bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-301: PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors
Authors: Higuchi Fumi , Cahill Daniel P. , Wakimoto Hiroaki 
Published: July 2017

Abstract
Background: Mismatch repair (MMR) deficiency through MSH6 alteration has been identified in approximately 30% of recurrent high grade gliomas, and represents a key molecular mechanism for the development of acquired resistance to the alkylating agent temozolomide (TMZ). Additionally, glioma progression post-TMZ treatment is frequently accompanied by distinct genomic alterations such as amplification of the MYC locus and resulting signaling activation. There is an urgent need to establish new treatment strategies that do not rely upon MMR to target MMR deficient, TMZ resistant glioma.
Methods: We first screened 14 compounds that modulate DNA damage response for their ability to suppress viability of an MSH6 knockdown, TMZ resistant glioma cell line. Efficacy of PLK1 inhibitors and combination with TMZ were assessed in glioblastoma cells lines and patient-derived glioblastoma neurosphere lines engineered with MSH6 silencing, MYC overexpression and controls. Impacts of PLK1 blockade on cell cycle distribution, apoptosis, and DNA damage effects were examined.
Results: The compound screening indentified PLK1 selective inhibitor, volasertib, as the most potent inhibitor of proliferation of both MMR intact and deficient glioblastoma cells. PLK1 inhibition induced G2/M cell cycle arrest, DNA damage and caspase-mediated apoptosis in glioblastoma cells, but no detectable toxicity in normal human astrocytes. Importantly, beneficial therapeutic effects of PLK1 inhibitors were not influenced by MMR deficiency due to MSH6 knockdown, whereas PLK1 inhibition had no additive or synergic effect when combined with TMZ. Furthermore, we found that MYC overexpression sensitized glioblastoma cells to PLK1 inhibitors.
Conclusions: Selective PLK1 inhibitors are potently cytotoxic to glioblastoma and their action is independent of MMR status of the cells. Cells with deregulated MYC are vulnerable to PLK1 inhibition suggesting genomic MYC alteration as a biomarker for PLK inhibitor sensitivity. Thus PLK inhibitor represents a novel therapeutic option for MMR deficient TMZ resistant recurrent gliomas, particularly those driven by MYC.
Citation Format: Fumi Higuchi, Daniel P. Cahill, Hiroaki Wakimoto. PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors [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 LB-301. doi:10.1158/1538-7445.AM2017-LB-301
Abstract LB-318: Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation
Authors: Torres-Guzmán Raquel , Baquero Carmen , Marugan Carlos , Mur Cecilia , Gharbi Severine I. , Gomez Sandra , Amat Joaquín , Boehnke Karsten , Iversen Philip W. , deDios Alfonso , Gong Xueqian , Buchanan Sean , Beckman Richard P. , Lallena Maria José J. 
Published: July 2017

Abstract
Lung cancer is the most common tumor cancer worldwide and approximately 15-25% of the patients with lung adenocarcinoma have KRAS driven tumors. These malignancies involve, in the majority of cases, a constitutive activation of KRAS signaling pathway (1,2) and are associated with poor prognosis in patients with advanced disease (metastatic setting).
Currently there is no specific therapy to target KRAS driven tumors approved by FDA (3), then finding alternative targeted therapies is a need to cover for this disease.
Pharmacological inhibition of CDK4 was been suggested as a beneficial therapy to treat NSCLC patients carrying K-RAS oncogenes; and researchers base the potential efficacy of this approach on a synthetic lethal interaction between K-ras and CDK4 in in this type of tumors (4). Hence, CDK4/6 inhibitors appear as promising therapy to treat this type of tumors.
Abemaciclib is a cell cycle inhibitor with selective activity against CDK4 and CDK6 and is being evaluated in advanced clinical trials for its potential to reduce NSCLC cancer growth. Here we describe studies towards the in-vitro mechanism of action of abemaciclib to reduce tumor cells growth in NSCLC cell lines harboring mutations in KRAS. Overall, abemaciclib reduces NSCLC cell growth as indicated by a reduction of cell number and proliferation biomarker Ki67 upon treatment. This tumor growth inhibition is mediated by arrest of cell cycle in G1 phase as a direct consequence of Rb phosphorylation blockade. In this study we are further reporting a phenotypic characterization of sensitive cell lines monitoring cell proliferation, senescence, and apoptosis markers using flow cytometry and high content imaging approaches as well as metabolic profiling.
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Ihle NT et al (2012) J Natl Cancer Inst. 104(3): 228-239.
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Roberts PJ et al (2010) J Clin Oncol. 28(31):4769-77
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Puyol M et al (2010) Cancer Cell 1(13): 63-73.
Citation Format: Raquel Torres-Guzmán, Carmen Baquero, Carlos Marugan, Cecilia Mur, Severine I. Gharbi, Sandra Gomez, Joaquín Amat, Karsten Boehnke, Philip W. Iversen, Alfonso deDios, Xueqian Gong, Sean Buchanan, Richard P. Beckman, Maria José J. Lallena. Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation [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 LB-318. doi:10.1158/1538-7445.AM2017-LB-318
Abstract LB-320: Reconstituting B55/protein phosphatase 2A activity in B55/PP2A-defective prostate cancer cells suppresses proliferation and tumorigenicity through pleiotropic mechanisms
Authors: Zhao Ziran , Kurimchak Alison , Makhov Petr , Johnson Katherine , Kolenko Vladimir , Duncan James , Graña Xavier 
Published: July 2017

