bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3328: Protochadherin 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis
Authors: Zhou Xiaorong , Updegraff Barrett L. , Guo Yabin , Peyton Michael , Girard Luc , Larsen Jill E. , Xie Xian-Jin , Zhou Yunyun , Hwang Tae Hyun , Xie Yang , Rodriguez-Canales Jaime , Villalobos Pamela , Behrens Carmen , Ignacio Wistuba I. , Minna John D. , O'Donnell Kathryn A. 
Published: July 2017

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the efficacy of membrane proteins as therapeutic targets in human malignancies, we examined cell-surface receptors that may act as drivers of lung tumorigenesis. Here we report that Protocadherin 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in NSCLC tumors, and high expression of PCDH7 is associated with poor clinical outcome. PCDH7 overexpression synergizes with KRAS and EGFR to induce MAPK signaling and tumorigenesis. Conversely, PCDH7 depletion suppresses ERK activation, sensitizes cells to MEK inhibitors, and reduces tumor growth. PCDH7 potentiates ERK signaling by facilitating interaction of protein phosphatase PP2A with its potent inhibitor, the SET oncoprotein. By establishing a previously unanticipated oncogenic role for PCDH7 in lung tumorigenesis, these results provide proof-of-concept support for the development of novel therapies that target PCDH7 at the cell surface of NSCLC cells. Experiments to evaluate the role of Pcdh7 in Kras-mediated lung tumorigenesis in vivo using autochthonous mouse models, which we expect to lend further support for therapeutic targeting of this protein, are in progress.
Citation Format: Xiaorong Zhou, Barrett L. Updegraff, Yabin Guo, Michael Peyton, Luc Girard, Jill E. Larsen, Xian-Jin Xie, Yunyun Zhou, Tae Hyun Hwang, Yang Xie, Jaime Rodriguez-Canales, Pamela Villalobos, Carmen Behrens, Wistuba I. Ignacio, John D. Minna, Kathryn A. O'Donnell. Protochadherin 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3328. doi:10.1158/1538-7445.AM2017-3328
Abstract 3329: Combinatorial blockade of ERBB receptors in HER2 low breast cancer
Authors: Berdiel-Acer Mireia , Reinz Eileen , Abnaof Khalid , Burmester Sara , Will Rainer , Korf Ulrike , Wiemann Stefan 
Published: July 2017

Abstract
Large number of breast cancer patients clinically classified as HER2 negative, show low/moderate levels of HER2 along with other ERBB receptors. Concomitant blockade of EGFR, ERBB2 and ERBB3 with specific therapeutic antibodies (cetuximab, trastuzumab/pertuzumab and lumretuzumab, respectively) appears as a beneficial approach to improve survival of patients who have failed to previous treatment strategies. Additionally, ERBB3 expression has been reported as a trastuzumab resistance mechanism in HER2 positive subtypes.We have confirmed a specific pattern of ERBB receptors expression in different breast cancer subtypes. Individual and combined blockade of the receptors with therapeutic antibodies has been tested in vitro using a metabolic viability assay (Cell Titer Glo) and their effects in cell cycle status measured by BrdU staining. All four therapeutic antibodies bind to the respective extracellular domains inhibiting downstream signaling pathways. Response to individual treatment is cell dependent and correlates with EGFR expression in the triple negative MDA-MB-468 but not in luminal T47D cancer cell line. Response of T47D cells to lumretuzumab is higher when combined with pertuzumab or trastuzumab, suggesting ERBB2/ERBB3 dimer as the most relevant one, an effect more evident upon ectopic addition of NRG1 (only ligand for ERBB3). Long exposure of MDA-MB468 cells to cetuximab induces ERBB3 expression and increases its sensitivity to cetuximab when combined. As well as, in the HER2+ BT474 cancer cell line resistant to trastuzumab, higher levels of ERBB3 also make cells more sensitive to alternative anti-ERBB therapies. To establish the role of ERBB4 (no specific therapeutic antibody) in the whole ERBB network, stable knock-down regulation (shRNA) has been performed in T47D cells. Although treatment of HER2 overexpressing breast tumors has been successful, targeting other ERBB members in a HER2 moderate/low scenario seems to be a promising approach in combinatorial therapies; even in resistant cell lines. Thus, better characterization of ERBB network should help to pave the way for a personalized treatment of HER2 low breast cancer. [U.K.: Deceased March, 2016]
