bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3919: Inhibition of HER2 and IGF2 in trastuzumab-resistant HER2 positive JIMT1 cells decreases cell growth and reduces activation of MAPK and AKT
Authors: Helu Xousaen M. , DeLeon Daisy 
Published: August 2015

Abstract
Breast cancer is the second leading cause of death in women. Overexpression of human epidermal growth factor receptor 2 (HER2) is detected in 20-30% of breast cancers. Increased levels of HER2 are linked to poor prognosis, more aggressive phenotype, and resistance to chemotherapy and hormonal treatment. HER2 is part of a four-member family of cell surface receptors that are implicated in transmission of signals controlling cell growth and differentiation. HER2 has an intracellular domain with tyrosine kinase catalytic activity. Dimerization of HER2 activates the MAPK and AKT pathways. The HER2 receptor also hetero-dimerizes with the IGF1 receptor (IGF1R) in trastuzumab-resistant cells. The insulin-like growth factor 2 (IGF2) has an important role in fetal and cancer development signaling through the IGF1R, insulin receptor (InsR), and a cross-talk with the estrogen receptors alpha and beta (ERα, ERß). Trastuzumab resistance occurs in 70% of patients with HER2 positive breast cancer. Therefore it is important to understand the mechanism of resistance so we can develop new therapies to help patients with trastuzumab-resistant rumors. Previous findings in our lab demonstrate an increased expression of IGF2 in the trastuzumab-resistant cell line JIMT1 when compared to trastuzumab-sensitive cell lines BT474, SKBR3, and ZR75-30. We hypothesize that to overcome trastuzumab-resistance in JIMT1 cells, dual inhibition of the HER2 and IGF2 is necessary to induce cell death. When JIMT1 cells were treated with trastuzumab and an IGF2 blocking antibody (IBA) a decrease in cell viability was observed, but changes in PARP cleavage were not present. We also analyzed the protein and phosphorylation levels of HER2, IGF1R, MAPK, and AKT. Our studies suggest that blocking both HER2 and IGF2 decreases cell viability and reduces phosphorylation of MAPK and AKT.
Citation Format: Xousaen M. Helu, Daisy DeLeon. Inhibition of HER2 and IGF2 in trastuzumab-resistant HER2 positive JIMT1 cells decreases cell growth and reduces activation of MAPK and AKT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3919. doi:10.1158/1538-7445.AM2015-3919
Abstract 3922: Novel hepatocyte growth factor and macrophage stimulating protein antagonists for the treatment of castration-resistant prostate cancer
Authors: Vanderwerff Brett , Church Kevin , Kawas Leen , Harding Joseph 
Published: August 2015

Abstract
Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that is refractory to androgen deprivation therapy and characterized by aggressive growth, extensive metastasis formation, and poor prognosis. CRPC is temporarily manageable by the first-line chemotherapeutic docetaxel, but will eventually progress as a chemoresistant cancer, prompting a need for additional therapeutics to either replace docetaxel or to be used in combination therapies that increase the effectiveness of chemotherapy. The aberrant activation of the tyrosine kinase receptor c-Met by the active, dimeric form of hepatocyte growth factor (HGF) and the tyrosine kinase receptor RON by macrophage stimulating protein (MSP) results in the overactivation of signaling pathways that encourage cell proliferation, migration, and survival, contributing to the malignant behavior and chemoresistance of many cancers. The onset of metastatic prostate cancer is associated with both increased serum levels of HGF and expression of c-Met and RON in metastatic growths. Our laboratory has developed small molecules that inhibit HGF dimerization, c-Met activation, and malignant cell behaviors in several cancer cell types. Considering the high degree of homology between HGF and MSP, we predict that our strategy for inhibiting the activation of HGF can be extended to develop compounds that dually inhibit HGF and MSP. We hypothesize that inhibiting HGF and MSP with our antagonists will correspondingly reduce activation of c-Met and RON and suppress tumor growth and metastasis in CRPC. We further anticipate a therapy that combines our antagonists and docetaxel will increase the efficacy of chemotherapy by blunting the pro-survival properties of the HGF/c-Met and MSP/RON systems. Preliminary results indicate that our HGF dimerization antagonist Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] significantly inhibits the migration of CRPC cells and increases their susceptibility to docetaxel treatment in vitro. The primary objective of this study is to investigate the feasibility of HGF, MSP, and HGF/MSP dual antagonists as a therapy for CRPC either alone or in combination with docetaxel.