Abstract
Prostate cancer accounts for close to 30,000 deaths annually in the United States. The most frequent alteration in the prostate oncogenome landscape is loss of chromosome 8p, which is also observed in other epithelial tumors. This region harbors NKX3.1, a prostate specific tumor suppressor, but 8p copy number loss does not correlate with its mRNA expression. The PPP2R2A gene, which encodes a regulatory subunit of protein phosphatase 2 (PP2A) designated B55, is located in 8p21.2 and is hemizygously lost in more that 50% of prostate adenocarcinomas. TCGA data analysis shows that hemizygous loss of PPP2R2A correlates with its reduced expression, poorer prognosis and that loss of PPP2R2A increases with metastasis to more than 80%. Of note, while homozygous loss is less common (4-10%), deletion of other subunits of the B55, but not other PP2A regulatory families, increases dramatically with metastasis despite their independent chromosomal locations. However, functional evidence that PPP2R2A acts as an haploinsufficient tumor suppressor and the potential mechanisms implicated are lacking. We have identified prostate cancer (PrCa) cell lines with reduced expression of B55 and shown that reconstitution of B55 expression reduces proliferation and induces senescence and loss of viability. B55 reconstitution in PC3 cells, an AR-negative model of human castration-resistant prostate cancer (CRPC), also blocks transformation in vitro and tumorigenicity in SCID mice. Reconstitution of B55 in PCa cells with reduced expression (PC3 and DU145 cells) induces cell cycle defects in G1, G2/M and mitosis diminishing and delaying phosphorylation of pRB pocket proteins and mitotic substrates and altering associated kinase networks. Mitogenic signaling is also attenuated. Importantly, the effects of B55 reconstitution are at least partially mimicked via treatment of these cells with PP2A activating drugs, which have anti-tumorigenic activity, indicating that development of specific B55/PP2A activating drugs targeting the unaltered B55 alleles remaining in PCa cells may have therapeutic potential for a high proportion of prostate tumors and perhaps other epithelial tumors such as luminal B breast and ovarian cancers which share this alteration.
Citation Format: Ziran Zhao, Alison Kurimchak, Petr Makhov, Katherine Johnson, Vladimir Kolenko, James Duncan, Xavier Graña. Reconstituting B55/protein phosphatase 2A activity in B55/PP2A-defective prostate cancer cells suppresses proliferation and tumorigenicity through pleiotropic mechanisms [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 LB-320. doi:10.1158/1538-7445.AM2017-LB-320
Abstract LB-323: Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2
Authors: Sakuragi Noriaki , Farah Mohamed Kamel , Mohamed Zeinab , Okasha Safwat , Watari Hidemichi , Mitamura Takashi , Khamisy sherif El , Ohba Yusuke 
Published: July 2017