Citation Format: Mireia Berdiel-Acer, Eileen Reinz, Khalid Abnaof, Sara Burmester, Rainer Will, Ulrike Korf, Stefan Wiemann. Combinatorial blockade of ERBB receptors in HER2 low breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3329. doi:10.1158/1538-7445.AM2017-3329
Abstract 334: PTEN-L regulates epithelial growth and macrophage function
Authors: Wolfe Andrew L. , Hopkins Benjamin D. , Riquelme Sebastián A. , Kitur Kipyegon , Ozturk Sait , Kang Kyeongah , Remark Romain , Rahman Adeeb , Lin Chyuan-Sheng , Merad Miriam , Szabolcs Matthias , Chen Shu-Hsia , Prince Alice , Parsons Ramon 
Published: July 2017

Abstract
PTEN is among the most frequently mutated and deleted tumor suppressor genes in many malignancies, including breast cancer. An alternatively translated long form of PTEN, termed PTEN-L, has divergent functionality from PTEN, although its function at the organism level has not been studied. Here, we report a knockout mouse with specific ablation of PTEN-L expression but intact expression of PTEN. These mice display mammary ductal hyperplasia characterized by increased luminal growth and increased numbers of macrophages in the surrounding stroma. Macrophages are particularly affected by PTEN-L loss, with significant changes to their secretomes and functional deficiencies in clearing bacterial infections, consistent with a shift toward an M2-like polarization. Overall, these findings demonstrate that PTEN-L has unique functions in regulating mammary epithelial growth and macrophage functionality that are independent of canonical PTEN.
Citation Format: Andrew L. Wolfe, Benjamin D. Hopkins, Sebastián A. Riquelme, Kipyegon Kitur, Sait Ozturk, Kyeongah Kang, Romain Remark, Adeeb Rahman, Chyuan-Sheng Lin, Miriam Merad, Matthias Szabolcs, Shu-Hsia Chen, Alice Prince, Ramon Parsons. PTEN-L regulates epithelial growth and macrophage function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 334. doi:10.1158/1538-7445.AM2017-334
Abstract 3347: Exploring the role of ASXL family of genes in enabling oncogenic AR-signaling in prostate cancer
Authors: Parolia Abhijit , Cao Xuhong , Chinnaiyan Arul 
Published: July 2017

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related mortality in North American men. In recent years, there has been mounting evidence establishing the centrality of epigenetic mechanisms in PCa initiation and progression. Accordingly, various epigenetic genes have been described to collaborate with the androgen receptor (AR) in enabling its oncogenic transcriptional program and aberrantly restoring its activity in metastatic castration resistant PCa (mCRPC). Concordantly, our lab has recently described two epigenetic genes, BRD4 & MLL2, as key co-activators of the AR signaling complex. Furthermore, we have demonstrated the therapeutic benefits of inhibiting the activity of these genes in advanced PCa. Thus, in a setting where invariably all metastatic PCa patients progress to evolve resistance to anti-AR therapy, epigenetic genes emerge as potent co-targets with the promise to improve patient outcomes. To To identify novel AR-collaborating genes, as part of a multi-institutional consortium, our lab had performed comprehensive molecular profiling of 150 mCRPC patient tumors. This study revealed multiple genetic aberrations in chromatin modifier genes. Interestingly, this list comprised of recurrent mutations in the ASXL family of genes in about ~5% of the cases. ASXL family members are epigenetic scaffolding proteins that assemble chromatin modifiers and transcription factors to specific genomic loci with histone modifications. Although intricately involved in the genesis of acute myeloid leukemia, hitherto, no study has comprehensively described the role of ASXL genes in PCa biology. Two members of this family, ASXL1 and ASXL2, are robustly expressed in PCa. Co-immunoprecipitation assays revealed that these proteins also reside in the AR-signaling complex. Notably, siRNA-mediated inhibition of these genes dramatically attenuated proliferation of AR-dependent PCa cells, but had minimal effect on non-neoplastic prostate cells. These preliminary results strongly implicate ASXL genes in the oncogenic re-programming of AR-activity and warrant further investigation towards exploring of their therapeutic value in currently incurable mCRPC.