Citation Format: Brett Vanderwerff, Kevin Church, Leen Kawas, Joseph Harding. Novel hepatocyte growth factor and macrophage stimulating protein antagonists for the treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3922. doi:10.1158/1538-7445.AM2015-3922
Abstract 3923: A role for fibroblast growth factor receptors in growth of atypical teratoid rhabdoid tumor cells and as potential therapeutic targets
Authors: Azorsa David O. , Pepper Oliver B. , Chakravadhanula Madhavi , Lee David W. , Montoya Justin J. , Ozols Victor , Bhardwaj Ratan , Arceci Robert J. 
Published: August 2015

Abstract
Malignant rhabdoid tumors are characterized by the loss of the SWI/SNF complex subunit SMARCB1. Atypical Teratoid Rhabdoid Tumor (ATRT) is a rare form of pediatric MRT that occurs in the CNS. Current treatment modalities for this tumor type continue to be surgical resection, chemotherapy and radiotherapy, but overall survival is still relatively low for younger children with this disease. We initially tested the sensitivity of three ATRT cell lines to 48 chemotherapeutic agents and selective inhibitors. Our results indicated that two cell lines CHLA-04-ATRT and CHLA-05-ATRT were sensitive to FGFR inhibition. Further analysis of a panel of five ATRT cell lines indicated that the cell lines CHLA-04-ATRT, CHLA-05-ATRT, CHLA-266 and BT-12 were sensitive to the FGFR inhibitors PD173074, BGJ398 and AZD4547. Interestingly, the ATRT cell line CHLA-06-ATRT did not show sensitivity to FGFR inhibition. Analysis of FGFR protein expression by immunoblot analysis indicated that CHLA-04-ATRT and CHLA-266 cells expressed both FGFR1 and FGFR2, while the cell lines CHLA-05-ATRT and BT-12 expressed only FGFR1. The CHLA-06-ATRT cell line did not show expression of any FGFRs. We further demonstrated functional FGFR activity in the ATRT cell lines by treating growth factor-deprived ATRT cells with FGF-1 or FGF-2, both of which led to dose dependent cell growth only in the cell lines expressing FGFR1 or FGFR2. We are currently investigating the expression of FGFR isoforms in ATRT patient samples. Taken together, our results demonstrate a potential role for FGFR1 and FGFR2 in the survival and proliferation of ATRT cells and indicate that FGFRs could serve as potential targets for therapy in ATRT.
Citation Format: David O. Azorsa, Oliver B. Pepper, Madhavi Chakravadhanula, David W. Lee, Justin J. Montoya, Victor Ozols, Ratan Bhardwaj, Robert J. Arceci. A role for fibroblast growth factor receptors in growth of atypical teratoid rhabdoid tumor cells and as potential therapeutic targets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3923. doi:10.1158/1538-7445.AM2015-3923
Abstract 3930: Targeted cancer gene sequencing identifies potential causative novel candidate mutations among Caucasian colon carcinogenesis
Authors: Ashktorab Hassan , Nickerson Michael , Varma Sudhir , Mokarram Pooneh , Naghibalhossaini fakhraddin , Moore Lee , Boland Joseph , Bass Sara , Yeager Meredith , Haung Wen-Yi , Brim Hassan 
Published: August 2015

Abstract
Much of the sporadic colorectal cancer's (CRC) underlying genetic ‘cancer driver’ mutations are unknown in patients from specific ethnic groups. Here, we report the identification of distinct novel variants from adenoma and CRC patients in mismatch repair (MMR) genes MHS3 and MSH6, and in PIK3CA and APC.
