bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 351: mTOR-ERK co-targeting strategies for head and neck cancer therapy
Authors: Wang Zhiyong , Delgado Esteban , Yamaguchi Kosuke , Iglesias-Bartolomé Ramiro , Amornphimoltham Panomwat , Molinolo Alfredo , Chen Qianming , Gutkind J.Silvio 
Published: July 2017

Abstract
Despite therapeutic advances in the past decade, head and neck squamous cell carcinoma (HNSCC) continues to be a major public health concern. Although recent studies of human cancer genomes identified remarkable complexity of genomic alterations in HNSCC, surprisingly, most aberrations have fallen within key driver signaling pathways. Among them, PI3K/AKT/mTOR pathway is most frequently activated in over 80% of the HNSCC patients. We showed that the majority of HNSCC lesions exhibit high levels of phosphorylated ribosomal S6 protein (pS6), key downstream target of the AKT-mTOR pathway, and that inhibition of mTOR by the use of rapamycin causes a rapid decrease in the level of pS6 and the apoptotic death of HNSCC tumor xenografts, thereby causing tumor regression. Our initial studies identified the AKT-mTOR pathway as a potential therapeutic target for HNSCC and provided strong rational to initiate multiple clinical trials. Indeed, inhibitors of PI3K/AKT/mTOR block mTOR activity and exert a beneficial response in HNSCC patients. However, therapeutic resistance was evidenced in several trials, which might be due to the activation of adaptive survival signaling in tumor cells. To explore the therapeutic option that can overcome the resistance, we performed a synthetic lethality screen in HNSCC cell lines using shRNA libraries. We found that multiple molecules involved in ERK pathway were highly represented. Furthermore, treating HNSCC cell lines harboring activated mTOR with small molecule inhibitors that target PI3K/AKT/mTOR pathway can sequentially induce ERK activation, which is consistent with the findings observed in numerous clinical trials. We demonstrated that co-targeting mTOR and ERK using trametinib, a MEK1/2 inhibitor or cetuximab, an EGFR monoclonal antibody, exhibited the synergistic effect by sensitizing HNSCC to priming with the mTOR inhibitor. Specifically, mTOR-ERK co-targeting prevented the growth of HNSCC tumor xenografts by decreasing cell proliferation, reducing lymphangiogenesis and activating apoptosis. In addition, we have recently used a phosphoproteomics approach to identify the molecular mechanisms of ERK feedback activation caused by PI3K/AKT/mTOR inhibition. Overall, our promising findings from these preclinical studies suggest that the use of mTOR-ERK co-targeting strategies may provide the novel alternative approach to achieve durable responses (cure) in HNSCC cancer patients.
Citation Format: Zhiyong Wang, Esteban Delgado, Kosuke Yamaguchi, Ramiro Iglesias-Bartolomé, Panomwat Amornphimoltham, Alfredo Molinolo, Qianming Chen, J.Silvio Gutkind. mTOR-ERK co-targeting strategies for head and neck cancer therapy [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 351. doi:10.1158/1538-7445.AM2017-351
Abstract 3512: Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia
Authors: Song Chunhua , Ge Zheng , Li Jianyong , Chen Baoan , Dovat Elanora , Dovat Katarina , Payne Jonathon , Dovat Sinisa 
Published: July 2017

Abstract
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL.