Citation Format: Abhijit Parolia, Xuhong Cao, Arul Chinnaiyan. Exploring the role of ASXL family of genes in enabling oncogenic AR-signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3347. doi:10.1158/1538-7445.AM2017-3347
Abstract 336: PIK3CB/p110B is a survival factor in glioblastoma
Authors: Pridham Kevin J. , Guo Sujuan , Sheng Zhi 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) is lethal even after surgical removal of the tumor, radiation, and chemotherapy. Residual tumor cells form an intractable tumor in nearly all patients within two years. Recurrent GBM is incurable due to resistance to current therapies. Inhibitors of PI3K (phosphatidylinositol-4,5-biphosphate 3-kinase)-a signaling pathway that causally contributes to tumor formation/recurrence-have been used to treat recurrent GBMs and achieved modest clinical effect. This is perhaps attributed to non-selective inhibition of PI3K isoforms, which yields intolerable toxicity. Class IA PI3K isoforms include three catalytic subunits (PIK3CA, B, or D that encodes p110α, β, or δ) and three regulatory subunits (PIK3R1-3 that encodes p85 isoforms). Our recent work indicates that PIK3CB levels positively correlate with the chances/risk of GBM recurrence, while being inversely associated with patient prognosis. This suggests that PIK3CB/p110β is important for GBM cell survival. To test this hypothesis, we first measured the expression of PI3K isoforms in a panel of 9 GBM cell lines. We found that U87MG, SF295, and U251 expressed much higher levels of p110β, coinciding with the levels of phosphorylated AKT. We then knocked down PIK3CA, B, and D in human U87MG cells and found that only depletion of PIK3CB/p110β resulted in an inactivation of downstream AKT. Moreover, knockdown of PIK3CB/p110β, but not other isoforms, induced substantial growth inhibition in U87MG, SF295 and U251 cells. This is congruent with the result that inhibition of PIK3CB/p110β activated apoptosis in U87MG cells. We also report that treatment of p110βhigh GBM cells with isoform specific inhibitors selectively represses the viability of these cells. Finally, we report that ectopic expression of p110β, but not p110α or δ, partially rescued U87MG cells from growth inhibition induced by TGX-221, a p110β-selective inhibitor. Collectively, our results demonstrate that PIK3CB/p110β is an important selective survival factor in GBM, underscoring the divergent roles of PI3K isoforms in GBM disease progression/recurrence and future therapeutic intervention.
Citation Format: Kevin J. Pridham, Sujuan Guo, Zhi Sheng. PIK3CB/p110B is a survival factor in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 336. doi:10.1158/1538-7445.AM2017-336
Abstract 3365: Epigenetic inactivation of PTPRT and sensitivity to STAT3 inhibition in lung cancer
Authors: Sen Malabika , Kindsfather Audrey , Herman James G. 
