correlates with mTOR inhibition. We designed a simple in vitro model of relapse in which B-ALL cells were treated for 3 days with chemotherapy alone or with mTOR inhibitor, followed by 9 days of culture without drugs. Including mTOR inhibitor in the first culture period resulted in a striking increase in outgrowth of viable cells compared to chemotherapy alone. Mechanistic studies show that resistance does not correspond with effects on cell cycle. Preliminary data indicate that mTOR inhibition enhances DNA repair in B-ALL cells treated with etoposide or AraC. Further studies to define the resistance mechanisms and reverse the protective effect could potentially augment the effectiveness of inhibiting the PI3K/AKT/mTOR pathway. Our results will lead to a better understanding of how to best utilize PI3K pathway inhibitors in combination with standard chemotherapy as an option for high-risk B-ALL cases driven by oncogenic PI3K/AKT/mTOR signaling.
Citation Format: Thanh-Trang Vo, David A. Fruman. mTOR inhibitors protect from apoptosis in B-ALL cells treated with chemotherapeutic drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5477. doi:10.1158/1538-7445.AM2014-5477
Abstract 5478: A novel chloroquine derivative inhibits proteasome function, deregulates centrosome cycle and has selective anti-tumor activity
Authors: Pundir Sheetal 
Published: May 2015

Abstract
The use of chloroquine as a lead compound in anticancer drug discovery is being widely explored because of its low toxicity and ability to sensitize cancer cell killing when used in combination with radiotherapy. Therefore we designed and screened chloroquine analogs using hybrid pharmacophore approach. We report here anti-cancer activity and characterization of a novel anti-cancer compound VR23 derived from chloroquine. Biological investigation revealed that the derivative VR23 inhibits proteasome function, selectively kills cancer cells, causes the formation of supernumerary centrosomes, tri- and multi-polar mitosis, and slows down the progression of cells through cell cycle. In addition VR23 has shown promising anti-cancer activity in animal work.
Further, proteasome inhibition deregulates the translocation of cyclin E and other centrosomal proteins including plk4 and plk1 on centrosomes. This, in turn, leads to formation of supernumerary centrosomes, mitotic catastrophe, p38 stress kinase mediated activation of apoptosis, and eventually cancer cell death.
The work elucidates the consequences of the use of proteasome inhibitor on centrosome duplication cycle which, in turns also delays cell cycle progression and leads to the formation of irregular microtubule asters. Interestingly such phenotype was absent from non-malignant cell line.
Citation Format: Sheetal Pundir. A novel chloroquine derivative inhibits proteasome function, deregulates centrosome cycle and has selective anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5478. doi:10.1158/1538-7445.AM2014-5478