Citation Format: Chunhua Song, Zheng Ge, Jianyong Li, Baoan Chen, Elanora Dovat, Katarina Dovat, Jonathon Payne, Sinisa Dovat. Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia [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 3512. doi:10.1158/1538-7445.AM2017-3512
Abstract 3516: RUNX1 controls EGFR signaling pathway in non-small cell lung cancer cells
Authors: Matsuo Akihiko 
Published: July 2017

Abstract
Epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy for non-small lung cancer (NSCLC). Mitogen-inducible gene 6 (Mig6) is known to be a negative feedback regulator of EGFR. Mig6 inhibits EGFR kinase activity and promote wild-type EGFR trafficking to the degradation pathway. Down-regulation of Mig6 is found in poor prognostic NSCLC. Previous gene array analysis results suggested that Mig6 is downregulated by runt-related transcription factor 1 (RUNX1), yet the detailed relationship between RUNX1 and Mig6 in NSCLC has not been elucidated. Herein we demonstrate that RUNX1 inhibition is effective for wild-type EGFR NSCLC. Tet-inducible shRNA mediated RUNX1 knockdown in wild-type EGFR cell line LU99A led to the increased expression of Mig6 and decreased expression of phosphorylated form of EGFR as well as deactivation of EGFR/ERK pathway. RUNX1 knockdown subsequently induced apoptosis in LU99A cells. Silencing of Mig6 in LU99A cells promoted the proliferation of these cancer cells and increased expression of phosphorylated form of EGFR, highlighting the importance of this EGFR signaling cascade in the maintenance of wild-type EGFR NSCLC. Indeed, RUNX1 overexpression promoted cell proliferation and decreased expression of Mig6 and increased phosphorylated form of EGFR. Notably Mig6 knockdown in RUNX1 knockdown LU99A cells increased their proliferation rates, indicating that Mig6 plays an important role in RUNX1-mediated pro-oncogenic pathway. We next examined the efficacy of a novel small molecule which specifically binds and inhibits the RUNX1 (We named it as CM). CM was drastically effective for wild-type EGFR NSCLC cell lines A549 and LU99A which are naturally resistant to EGFR Tyrosine kinase inhibitor: gefitinib. In addition, CM suppressed tumor growth of xeno-transplanted A549 cells in immune-deficient mice in vivo. Our study underscores the importance of RUNX1 inhibition therapy in the management of gefitinib-resistant NSCLC patients.
Citation Format: Akihiko Matsuo. RUNX1 controls EGFR signaling pathway in non-small cell lung cancer cells [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 3516. doi:10.1158/1538-7445.AM2017-3516
Abstract 3523: Arginyltransferase1 as a novel suppressor of prostate cancer metastasis
Authors: Birnbaum Michael , Kumar Akhilesh , Morgan William , Zhang Fangliang 
Published: July 2017

Abstract
Arginylation is a post-translational modification wholly mediated by Arginyltransferase 1 (Ate1). Our studies have shown that Ate1 and arginylation are upregulated during stress conditions. In addition, it was recently shown that Ate1-deficient fibroblasts demonstrate cancer-like characteristics including genomic instability and mutagenesis. While Ate1’s role in cancer is poorly understood, our preliminary studies suggest that Ate1 is an important regulator of metastasis and cancer progression in prostate cancer models. In this study, our data suggests that Ate1 is essential for normal cell stress response in conditions including cellular oxidant, apoptosis inducing drugs, and radiation. Further, we show that a loss of Ate1 in LnCaP prostate cancer cells increases anchorage-independent growth in the soft-agar assay, and that a loss of Ate1 in PC-3 prostate cancer cells increases matrigel invasion in the Boyden chamber assay. To text how Ate1 affects metastasis in vivo, PC-3 cells with Ate1 or control shRNA were orthotopically implanted into the prostates of immunocompromised mice to observe metastasis. While very little metastasis was observed in PC-3 control cells, PC-3 cells with reduced Ate1 achieved much higher levels of metastasis. In conclusion, our data suggests that the loss of Ate1 in prostate cancer promotes cancer progression phenotypes and cell survival. In future studies, we will examine if Ate1 levels in human prostate cancers in prostate cancer prognosis.