Published: July 2017

Abstract
Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor is persistently activated in several malignancies including lung cancer. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 transcriptional activity, and is methylated in many types of human cancer. Loss-of-function of PTPRT by promoter methylation contributes to STAT3 mediated growth and survival and represent one of the plausible mechanism of STAT3 hyperactivation. We report identification of hypermethylation in CpG islands of the PTPRT promoter which correlates with its transcriptional silencing as well as expression of pSTAT3 protein and STAT3 target genes in both lung cancer cell lines and primary human tumors. Analyses of the TCGA (The Cancer Genome Atlas) data revealed that PTPRT promoter is frequently hypermethylated in a subset of lung squamous cell carcinoma and approximately 25% of adenocarcinoma tumors in association with downregulation of PTPRT mRNA expression. This observation was verified in vitro using lung cancer cell lines. Out of the 7 lung cancer cell lines examined, one lung cancer cell line showed lack of methylation (only unmethylated sequences) of the PTPRT promoter region and revealed mRNA expression (H520). All 6 cell lines which showed PTPRT promoter methylation had nearly absent PTPRT mRNA and had high levels of pSTAT3Tyr705, while H520 had little or no pSTAT3Tyr705 protein expression. Silencing of PTPRT using siRNA in H520, where PTPRT was not endogenously silenced by promoter hypermethylation, resulted in the upregulation of the STAT3 target genes such as cyclin D1 and Bcl-XL mRNA and protein expression as well as increased pSTAT3Tyr705 level. Analyses of the methylation status in the PTPRT promoter region in primary lung tumor samples revealed methylation in one of the 3 tumor samples. This correlated with increased STAT3 target genes (cyclin D1 and Bcl-XL) mRNA expression. In lung cancer cell lines, PTPRT promoter methylation is associated with sensitivity to STAT3 inhibition. Our data suggests that silencing of PTPRT by promoter hypermethylation is a frequent mechanism of STAT3 hyperactivation, and targeting STAT3 may be an effective molecular targeted approach in the treatment of this subset of lung cancer.
Citation Format: Malabika Sen, Audrey Kindsfather, James G. Herman. Epigenetic inactivation of PTPRT and sensitivity to STAT3 inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3365. doi:10.1158/1538-7445.AM2017-3365
Abstract 3380: Synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition in ovarian clear cell carcinoma
Authors: Berns Katrien , Caumanns Joseph J. , Hijmans E Marielle , Gennissen Annemiek , Evers Bastiaan , Wisman Bea A. , Meersema Gert Jan , Lieftink Cor , Beijersbergen Roderick L. , Itamochi Hiroaki , Zee Ate G. van der , Jong Steven de , Bernards René 
Published: July 2017

Abstract
Introduction:
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Given that ARID1A is inactivated by mutation in over 50% of ovarian clear cell carcinomas, we pursued an ARID1A synthetic lethal screening strategy to identify druggable targets in OCCC.
Experimental procedures:
We performed synthetic lethal kinome short hairpin (shRNA) screens in a large panel (n=14) of OCCC cell lines having different ARID1A mutation status. Hit validation was performed with isogenic ARID1A ko cell line pairs and in (patient-derived) xenograft mouse models.
Summary of the data:
We show here that BRD2 inhibition is synthetic lethal with ARID1A mutation in ovarian clear cell cancer cells. Importantly, inhibiting the BET family of proteins, to which BRD2 belongs, with small molecules specifically inhibits proliferation of ARID1A mutated cell lines both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. We demonstrate that ARID1A loss leads to upregulation of the WNT ligand WNT10B, possibly causing a WNT dependency in the ARID1A mutant lines. BET inhibitors cause a reduction in WNT10B expression and WNT target genes such as MYC, JUN and WISP1, providing a potential explanation for the observed synthetic lethal interaction with ARID1A loss.
Conclusions:
Our study uncovered a new synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition, suggesting a new treatment strategy for ARID1A mutant ovarian clear cell carcinomas.