We developed a panel of 20 frequently altered colon cancer genes comprised of ACVR2A, APC, ARID1A, BRAF, FAM123B, FBXW7, KRAS, MSH2, MSH3, MSH6, NRAS, PIK3CA, POLE, PTEN, SMAD2, SMAD4, SOX9, TCF7L2, TGFBR2, and TP53 for targeted sequencing in 65 colon tissues, comprised of 1 normal tissue sample, 2 adenomas, and 63 tumors. Multiplex PCR and Ion Torrent sequencing was used to examine 98.8% of the targeted exons and splice junctions at a depth of sequencing that allowed for high confidence variant calling (most bases were covered by ≥ 500 reads). After alignment and variant calling, we annotated the variants with information from the 1000 Genomes Project, COSMIC, Polyphen2, and PFAM domain and transcription factor motifs. Excluding synonymous SNVs, 3 variants in adenoma, and 692 variants in tumors were detected. Two were known pathogenic variants (MSH6 p.R965H and APC p.R1432X). Novel variants (286, 244, and 115) were found in MMR genes (MSH6 and MSH3), APC, and PIK3CA, respectively. Most of the MMR (n = 98), APC (n = 128), and PIK3CA (n = 43) variants are deleterious. Notably, among the 63 CRC cases, [(29/61 = 46%) 46%) for MSH3, MSH6] [(19/63 = 30%) (30%) for PIK3CA] [31/63 = 49%) (49%) for APC)] carried likely deleterious MMR, PIK3CA and APC mutations, respectively, suggesting the value of a broad cancer gene panel. These finding further highlight the relevance of APC, PIK3CA genes in CRC onset but also the potential underestimation of the MSI-H in sporadic CRC as many of the novel mutations in MMR gens detected here were of a deleterious nature.
Citation Format: Hassan Ashktorab, Michael Nickerson, Sudhir Varma, Pooneh Mokarram, fakhraddin Naghibalhossaini, Lee Moore, Joseph Boland, Sara Bass, Meredith Yeager, Wen-Yi Haung, Hassan Brim. Targeted cancer gene sequencing identifies potential causative novel candidate mutations among Caucasian colon carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3930. doi:10.1158/1538-7445.AM2015-3930
Abstract 3938: MafB and ETS2 potentiate Notch signaling in T-ALL
Authors: Pajcini Kostandin , Xu Lanwei , Lee Curtis , Cherry Sara , Pear Warren 
Published: August 2015

Abstract
Despite the high frequency of activating Notch mutations in human T-cell acute lymphoblastic leukemia (T-ALL), these naturally occurring Notch1 mutant alleles fail to efficiently drive leukemia onset, indicating a requirement for collaborating events that potentiate the Notch oncogenic program. We performed an in vitro gain-of-function screen to identify gene products that enhanced the signaling strength of naturally occurring Notch mutants. Both MafB and ETS2 emerged as candidates that individually potentiated Notch signaling, and when co-expressed, they dramatically enhanced signaling strength comparable to the levels induced by MAML1, a core component of the Notch transcriptional complex. Knockdown of MafB in mouse T-ALL cell lines suppressed the expression of common Notch target genes, including cMyc and Hes1, and sustained knockdown of MafB expression impaired T-ALL cell growth in cell competition assays. Notably, MafB is sufficient to enhance the oncogenic potential of naturally occurring Notch mutants in vivo, by significantly accelerating T-ALL onset. Moreover, this enhanced Notch pathway activation required MafB-ETS2 interaction, and facilitated the recruitment of PCAF and p300. Although all primary human T-ALL samples that express MafB display an elevated Notch pathway signature, the T-ALL samples positive for high levels of MafB expression, exhibit low levels of Notch1 expression, further suggesting a role for MafB as an enhancer. These data present a novel mechanism for the enhancement of the oncogenic potential of weak Notch mutants in leukemia and introduce MafB as a potential therapeutic target in T-ALL.
Note: This abstract was not presented at the meeting.
Citation Format: Kostandin Pajcini, Lanwei Xu, Curtis Lee, Sara Cherry, Warren Pear. MafB and ETS2 potentiate Notch signaling in T-ALL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2015-3938
Abstract 3942: Oncogenic BRAF fusion induces MAPK-pathway activation targeted by MEK inhibitor and phosphatidylinositol 3-kinase inhibitor combination treatment in mucosal melanoma
Authors: Kim Han Sang , Jang Kang Won , Jung Minkyu , Kim Soo Hee , Kim Tae-Min , Cho Byoung Chul 
Published: August 2015

Abstract
Background: Although remarkable progress has been made in the genomic characterization of cutaneous melanoma, the genetic alterations of primary mucosal melanoma (PMM) remain largely unknown. This study aims to investigate the recurrent mutations in PMM and to characterize the oncogenic potential of the newly identified ZNF767-BRAF fusion as well as its therapeutic implications in PMM.