Citation Format: Michael Birnbaum, Akhilesh Kumar, William Morgan, Fangliang Zhang. Arginyltransferase1 as a novel suppressor of prostate cancer metastasis [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 3523. doi:10.1158/1538-7445.AM2017-3523
Abstract 3527: Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma
Authors: Baba Masaya , Huang Ying , Motoshima Takanobu , Hasumi Hisashi , Hasumi Yukiko , Furuya Mitsuko , Nagashima Yoji , Yao Masahiro , Oike Yuichi , Kamba Tomomi , Schmidt Laura S. , Linehan W. Marston 
Published: July 2017

Abstract
Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a newly defined subset of RCC, which have chromosomal translocations involving the TFE3 transcription factor at Xp11.2. All translocations seen in Xp11.2 tRCC, including PRCC-TFE3, PSF-TFE3, ASPL-TFE3, CTLC-TFE3 and NONO-TFE3 produce chimeric TFE3 genes, which encode fusion TFE3 proteins retaining the basic helix-loop-helix leucine zipper (bHLH-Zip) structure for DNA binding, suggesting that these fusion TFE3 proteins function as oncogenic transcription factors. To clarify the molecular mechanism for Xp11.2 tRCC development, we have established cell lines, which express fusion TFE3 proteins (NONO-TFE3, PRCC-TFE3, PSF-TFE3) in a doxycycline dependent manner. Genes upregulated universally in all fusion TFE3 cell lines upon doxycycline addition were identified. In addition, we have generated an Xp11.2 translocation RCC mouse model, in which a floxed Neomycin cassette followed by a PRCC-TFE3 cDNA is inserted in the Rosa26 locus. By crossing these mice with cadherin 16-Cre transgenic mice, we can induce kidney specific PRCC-TFE3 expression resulting in RCC development. We will report and discuss the role of fusion TFE3 target genes in our mouse model and in clinical samples of Xp11.2 tRCC. Funded in part by FNLCR Contract HHSN261200800001E to LSS.
Citation Format: Masaya Baba, Ying Huang, Takanobu Motoshima, Hisashi Hasumi, Yukiko Hasumi, Mitsuko Furuya, Yoji Nagashima, Masahiro Yao, Yuichi Oike, Tomomi Kamba, Laura S. Schmidt, W. Marston Linehan. Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal 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 3527. doi:10.1158/1538-7445.AM2017-3527
Abstract 3529: Investigating the in vivo role of the EHF transcription factor in intestinal epithelial differentiation
Authors: Reehorst Camilla M. , Luk Ian Y. , Nightingale Rebecca , Davalos-Salas Mercedes , Dhillon Amardeep S. , Mariadason John M. 
Published: July 2017

Abstract
Objective: Poor tumor differentiation status is associated with worse patient outcome in colorectal cancer. However, the molecular basis for loss of differentiation in colon cancer is not well understood. We have found that the transcription factor Ets homologous factor (EHF) is highly expressed in the normal human and mouse colonic epithelium and is down-regulated in poorly-differentiated colorectal cancer cell lines. The aim of this study was to investigate the role of EHF in regulating normal colonic epithelial cell differentiation in vivo.
Methods: A novel mouse model was generated in which the Ets DNA binding domain (exon 8) of EHF was flanked by loxP sites (EHFlox/lox). To inactive EHF in the intestinal epithelium, EHFlox/lox mice were crossed to Villin-CreERT2 mice and recombination induced by tamoxifen treatment. Tamoxifen and vehicle treated mice were monitored weekly for up to one year. At each endpoint, tissue was collected and the effect of EHF deletion on intestinal cell proliferation and differentiation assessed by qRT-PCR and immunohistochemistry.
Results: Targeted inactivation of EHF in the small intestinal and colonic epithelium following tamoxifen treatment was confirmed at the DNA and RNA level. EHF inactivation in the intestinal epithelium had minimal effect on survival, weight gain and overall health of the animals. Furthermore, loss of EHF did not markedly affect cell proliferation or the overall architecture of the intestinal epithelium. Finally, EHF inactivation also had minimal effect on markers of absorptive, enteroendocrine or Paneth cell differentiation but did reduce the number of goblet cells in the colonic epithelium.
Conclusion: EHF does not play a major role in regulating cell proliferation in the mouse intestine but may play a role in regulating goblet cell differentiation. The role of EHF in intestinal tumourigenesis and response to stress are currently being investigated.
