bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2368: The phosphatase PRL3 as a novel therapeutic target in acute lymphoblastic leukemia
Authors: O'Leary Anna K. , Wei Min , Blackburn Jessica 
Published: August 2018

Abstract
Acute lymphoblastic leukemia (ALL) is one of the most prevalent cancers that is diagnosed in adolescents. The survival rate for ALL is good during the initial diagnosis but is much less optimistic for patients who have relapsed ALL, due to limited treatment options. Additionally, the high-dose cytotoxic chemotherapies that ALL patients are given have long-term adverse consequences. New and less toxic targeted therapies are needed for the treatment of ALL. We previously performed a large-scale transplantation screen in zebrafish to identify genes associated with high relapse potential in ALL, and a top hit from this screen was the protein tyrosine phosphatase 4A3, PTP4A3 or PRL3. Upregulation of PRL3 is correlated progression of colorectal, breast, and gastric cancers, and is associated with poor patient prognosis. We have found that PRL3 is highly expressed in a subset of patient ALL samples, and I am examining the role of PRL3 in ALL progression. We have found that PRL3 expression enhances ALL proliferation, and promotes leukemia survival after cytotoxic chemotherapy treatment. Small-molecule inhibition of PRL3 induces apoptosis in ALL, and synergizes with common ALL chemotherapies. I am currently examining the localization of PRL3 and identifying signaling pathways that it may be involved with to promote ALL progression. If my project is successful, it will provide scientific data that support our hypothesis that PRL3 is related to acute lymphoblastic leukemia. If there is a correlation between PRL3 and ALL, PRL3 could be used as a more effective and less toxic treatment for patients with ALL.
Citation Format: Anna K. O'Leary, Min Wei, Jessica Blackburn. The phosphatase PRL3 as a novel therapeutic target in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2368.
Abstract 2369: AMPK regulation of apoptosis through OSBP
Authors: Ong Kai Li , Thurgood Trever , Christensen Michael , Malmrose Jonny , Ng Denise , Grose Julianne 
Published: August 2018

Abstract
Alterations in lipid metabolism have been frequently reported in tumor progression, with impaired PI(4,5)P2 homeostasis in the plasma membrane implicated in various cancers and metabolic disorders. Oxysterol binding protein (OSBP) and its related proteins (ORPs) constitute a large family of ubiquitously expressed, evolutionarily conserved lipid binding proteins that play critical roles in intracellular lipid trafficking. OSBP and ORPs associate with a wide range of cellular activities, however their functions and regulations are largely unclear. Emerging evidence has supported an essential role of OSBP in cell signaling pathways and cancer development. We recently identified yeast oxysterol binding protein Osh7 as a true substrate of yeast AMPK (Snf1). AMPK's involvement in cancer has been extensively studied in the past decade, and is an important mediator of cellular energy homeostasis. Despite many downstream targets identified, AMPK is not known to regulate oxysterol binding protein activities. We found that Snf1 may be responsible for the degradation of Osh7 and cells deficient in Osh7 and its homolog Osh6 display higher rates of apoptosis. Understanding the regulation of OSBP by AMPK may aid in better targeting AMPK for cancer treatment and prevention, at the same time provide a better understanding to the roles of OSBP in cancer development.
Citation Format: Kai Li Ong, Trever Thurgood, Michael Christensen, Jonny Malmrose, Denise Ng, Julianne Grose. AMPK regulation of apoptosis through OSBP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2369.
Abstract 2384: Preclinical evaluation of PD and efficacy of novel potent selective and orally bioavailable CDK12 covalent inhibitors in TNBC model
Authors: Poddutoori Ramulu , Rajagopalan Sujatha , Mukherjee Subhendu , Marappan Sivapriya , S Samiulla D , Sivakumar Sasirekha , Nayak Shilpa S. , V Ravindra M. , Murtuza Hadianawala , S Devaraja T. , Kondela Srinivas , Tgore Suraj , Dhudashiya Amit A. , B Charamanna K. , Antony Thomas , Daginakatte Girish , Giri Sanjeev , Chelur Shekar , Ramachandra Murali , Pandit Chetan , Samajdar Susanta 
Published: August 2018