Abstract
Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (TX) is widely used for ovarian cancer treatment. However, ovarian cancer often acquire chemoresistance. MicroRNAs (miR) have been reported to regulate many tumours’ chemoresistance. Here, we investigated the comparative microRNA expression profile between the ovarian cancer cells and their taxane-resistant counterpart, KF-TX to get novel markers for taxane resistance in ovarian cancer. The array data revealed that miR-486, miR143,miR145 and miR363 are the most upregulated miRNAs in association with TX resistance. However, miR-155, miR-100, miR-31 and miR-629 are the most significantly downregulated miRNAs after resistance development. We then focused on the role of miR-363 in chemoresistance of the ovarian cancer. qRT-PCR indicated that miR-363 was upregulated in KF-TX cells, confirming the array data, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assays and expression analysis. Furthermore, we validated the role of LATS2 in the TX-response by sh-based silencing, which also confers TX-resistance in the responsive ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while downregulation of the same gene in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance and poor prognosis. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Noriaki Sakuragi, Mohamed Kamel Farah, Zeinab Mohamed, Safwat Okasha, Hidemichi Watari, Takashi Mitamura, sherif El Khamisy, Yusuke Ohba. Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2 [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 LB-323. doi:10.1158/1538-7445.AM2017-LB-323
Abstract LB-326: A novel oncomiR negatively regulates PTEN pathway in prostate cancer
Authors: Bhat Nadeem S. , Colden Melissa , Arora Prerna , Dar Altaf A. , Saini Sharanjot , Shahryari Varahram , Yamamura Soichiro , Tanaka Yuichiro , Katu Taku , Hashimoto Yutaka , Shiina Marisa , Kulkarni Priyanka , Dasgupta Pritha , Imai-sumida Mitsuho , Maekawa Shigekatsu , Deng Guoren , Dahiya Rajvir , Majid Shahana 
Published: July 2017

Abstract
Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that a novel microRNA, microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Kaplan-Meier and ROC analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Nadeem S. Bhat, Melissa Colden, Prerna Arora, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Taku Katu, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-sumida, Shigekatsu Maekawa, Guoren Deng, Rajvir Dahiya, Shahana Majid. A novel oncomiR negatively regulates PTEN pathway 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 LB-326. doi:10.1158/1538-7445.AM2017-LB-326
Abstract LB-327: Restoration of MYC-repressed miR-29 in pancreatic cancer cells leads to increased reactive oxygen species and gemcitabine sensitization
Authors: Kwon Jason J. , Quirin Kayla , Aljoufi Arafat , Nafiseh Amira , Kota Janaiah 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) still remains to be one of the most highly malignant human diseases and is resistant to the majority of current therapeutic modalities. Oncogene MYC has been known to be upregulated in PDAC and plays a key role in carcinogenesis and tumor progression. In our previous work, we found the downregulation of miR-29 is a common phenomenon of PDAC, and its restored expression reduced cancer cell migration/invasive potential, anchorage independent growth, and sensitized them to gemcitabine. Furthermore, we showed that miR-29 blocks autophagy in cancer cells by targeting key autophagy related proteins. However, the mechanism associated with the loss of miR-29 in PDAC has yet to be elucidated. Here we demonstrate that MYC inhibits miR-29 expression in PDAC. MYC nuclear localization negatively correlates with miR-29 expression in various pancreatic cancer cell lines, and knockdown of MYC led to an increased expression of both primary miR-29a/b1 transcript and mature miR-29a. Furthermore, miR-29 overexpression in combination with gemcitabine led to decreased cancer cell viability and increased intracellular reactive oxygen species (ROS) and cell death. Our findings show for the first time that MYC represses miR-29 in PDAC, and miR-29 sensitizes pancreatic cancer cells to gemcitabine through increased intracellular ROS. Taken together our results, indicating the potential use of miR-29a as a novel therapeutic agent for PDAC.
Citation Format: Jason J. Kwon, Kayla Quirin, Arafat Aljoufi, Amira Nafiseh, Janaiah Kota. Restoration of MYC-repressed miR-29 in pancreatic cancer cells leads to increased reactive oxygen species and gemcitabine sensitization [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 LB-327. doi:10.1158/1538-7445.AM2017-LB-327
Abstract LB-328: Mir-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44
Authors: Cheng Ann-Joy , Lu Ya-Ching , Chang Joseph T. 
Published: July 2017