Citation Format: Camilla M. Reehorst, Ian Y. Luk, Rebecca Nightingale, Mercedes Davalos-Salas, Amardeep S. Dhillon, John M. Mariadason. Investigating the in vivo role of the EHF transcription factor in intestinal epithelial differentiation [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 3529. doi:10.1158/1538-7445.AM2017-3529
Abstract 3533: Connections between NF-κB misregulation and carcinogenesis
Authors: Chyong Donian I. , Naderi Aurian , Lee Chase , Arpornsuksant Ty , Lu Allison , Dilip Megha , Zhang Margaret , Surh Young-Joon , Lee Eun-Ji , Na Hye-Kyung 
Published: July 2017

Abstract
In this review poster, we researched the function, regulation, and structure of NF-κB as it relates to carcinogenesis. Found in almost all animal cells, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor that plays various roles in cellular proliferation, cell survival, inflammation, and T cell activation. There are two different NF-κB signaling pathways: the canonical pathway and the non-canonical pathway. NF-κB forms a p50/Rel A heterodimer in the canonical pathway and a p52/ Rel B heterodimer in the non-canonical pathway. NF-κB protein is normally sequestered in the cytoplasm as an inactive complex with a κB inhibitor (IκB) protein. Outside stimuli such as reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) activate cell surface receptors such as Toll-Like Receptors (TLRs) and Receptor Activators of NF-κB (RANK). These surface receptors, in turn, activate IκB kinase (IKK). IKK phosphorylates IκB, which causes ubiquitination of IκB, signaling proteasomes to degrade it. NF-κB then enters the nucleus through a nuclear pore and forms a transcription complex with coactivators and RNA polymerase. NF-κB binds to specific DNA-binding sites to induce transcription. One of the target genes of NF-κB encodes IκBs, so NF-κB regulates its own activity through a negative feedback loop. Because the cell maintains storage of the signaling protein NF-κB in the cytoplasm, NF-κB allows the cell to respond to sudden stimuli by activating quick changes in gene expression. Because proteins that promote cellular proliferation and cell survival are mainly transcribed through NF-κB activation, uncontrolled overactivation of this transcription factor has major implications in carcinogenesis. Many types of cancer cells have high levels of constitutively active NF-κB. Mutations in the genes for NF-κB itself or its inhibitors such as IκBs often found in cancer cells can cause cells to accelerate their proliferation or confer resistance to apoptosis. Some types of cancer cells secrete signaling molecules, inducing improper NF-κB activity. Because of the tumor promoting characteristics of NF-κB activation, a focus of current research is to find methods of suppressing NF-κB to kill cancer cells or slow their growth. We designed a 3D-printed model of the p50/RelA NF-κB protein using Jmol to highlight the relationship between its structure and function.
Citation Format: Donian I. Chyong, Aurian Naderi, Chase Lee, Ty Arpornsuksant, Allison Lu, Megha Dilip, Margaret Zhang, Young-Joon Surh, Eun-Ji Lee, Hye-Kyung Na. Connections between NF-κB misregulation and carcinogenesis [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 3533. doi:10.1158/1538-7445.AM2017-3533
Abstract 3535: Methylation regulates HEY1 expression in glioblastoma
Authors: Guda Maheedhara Reddy , Tsung Andrew J. , Asuthkar Swapna , Labak Collin M. , Lu Yining , Martin Sarah E. , Durbaka Prasad V. , Velpula Kiran K. 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system despite the existence of multi-modal therapeutic approaches. The poor prognosis in GBM patients is due in part to its resistance to available treatments, which calls for identifying novel molecular therapeutic targets. In this study, we identified an interesting biomarker, Hairy/Enhancer-Of-Split related with YRPW Motif (HEY1), a mediator of Notch signaling, which contributes to the pathogenesis of GBM. Datamining studies and our immunohistochemistry and immunoblot analysis showed that HEY1 is highly expressed in GBM patient specimens. Recent studies indicate that methylation status may control the expression of cancer phenotype. Our studies using bisulphite sequencing on the patient samples showed that HEY1 promoter was hypermethylated in the normal brain when compared to GBM specimens. Treatment on the 4910 and 5310 xenograft cell lines with sodium butyrate (NaB) greatly decreased HEY1 expression owing to its promoter hypermethylation with a concomitant increase in DNMT1 expression confirming that promoter methylation regulate the HEY1 expression in GBM. NaB treatment also induced cell apoptosis as evaluated by flow cytometric analysis. Silencing HEY1 reduced invasion, migration and proliferation in 4910 and 5310 cells. Further, immunoblot and q-PCR analysis demonstrated the existence of a potential positive regulatory loop between HEY1 and p53. Additionally, DNA microarrays with HEY1 recombinant protein demonstrated good correlation with p53 and provided various bonafide targets of HEY1. Collectively, these studies suggest HEY1 as an important predictive marker for GBM, thus indicating a potential target for future GBM therapy.