Abstract
Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase that participates in various cellular processes such as DNA damage response, splicing and pre-mRNA processing. In association with Cyclin K (CycK), CDK12 regulates transcription elongation by phosphorylating RNA polymerase II (RNAP II) at Serine 2 in the C-terminal domain (CTD). Overexpression of CDK12 in various tumor types suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. Considering its critical role in transcription and RNA processing CDK12 is emerging as a potential therapeutic target for cancer. Multiple series of potent and selective CDK12 covalent inhibitors were identified by iterative medicinal chemistry efforts and SAR-based approaches. Early compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumour activity. Very potent and highly selective CDK12 inhibitors have been identified from two distinct chemical series. The covalent mode of action for these biochemically potent compounds has been confirmed by CDK12 target engagement assay in the cellular context. These selective inhibitors showed significant anti-proliferative activity in TNBC and other cancer cell lines, which correlated with inhibition of pS2 (RNAP II), a bonafide CDK12 substrate and target engagement. In vivo target engagement, PD and efficacy data for optimized compounds with good oral bioavailability in a TNBC (HCC-70) xenograft model along with will be presented.
Citation Format: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D S, Sasirekha Sivakumar, Shilpa S. Nayak, Ravindra M. V, Hadianawala Murtuza, Devaraja T. S, Srinivas Kondela, Suraj Tgore, Amit A. Dhudashiya, Charamanna K. B, Thomas Antony, Girish Daginakatte, Sanjeev Giri, Shekar Chelur, Murali Ramachandra, Chetan Pandit, Susanta Samajdar. Preclinical evaluation of PD and efficacy of novel potent selective and orally bioavailable CDK12 covalent inhibitors in TNBC model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2384.
Abstract 2387: The oncogenic role and therapeutic potential of PTPN11 in melanoma
Authors: Hill Kristen Suzanne , Roberts Evan , Marin Ellen , Wang Xue , Teer Jamie , Messina Jane , Wu Jerry , Kim Minjung 
Published: August 2018

Abstract
The RAS/RAF/MEK/ERK signaling pathway, which is intricately regulated by multiple proteins including PTPN11 (Tyrosine-Protein Phosphatase Non-Receptor Type 11, encoding SHP2), is frequently activated in melanoma. Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been established in melanoma. Recently, we preformed whole exome sequencing on tumors generated by a mouse model driven by loss of PTEN and CDKN2A (INK4A/ARF) and identified several conserved cross-species orthologous mutations in Kras, Erbb3, and Ptpn11. In this study, we addressed the functional roles of PTPN11 in melanoma tumorigenesis and tumor maintenance; as well as, PTPN11's effect on the RAS/RAF/MEK/ERK signaling pathway and its activation status in human melanoma.
PTPN11 can be activated by receptor tyrosine kinases (RTKs) or by point mutations. We observed activating phosphorylation on Tyr 542 of PTPN11 in 40% (n=15/38) of melanoma specimens and the majority of human melanoma cell lines (n=14), supporting frequent activation of PTPN11 in human melanoma even though the mutation rate is low (1~3%). PTPN11 knock-down suppressed ERK activation in NRAS mutant and BRAF/NRAS wild-type melanoma cells, but not in BRAF mutant cells. Moreover, we have shown that expression of active PTPN11E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition. Alternatively, knock-down of Ptpn11 reduces colony growth and ERK activation. We generated a tet-inducible, melanocyte-specific, PTPN11E76K transgenic mouse model in a PTEN and CDKN2A null background and observed melanoma formation. Implantation of melanoma cells derived from this model showed doxycycline dependent tumor growth in nude mice. Doxycycline withdrawal and subsequent extinction of PTPN11E76K caused regression of established tumors, supporting the tumor maintenance role of PTPN11. Subsequently, tumor tissue from this model underwent phosphor-tyrosine proteomic analysis to identify downstream effectors of PTPN11's protein tyrosine phosphatase activity. The proteins identified in this analysis are currently being confirmed. These data support the oncogenic roles of PTPN11 in melanoma by regulating RAS/RAF/MAPK pathway activation and the value of PTPN11 as a novel and actionable therapeutic target.
Citation Format: Kristen Suzanne Hill, Evan Roberts, Ellen Marin, Xue Wang, Jamie Teer, Jane Messina, Jerry Wu, Minjung Kim. The oncogenic role and therapeutic potential of PTPN11 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2387.
Abstract 2394: Racial disparity in bladder cancer and identification of altered metabolism in African American compared to European American bladder cancer
Authors: Vantaku Venkata Rao , Donepudi Sri Ramya , Dorsey Tiffany , Putluri Vasanta , Ambati Chandrashekar , Wei Tang , Ittmann Michael M. , Terris Martha K. , Lerner Seth , Ambs Stefan , Lotan Yair , Sreekumar Arun , Putluri Nagireddy 
Published: August 2018