Citation Format: Katrien Berns, Joseph J. Caumanns, E Marielle Hijmans, Annemiek Gennissen, Bastiaan Evers, Bea A. Wisman, Gert Jan Meersema, Cor Lieftink, Roderick L. Beijersbergen, Hiroaki Itamochi, Ate G. van der Zee, Steven de Jong, René Bernards. Synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition in ovarian clear cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3380. doi:10.1158/1538-7445.AM2017-3380
Abstract 3385: Genomic landscapes of pulmonary sclerosing hemangioma
Authors: Jung Seung-Hyun , Kim Min Sung , Shin Sun , Han Mi-Ryung , Cho Yu Jin , Kim So Youn , Lee Sug Hyung , Chung Yeun-Jun 
Published: July 2017

Abstract
Pulmonary sclerosing hemangioma (PSH) is a benign tumor that usually presents as a solitary, well-defined mass in the lung. The PSH predominantly affects females with a higher incidence in the Far East. Histologically, the tumor cells in PSH consist of two cell types (cuboidal epithelial and polygonal stromal cells). Immunohistochemical and ultrastructural studies have identified that both cells are derived from undifferentiated respiratory epithelium that is the histologic origin of lung adenocarcinoma as well. Previous studies have shown that PSH and adenocarcinoma in the lung share some immunohistochemical and genetic features. However, as for somatic mutations, whereas many driver genes for lung adenocarcinomas have been identified, there have not been any candidate driver mutations identified in PSHs, except for low frequency mutations in β-catenin and TP53. Frequent somatic mutations identified in lung adenocarcinomas such as KRAS and EGFR have not been detected in PSH, suggesting that genomic alterations of these two lung tumors might be different from each other. Also, there is no evidence of PSH progression to lung cancers. These earlier data indicate that despite the common cellular origin of PSH and lung adenocarcinoma, genetic mechanisms for their development may be different. Based on the established concept that PSH is a true tumor, we hypothesize that it may harbor somatic mutations. In this study, we conducted whole exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and β-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent β-catenin mutations (overall 3/68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Since the AKT1 mutations were not found to co-occur with β-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be a single most common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas including a high rate of AKT1 mutation in PSHs. These genomic features of PSH discovered in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors.
Citation Format: Seung-Hyun Jung, Min Sung Kim, Sun Shin, Mi-Ryung Han, Yu Jin Cho, So Youn Kim, Sug Hyung Lee, Yeun-Jun Chung. Genomic landscapes of pulmonary sclerosing hemangioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3385. doi:10.1158/1538-7445.AM2017-3385
Abstract 34: A MET x MET bispecific antibody that induces receptor degradation potently inhibits the growth of MET-addicted tumor xenografts
Authors: DaSilva John 
Published: July 2017

Abstract
Aberrant regulation of MET receptor tyrosine kinase signaling is associated with development and progression of various human tumors. Elevated MET signaling during tumorigenesis results from MET amplification, mutation or up-regulation of the ligand, HGF. MET amplification is thought to be a key driver of oncogenesis in non-small cell lung cancers (NSCLC) and oesophagogastric malignancies. In addition, mutations resulting in exon 14 deletion of MET have been described as oncogenic drivers in a subset of NSCLC. Both preclinical and recent clinical results indicate that tumors harboring these genetic alterations respond to MET inhibitors, validating MET as a cancer driver.
We have developed a novel bispecific antibody that binds to two distinct epitopes on MET. The METxMET bispecific antibody blocks HGF binding and exhibits very low agonist activity (much weaker than either of its parental antibodies). Furthermore, the METxMET bispecific antibody effectively promotes MET degradation, thereby inhibiting ligand-independent signaling in MET-amplified tumor cells. The METxMET bispecific antibody exhibits strong anti-tumor efficacy in xenograft models harboring MET genetic alterations, either completely inhibiting tumor growth (EBC1 MET-amplified NSCLC) or promoting substantial tumor regression (SNU5 MET-amplified gastric cancer, Hs746T MET-amplified/MET exon 14 skip gastric cancer). Analysis of lysates from SNU5 tumors treated with the METxMET bispecific antibody confirms its ability to effectively promote MET degradation in vivo. Finally, the METxMET bispecific antibody strongly inhibits the growth of a glioblastoma xenograft model (U118) driven by autocrine HGF signaling. In summary, we have generated a novel METxMET bispecific antibody that potently inhibits the growth of MET-dependent tumor xenografts. Our data suggest that antibody-mediated MET degradation may be an effective clinical strategy in tumors harboring MET genetic alterations.
Citation Format: John DaSilva. A MET x MET bispecific antibody that induces receptor degradation potently inhibits the growth of MET-addicted tumor xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 34. doi:10.1158/1538-7445.AM2017-34