Methods: A total of 46 PMMs underwent exon-capture sequencing of 111 cancer-associated genes to identify somatic non-synonymous mutations, copy number alterations, and structural variations. A cancer cell with a novel ZNF767-BRAF fusion was established from a patient with PMM of the respiratory tract, who was refractory to vemurafenib. To characterize the oncogenic functions of the novel ZNF767-BRAF fusion, we performed western blot, soft agar growth assay and in vivo tumor. The inhibitory effects of vemurafenib, trametinib, buparlisib and LEE011 monotherapy and their combination treatment were measured in vitro and in vivo.
Results: Targeted exon-capture sequencing of 46 PMMs revealed a total of 48 somatic non-synonymous mutations in 26 genes. Eight genes harbored recurrent mutations on NRAS (n = 6; 13%) and TP53 (n = 4; 9%) along with BRAF, KIT, MAP3K9, C8A, KRAS, FGFR3 (all observed in two cases; 4%). Of note, a novel ZNF767-BRAF fusion was identified in a PMM of the respiratory tract refractory to vemurafenib treatment. ZNF767-BRAF fusion was validated by Sanger sequencing. We show that ZNF767-BRAF encoded protein promotes the dimerization of RAF and potently activates mitogen-activated protein kinase pathway. The ectopic expression of ZNF767-BRAF fusion induced tumor formation as shown in colony forming assay and tumor xenograft model. The treatment of trametinib inhibited the growth of PMM cells harboring the ZNF767-BRAF fusion but vemurafenib showed no inhibitory effects. Compared with either agent alone, the combination of trametinib and buparlisib showed synergistic antitumor effects in vitro and in vivo.
Conclusions: The genomic makeup of PMM is remarkably diverse and distinct from that of cutaneous melanoma. BRAF fusion defines a new molecular subset of PMM and can be therapeutically targetable by the combination of MEK inhibitor and PI3K Inhibitor.
Citation Format: Han Sang Kim, Kang Won Jang, Minkyu Jung, Soo Hee Kim, Tae-Min Kim, Byoung Chul Cho. Oncogenic BRAF fusion induces MAPK-pathway activation targeted by MEK inhibitor and phosphatidylinositol 3-kinase inhibitor combination treatment in mucosal melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3942. doi:10.1158/1538-7445.AM2015-3942
Abstract 3955: A primary cell-based assay to identify initiating oncogenic events in neuroblastoma
Authors: Olsen Rachelle , Otero Joel , Yin Zhirong , Garcia-Lopez Jesus , Freeman Kevin 
Published: August 2015

Abstract
The pediatric cancer neuroblastoma (NBL) forms from immature cells of the sympathetic nervous system (SNS). A prominent category of high-risk NBL is MYCN amplification with loss of heterozygosity (LOH) at 1p36. This LOH includes the chromatin remodeling factor, CHD5, a proposed tumor suppressor of NBL and can include ARID1A, a component of the SWI/SNF chromatin remodeling complex.
To identify genetic changes that cooperate with MYCN amplification in initiating NBL we developed an assay based on oncogenic transformation of neural crest cells (NCCs), the progenitors of the SNS. Isolation of NCCs from E9.5 mouse embryos resulted in a population that was ∼90% positive for the NCC markers p75, Sox10, and Ascl1, suggesting a highly enriched population.
Next, we tested the ability of N-Myc infected NCCs to form tumors in vivo. In pilot experiments using NCCs with compromised p53, we obtained subcutaneous tumors following injection of NCCs in nude mice. Resulting tumors were diffusely positive for neuronal markers such as synaptophysin, MAP2, and Tyrosine hydroxylase (TH). Tumors also contained focal areas of divergent differentiation characteristic of melanoma, Schwannoma, and osteosarcoma, all cancers that can arise from NCC lineages. To our knowledge, this is the first report of cancer from transformed primary neural crest cells.
To more closely model NBL genetics, we replaced loss of p53 with shRNA to knockdown CHD5 and ARID1A prior to N-Myc infection. Injection of the resulting NCCs also resulted in tumor formation in nude mice. Tumors were uniformly positive for neuronal markers including TH and Ascl1, as well as Phox2B, a marker of undifferentiated NBL, and with no evidence of other cancers. Future studies in understanding the interactions of N-Myc overexpression with loss of these chromatin remodeling factors should further increase our understanding of NBL development.