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR Annual Meeting 2018 Official Press Program. It will be posted online following its presentation.
Citation Format: Venkata Rao Vantaku, Sri Ramya Donepudi, Tiffany Dorsey, Vasanta Putluri, Chandrashekar Ambati, Tang Wei, Michael M. Ittmann, Martha K. Terris, Seth Lerner, Stefan Ambs, Yair Lotan, Arun Sreekumar, Nagireddy Putluri. Racial disparity in bladder cancer and identification of altered metabolism in African American compared to European American bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2394.
Abstract 2410: RIPK1-mediated induction of mitophagy compromises the viability of extracellular matrix-detached cells
Authors: Hawk Mark A. , Schafer Zachary T. 
Published: August 2018

Abstract
For cancer cells to survive during ECM-detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to ROS generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a novel role for receptor-interacting protein kinase-1 (RIPK1) in the modulation of mitochondrial ROS levels and cell viability during ECM-detachment. We find that RIPK1 activation during ECM-detachment results in the induction of PINK1-dependent mitophagy through a mechanism requiring the mitochondrial phosphatase PGAM5. As a consequence of mitophagy induction, ECM-detached cells experience diminished IDH2-mediated NADPH production in the mitochondria and the subsequent elevation in mitochondrial ROS levels leads to non-apoptotic cell death. Furthermore, we find that antagonizing RIPK1 or PGAM5 enhances tumor formation in vivo. Intriguingly, upon mining a meta-analysis of published lung cancer patient microarray data sets, we find that low RIPK1 expression in lung cancer patients correlates with decreased overall and progression-free survival. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for novel therapeutics aimed at specifically eliminating ECM-detached cancer cells and deterring tumor progression.
Citation Format: Mark A. Hawk, Zachary T. Schafer. RIPK1-mediated induction of mitophagy compromises the viability of extracellular matrix-detached cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2410.
Abstract 2416: CREB orchestrates metabolic reprogramming in PDGFRA-addicted lung squamous cell cancer
Authors: Xu Jun , Jin Nan , Huang Min , Ding Jian , Geng Meiyu 
Published: August 2018