Abstract
Cancer stem cells preferentially acquire the specific characteristics of stress tolerance and high mobility, allowing them to progress to a therapy-refractive state. To identify a critical molecule to regulate cancer stemness is indispensable to erratically cure cancer. In this study, we identified miR-520b as a novel molecular target to suppress head-neck cancer (HNC) with stemness phenotype. MiR-520b inhibited cellular migration and invasion via the mechanism of epithelial-mesenchymal transition. It also sensitized cells to therapeutic drug and irradiation. Significantly, miR-520b suppressed spheroid cell formation, as well as reduced expressions of multiple stemness regulators (Nestin, Twist, Nanog, Oct4). The CD44 molecule was identified as a direct target of miR-520b, as shown by the reverse correlative expressions, the response to miR-520 modulation, the luciferase reporter assay, and the functional rescue analyses. These cellular results were confirmed by a tumor xenograft mice study. Administration of miR-520b dramatically restrained tumorigenesis and liver colonization. Conversely, miR-520b silencing led to an acceleration of tumor growth. Taken together, our study demonstrated that miR-520b inhibits the malignancy of HNC through regulation of cancer stemness conversion by targeting CD44. MiR-520b may serve as an emerging therapeutic target that may be further developed for the intervention of refractory HNC.
Note: This abstract was not presented at the meeting.
Citation Format: Ann-Joy Cheng, Ya-Ching Lu, Joseph T. Chang. Mir-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44 [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 LB-328. doi:10.1158/1538-7445.AM2017-LB-328
Abstract SY19-01: Tumor-elicited inflammation in colorectal cancer
Authors: Karin Michael 
Published: July 2017

Abstract
The majority of sporadic human colorectal cancer is initiated by genetic loss or inactivation of tumor suppressor APC (Absent in Polyposis Coli). In addition to activation of beta-catenin signaling, we found that loss of APC results in upregulation of IL-6 signal transducer (IL6/gp130), thereby leading to activation of STAT3 and YAP, two transcription factors that make important contributions to colorectal tumorigenesis. In addition, APC loss results in deterioration of the intestinal epithelial barrier and immune homeostasis, barrier loss due to downregulation of genes encoding tight junction proteins, and suppression of mucin production. Together, such changes promote the invasion of inflammation-inducing colitogenic bacteria and their products. Loss of immune homeostasis is due to defective luminal transport of IgA dimers caused by loss of polyimmunoglobin receptor (PIgR) and CCL28, a chemokine responsible for recruitment of IgA-producing plasma cells. Defective luminal transport of IgA results in dysbiosis and over-representation of inflammation-causing bacteria that can accelerate colorectal tumor genesis through upregulation of IL-17 production.
Citation Format: Michael Karin. Tumor-elicited inflammation in colorectal 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 SY19-01. doi:10.1158/1538-7445.AM2017-SY19-01
Abstract SY22-03: Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer
Authors: Soga Tomoyoshi 
Published: July 2017

Abstract
Metabolic reprogramming is a common hallmark of cancer. Most cancer cells produce ATP and the precursors of biomass (e.g., nucleotides, amino acids, and lipids) by shifting from oxidative phosphorylation to aerobic glycolysis, commonly known as the “Warburg effect.” Recently these cancer-specific metabolic pathways have been considered as attractive targets for cancer therapy. However, the mechanisms underlying the control of cancer cell metabolism are poorly understood. To address underlying mechanisms that induce metabolic reprogramming of cancer metabolism, we applied capillary electrophoresis mass spectrometry (CE-MS) metabolic profiling to paired normal tissues and tumor tissues obtained from 275 patients with colon cancer. Significant changes in the levels of many metabolites were observed between normal and tumor tissues. Unexpectedly, metabolite levels altered quite early and remained unchanged among cancer stages. S-Adenosylmethionine (SAM) was the most increased metabolite. Glucose was the second most decreased metabolite in tumor tissues, whereas lactate, the final product of glycolysis, was increased, which indicates activation of glycolysis (the Warburg effect). We then applied transcriptome analysis to paired normal-cancer colon tissues and revealed that alterations in mRNA levels also occurred at the adenoma stage. Regarding energy metabolism, mRNAs encoding glycolysis purine/pyrimidine synthesis, one-carbon metabolism, and fatty acid synthesis were highly expressed, whereas those in fatty acid oxidation were down-regulated in tumor tissue. Colon cancer is associated with mutations in oncogenes and tumor suppressor genes such as adenomatous polyposis coli (APC), Kirsten-ras (KRAS), and TP53. We applied next-generation sequencing technologies for the detection of somatic mutations to the tumor tissues and found mutation frequencies of 78% in APC, 68% in TP53, and 48% in KRAS. Similar to metabolome and transcriptome data, these mutations were umbiased among cancer stages. We investigated whether gene mutations including APC, KRAS, and TP53 mutations affected metabolism. Regardless of the presence or absence of the mutations, the levels of most metabolites were unaltered in tumor tissues. This raises the question of which molecules contribute to the regulation of metabolic reprogramming of colorectal cancer metabolism.
Citation Format: Tomoyoshi Soga. Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal 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 SY22-03. doi:10.1158/1538-7445.AM2017-SY22-03