Citation Format: Rachelle Olsen, Joel Otero, Zhirong Yin, Jesus Garcia-Lopez, Kevin Freeman. A primary cell-based assay to identify initiating oncogenic events in neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3955. doi:10.1158/1538-7445.AM2015-3955
Abstract 396: Ibrutinib exerts potent antifibrotic activity in a mouse model of pancreatic adenocarcinoma
Authors: Massó-Vallés Daniel , Jauset Toni , Serrano Erika , Sodir Nicole M. , Pedersen Kim , Affara Nesrine I. , Whitfield Jonathan R. , Beaulieu Marie-Eve , Evan Gerard I. , Elias Laurence , Arribas Joaquín , Soucek Laura 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a disease with a poor prognosis characterized by a dense stromal fibroinflammatory reaction that is a significant obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells that are a key component of the PDAC microenvironment and whose infiltration often correlates with poor patient outcome. Reducing the stroma is of key importance for improving the standard of care. We have previously successfully utilized ibrutinib, a clinically-approved Bruton's Tyrosine Kinase inhibitor, as a mast cell blocker in a mouse model of β cell tumorigenesis. Here, we made use of a transgenic mouse model of PDAC and patient derived xenografts (PDXs) to assess ibrutinib's impact on the tumor microenvironment and animal survival. Across these various experimental pre-clinical models, we show that ibrutinib significantly diminishes tissue fibrosis, increases survival and improves the outcome of standard care. Our results suggest that ibrutinib could be deployed to one more type of cancer and open the way to new clinical trials assessing its therapeutic impact in PDAC patients.
Citation Format: Daniel Massó-Vallés, Toni Jauset, Erika Serrano, Nicole M. Sodir, Kim Pedersen, Nesrine I. Affara, Jonathan R. Whitfield, Marie-Eve Beaulieu, Gerard I. Evan, Laurence Elias, Joaquín Arribas, Laura Soucek. Ibrutinib exerts potent antifibrotic activity in a mouse model of pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 396. doi:10.1158/1538-7445.AM2015-396
Abstract 3968: Identification of microRNAs markers in patients with oral squamous cell carcinomas for the presence of lymph nodes metastasis
Authors: Zamunér Fernando Tadeu , Carvalho André Lopes , Kowalski Luiz Paulo , Vettore André Luiz 
Published: August 2015

Abstract
Introduction: Oral cancer is the most common subset of head and neck squamous cell carcinomas (OSCC). These tumors often have an aggressive clinical outcome hallmarked by a propensity for local invasion and regional nodal metastasis. The presence of metastatic disease in cervical lymph nodes is an important prognostic factor and it influences in the choice of the therapeutic strategy to be adopted. Thus, the identification of molecular markers able to select patients who are at high risk for lymph node metastasis and/or locoregional recurrence could be of great value. Recent studies have shown that microRNAs can be regulators of the tumor metastasis process by the activation of various signaling pathways involved in this process being useful in diagnosis, determination of disease prognosis and prediction of therapeutic response. PURPOSE: to identify microRNAs expressed in OSCC associated with the presence of lymph node metastasis. METHODS: Tumor samples were obtained from patients diagnosed with OSCC at the Head and Neck Surgery Department, Cancer Hospital of Barretos. For microRNA microarrays experiments, total RNA from 32 tumor samples (12 without lymph node metastasis and 12 with metastasis) was extracted labelled and hybridizated Analysis of microarray data was performed using GeneSpring GX 12.0 and R program. RESULTS: This analysis allowed the identification of 10 microRNAs differentially expressed in the comparison between metastatic and non-metastatic OCCS cases. These microRNAs will be validate and selected by qRT-PCR in an independent cohort of OSCC patients and correlate the molecular data with the clinical features of the patients.
Citation Format: Fernando Tadeu Zamunér, André Lopes Carvalho, Luiz Paulo Kowalski, André Luiz Vettore. Identification of microRNAs markers in patients with oral squamous cell carcinomas for the presence of lymph nodes metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3968. doi:10.1158/1538-7445.AM2015-3968