Abstract
Aberration of platelet-derived growth factor receptor A (PDGFRA) gene has been increasingly identified in multiple types of human cancers, including hematologic malignancies, gastrointestinal stromal tumor (GIST), medulloblastomas and gliomas. In particular, amplification of 4q12 that contains PDGFRA locus has been reported in 3% to 7% of lung adenocarcinomas and 8% to 10% of lung squamous cell carcinomas. However, it remains unclear how amplified PDGFRA drives malignancy of lung squamous cell cancer. To address this question, we used a lung squamous cell cancer cell line NCI-H1703, which has been previously reported to have 24-fold amplification of the 4q12 region. Either siRNA knockdown or small-molecule inhibition of PDGFRA significantly inhibited cell growth, suggesting that PDGFRA was required for driving cell proliferation. We further showed that both oxidative phosphorylation and aerobic glycolysis were significantly affected followed by interference of PDGFRA, by measuring of oxygen consumption rate (OCR) and extra cellular acidification rate (ECAR). In particular, ATP generation level and maximum respiratory capacity, the key parameters of mitochondrial function, were significantly decreased in mitochondrial pressure testing. These observations suggested that oncogenic PDGFRA drove the metabolic reprogramming and promoted tumor malignancy in lung squamous cell cancer. To further explore the regulatory mechanism of the observed metabolic phenotype, we took the approach of genetic sequencing technology to analyze the transcriptome in PDGFRA-driven NCI-H1703 cells treated with or without PDGFRA inhibitor. It revealed that PDGFRA-driven transcriptional regulation of metabolic genes underpinned the specific metabolic phenotypes of mitochondrial function. In addition, analysis of transcriptome as well as a phosphorylated kinase array revealed that a transcription factor, cAMP response element-binding protein (CREB), regulated the metabolic gene expression in PDGFRA-addicted cells. Knockdown of CREB disrupted metabolic gene expression and the mitochondrial function, consistent with aforementioned findings of PDGFRA, suggesting that transcriptional regulation of metabolic genes was orchestrated by CREB. Together, we herein firstly provide the molecular link between oncogenic PDGFRA and metabolic vulnerability and reveal the important role of CREB in orchestrating metabolic reprogramming in PDGFRA-addicted lung squamous cell cancer.
Citation Format: Jun Xu, Nan Jin, Min Huang, Jian Ding, Meiyu Geng. CREB orchestrates metabolic reprogramming in PDGFRA-addicted lung squamous cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2416.
Abstract 2417: eIF4E phosphorylation licenses Myc-driven metabolic and stress reprogramming
Authors: Ruan Hang , Li Xiangyun , Leibowitz Brian , Tong Jingshan , Lu Xinghua , Sonenberg Nahum , Xu Xiang , Zhang Lin , Yu Jian 
Published: August 2018

Abstract
eIF4E, Eukaryotic Translation Initiation Factor 4E, regulates the rate limiting cap-binding step in mRNA translation. Oncogenic pathways converge to increase eIF4E expression, as well as phosphorylation of eIF4E (S209) and its inhibitor 4EBPs, which are believed to facilitate the translation of “weak'' mRNAs including cell type-specific and oncogenic targets. eIF4E phosphorylation, but not eIF4E, is dispensable for normal development. Pharmacologic inhibition of either p-eIF4E or p-4EBP has limited antitumor efficacy. Our current study aims to better define the role of p-eIF4E in colon cancer. We find that p-eIF4E, not eIF4E transcript or protein is elevated in human colon tumors and precursors. Knockin (KI) of phosphorylation-defective eIF4E mutant allele (4ES209A) in human colon cancer cells strongly suppresses Myc translation and cell growth under stress or in mice, while minimally impacting Cap binding or global translation. Surprisingly, p-eIF4E is found to be required to maintain p-4EBP1 levels, dissociate eIF4E from 4E-BP1, and stimulate glutamine metabolism via integrated stress response (ISR). Further, p-eIF4E and p-4EBP1 are highly elevated in the polyps in APC min/+ mice compared to adjacent normal intestinal crypts, and 4ES209A KI significantly inhibits intestinal polyposis and glutamine metabolism gene signatures. Finally, p-eIF4E renders CRC cells addicted to glutamine and glutaminolysis by preventing Myc- and ISR-driven metabolic crisis and cell death. In summary, we demonstrate that eIF4E phosphorylation is central to oncogenic translation, and is required to license Myc-driven metabolic adaptation and addiction via ISR-dependent transcriptional programs in colon cancer. These novel findings help reconcile the long-standing and context-dependent roles of ISR in cancer cell growth, death, plasticity and heterogeneity, and provide new ways for its therapeutic exploitation.
Citation Format: Hang Ruan, Xiangyun Li, Brian Leibowitz, Jingshan Tong, Xinghua Lu, Nahum Sonenberg, Xiang Xu, Lin Zhang, Jian Yu. eIF4E phosphorylation licenses Myc-driven metabolic and stress reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2417.
Abstract 2430: Targeting Nrf2 in esophageal adenocarcinoma sensitizes cancer cells to cisplatin treatment
Authors: Peng Dunfa , Hu Tianling , Zhu Shoumin , El-Rifai Wael 
Published: August 2018