Citation Format: Maheedhara Reddy Guda, Andrew J. Tsung, Swapna Asuthkar, Collin M. Labak, Yining Lu, Sarah E. Martin, Prasad V. Durbaka, Kiran K. Velpula. Methylation regulates HEY1 expression 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 3535. doi:10.1158/1538-7445.AM2017-3535
Abstract 3546: LIN28B/MYC loop regulates aerobic glycolysis and tumor acidic microenvironment to promote cancer stemness and cancer progression
Authors: Chen Chong , Bai Lipeng , Cao Fengqi , wang shengnan , Liu Yan , Guo Jian , Si Qin , Xiang Rong , Luo Yunping 
Published: July 2017

Abstract
Substantial evidences have proven that targeting cancer addictive metabolism could suppress tumor progression. Tumor microenvironment (TME) supports the development of metabolic reprograming of tumor cells. The function of cancer stem cells (CSCs) closely related with its own metabolic alteration. However, the relationship between CSCs’ metabolic reprograming and their supportive TME, as well as underlying mechanism remains largely unknown. In this study, we have demonstrated a novel mechanism that the LIN28B/MYC positive regulation loop could promote the aerobic glycolysis of cancer cells and glycolysis-derived lactate and further enhance the cancer stemness to facilitate tumor progression. 1) Metabolic analysis revealed that glycolysis (ECAR) was suppressed after LIN28B was knocked down in MDA-MB-231 or H1299 cancer cells respectively. Consistently, both the glucose-uptake and lactate-secretion were attenuated in shLIN28B cancer cells. Importantly, either the glucose accumulation in cancer tissues or lactate secretion in serum was reduced in mouse injected with shLIN28B cancer cells. 2) Metabolic analysis revealed that CSCs possessed higher ECAR and higher level of LIN28B, MYC and HIF1a. Furthermore, glycolysis-derived lactate not only increase the proportion of ALDH+ cells, but also enhance the tumorsphere forming ability and mobility of cancer cells. 3) MicroRNAs screening analysis revealed that 6 miRNAs were up-regulated above 2 folds after LIN28B was knocked down in MDA-MB-231 cells. Metabolic analysis revealed that miR-34a-5p could suppress the aerobic glycolysis (ECAR) in MDA-MB-231 cells. 4) LIN28B inhibitor could reduce the expression of LIN28B and MYC in vitro and then suppressed tumor growth and metastasis in vivo. Taken together, our study demonstrated that LIN28B/MYC loop could sustain the aerobic glycolysis of cancer cells and then enhance the function of CSCs via regulating the tumor acid microenvironment, thus, established the LIN28B/MYC as a central node in connecting tumor metabolism and tumor microenvironment, and could serve as a therapeutical target.
Citation Format: Chong Chen, Lipeng Bai, Fengqi Cao, shengnan wang, Yan Liu, Jian Guo, Qin Si, Rong Xiang, Yunping Luo. LIN28B/MYC loop regulates aerobic glycolysis and tumor acidic microenvironment to promote cancer stemness and cancer progression [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 3546. doi:10.1158/1538-7445.AM2017-3546