Abstract
Background: The incidence rate of the esophageal adenocarcinoma (EAC) has increased rapidly among men since 1976 in the USA. EAC is considered to originate from premalignant Barrett's esophagus (BE) which results from chronic gastroesophageal reflux disease (GERD). It has been reported that oxidative stress is steadily increased in GERD-BE-EAC progression cascade. NFE2-related factor 2 (Nrf2) is a major regulator of cellular anti-oxidant properties that maintains cell viability and cellular homeostasis.
Methods and Results: Using Western blot analysis, we detected overexpression of Nrf2 protein in several EAC cell lines, as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines. Nrf2 overexpression was also confirmed in primary EAC samples, using immunohistochemistry on a tissue microarray that contained 76 EACs. Knockdown of Nrf2 by siRNA or CRISPR/CAS9 in EAC cells (FLO1 and OE33), that have constitutive high levels of Nrf2, enhanced the sensitivity of cancer cells to cisplatin (CDDP). We confirmed these results by using a Nrf2 specific inhibitor (Brusatol). Further studies demonstrated that dysfunction of Nrf2, either through knockdown of Nrf2 expression or using its specific inhibitor, depleted several Nrf2 target genes such as GR, HO-1, GSTM2, GPX3 and GPX4, which have anti-oxidative properties, leading to a significant increase in cellular ROS levels. The excessive ROS levels resulted in an increase in oxidative DNA damage (measured by 8-oxoguanine) and double strand breaks (measured by p-H2AX) which were further increased by treatment with CDDP with subsequent increase in cancer cell death.
Conclusion: These results indicate that constitutive overexpression of Nrf2 in EAC cells protects tumor cells from high level of ROS and favors tumor cell survival and drug resistance. Targeting Nrf2 through its specific inhibitor may have a therapeutic window in EAC. Additional studies are ongoing to determine the molecular mechanisms underlying NRF2 overexpression in EACs.
Citation Format: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai. Targeting Nrf2 in esophageal adenocarcinoma sensitizes cancer cells to cisplatin treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2430.
Abstract 2438: Reducing plate edge effect by controlling cell handling conditions for in vitro tumor hypoxia assays
Authors: Henn Alicia , Darou Shannon , Yerden Randy 
Published: August 2018

Abstract
To reduce the impact of high variability in the edge wells of 96-well plates, the "edge effect", researchers often fill edge wells with buffer to try to insulate the rest of the plate. This removes over a third of the wells from the assay, adding cost, handling time, and space problems to in vitro assays. This is of particular concern for researchers working with cells in low oxygen, as handling more plates increases the time that cells are out of optimum conditions, risking HIF-1a modulation. For this project, we tested the idea that controlling the entire cell handling space to conditions that match the incubator, including the working space floor temperature and gas levels, may help reduce the edge effect seen in 96-well plates. The null hypothesis was that cell handling conditions would make no difference in the variability of cell density in 96-well plates loaded in traditional room air conditions compared to plates loaded in controlled conditions matching the incubator. To address cell loading specifically, A549 cells were harvested from cell culture flasks in traditional cell handling conditions (room temp, 20% O2, 0% CO2), then split. Half of the cells were transferred to an Xvivo System for controlled cell handling conditions. The cells in both conditions were transferred to media pre-conditioned to hypoxic incubator conditions and then plated in 96-well plates. Temperature mapping was performed with 16 thermal probes simultaneously in replicate plates loaded with medium only. The cells were incubated for 24 hours, then stained for cell density, and read on a plate reader. Cell viability was greater than 90% (n=4 plates/condition/trial x 4 trials). We found that edge well temperatures were more stable in plates handled in unbroken optimal conditions and edge effect on cell density was greatly reduced. In room temperature conditions, columns 1 and 12 cooled most rapidly. We concluded that full-time control of environmental conditions allowed for use of the whole plate with reduced edge effect. This helps reduce cost, time, number of plates and the risks to cells during cell handling.
Citation Format: Alicia Henn, Shannon Darou, Randy Yerden. Reducing plate edge effect by controlling cell handling conditions for in vitro tumor hypoxia assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2438.