bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2821: Tousled like Kinase 1 binds to and regulates the protein kinase Nek1: Its implication in prostate cancer
Authors: Singh Vibha , Jaiswal Praveen K. , Koul Hari K. , Yu Xiuping , Benedetti Arrigo 
Published: August 2018

Abstract
Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in the United States. Tousled Like kinases (TLKs) are involved in numerous cellular functions, including the DNA Damage Response (DDR). Through a novel proteomic approach, we have identified that NIMA kinase NEK1 strongly interacts and co-localizes with TLKs and has a role in the DDR, upstream of ATR and Chk1. In the present study we have tested Thioridazine (THD), an anti-psychotic drug and inhibitor of TLKs in inhibiting the activity of NEK1 in prostate cancer cell lines and LNCaP cell derived xenografts in NOD/SCID mice and the subsequent role of ATR-Chk1 axis following DNA damage.
Material & Methods: We have used a prostate cancer cell line viz. LNCaP, C4-2, C4-2b, 22Rv1, DU145 and PC3 and normal prostate cell line RWPE-1. Clonogenic activity was measured by colony formation assay. Immunoblotting was done for TLKs, NEK1, p-ATR and p-Chk1 protein in PCa cell line and tumor xenografts tissues. LNCaP xenografts in NOD/SCID mice were used in present study. We have used THD (alone) or in combination with the anti-androgen drug bicalutamide in PCa cell lines as well as in xenografts mice model.
Results: Treatment with THD suppresses the outgrowth of androgen-independent (AI) colonies of LNCaP cells cultured with bicalutamide. Moreover, THD significantly inhibited the colony formation efficiency of several PCa cells in vitro (even of androgen independent lines). Intra-Peritoneal (I.P.) administration of THD or Bicalutamide long-term was not very effective in inhibiting tumor growth. In contrast, combination therapy of THD and Bicalutamide remarkably inhibited the tumor growth in LNCaP xenografts model. Further p-ATR and p-Chk1 axis was inhibited by treatment with THD and in combination with bicalutamide as evident by immunoblotting of residual tumors. In cells, following DNA damage, addition of the TLK inhibitor THD impaired ATR and Chk1 activation, indicating the existence of a TLK1&gt;NEK1&gt;ATR&gt;Chk1 pathway.
Conclusions: Our data indicated that THD repressed growth of PCa cells in vitro and in vivo, and for Androgen-dependent (LNCaP) cells, in combination with bicalutamide it was very effective at preventing outgrowth of AI cells and hence as a targeted ADT adjuvant therapy. Moreover, THD impaired DDR. Collectively, these results strongly suggest that THD might be a novel anti-tumor agent for use in prostate cancer.
Citation Format: Vibha Singh, Praveen K. Jaiswal, Hari K. Koul, Xiuping Yu, Arrigo Benedetti. Tousled like Kinase 1 binds to and regulates the protein kinase Nek1: Its implication in prostate 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 2821.
Abstract 2833: Single-cell imaging reveals MAPK pathway reactivation in drug-tolerant melanoma cells
Authors: Yang Chen , Tian Chengzhe , Spencer Sabrina L. 
Published: August 2018

Abstract
Spontaneous genetic mutations allow an initially drug-sensitive population of cancer cells to acquire a drug-resistant phenotype. However, little is known about how drug-sensitive cells first evade drug action and survive in the presence of drug, referred to as "drug tolerance," a crucial step on the road to resistance. In this study, we combined single-cell time-lapse microscopy and MATLAB-based automated cell tracking to identify the molecular basis of drug tolerance. By simultaneously monitoring CDK2 and ERK activity in single cells, we found that melanoma cells harboring a BRAF-V600E mutation have high ERK activity and consecutively cycled with an inter-mitotic time of around 14 hr in full growth media. Upon treatment with dabrafenib, an ATP competitive B-Raf inhibitor, all cells entered a CDK2-low quiescence with reduced ERK activity. Strikingly, after 72 hr of dabrafenib treatment, a fraction of cells escaped drug action, re-entered the cell cycle, and divided once in presence of drug before re-entering a transient quiescence. Additional cells continued to escape and divide in the presence of drug, with a steady-state level of about 10% of the population engaged in the cell cycle at any point during the week-long observation period. We refer to cells that re-entered the cell cycle as "escapees" and cells that stayed in quiescence during the observation period as "non-escapees." Remarkably, we found that escapees showed significantly higher ERK activity than non-escapees after a few days of treatment, even though their initial ERK activities were indistinguishable. To test whether reactivation of the MAPK pathway is the cause of cell cycle re-entry, we co-treated cells with dabrafenib and the MEK inhibitor trametinib. This co-treatment resulted in even lower ERK activity and elimination of the escapee population. This result implies that dabrafenib, even at high doses, does not fully turn off the MAPK pathway, thereby enabling eventual escape from drug. By monitoring escaping cells at the molecular level in real time, our work thus suggests a possible mechanism for cells to develop drug tolerance in less than three days, long before acquiring genetic mutations.
Citation Format: Chen Yang, Chengzhe Tian, Sabrina L. Spencer. Single-cell imaging reveals MAPK pathway reactivation in drug-tolerant melanoma 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 2833.
Abstract 2843: Calcium blockers modulate the steroid resistance in acute lymphoblastic leukemia
Authors: Jung Hyun Joo 
Published: August 2018

Abstract
Background: Acute lymphoblastic leukemia (ALL) is one of common cancers in children and adults, and a fair number of ALL patients still die although the overall survival rate is approaching 90% with risk-directed therapy in many developed countries. Response to steroid is the most important prognostic factor of patients with ALL, and the development of steroid resistance is lethal to the ALL patients. To improve survival for steroid-resistant ALL patients, it is necessary to develop new concepts to overcome the steroid resistance of ALL.
Methods: We generated the steroid-adapted subclones through prolonged cultures of ALL cell lines with gradually increased steroid concentration.Also, we used biochemical and molecular methodologies to demonstrate the signaling axis of tissue transglutaminase (TG2)-nuclear factor-kappa B (NF-kappa B) and cell cycle to evaluate the effect of calcium blockers on the steroid-resistant ALL cells.
Results: Steroid-adapted ALL cells that were generated by culture with gradually increased steroid concentration were much more resistant to steroid than their parent ALL cells. We found that calcium blockers altered TG2 activity and nuclear factor-kappa B (NF-kappa B) expression in these steroid-resistant ALL cells. Also, calcium blockers induced the change of expression of NF-kappa B target genes in steroid-adapted ALL cells. In addition, calcium blockers induced the change of ABC transporter expression and the quiescence of steroid-resistant ALL cells. We also found that calcium blockers induced apoptosis of steroid-resistant ALL cells and reduced the steroid resistance of steroid-resistant ALL cells.
Conclusion: This study shows that calcium blockers improved the cytotoxicity of steroid on steroid-resistant ALL cells via manipulation of TG2 and NF-kappa B activities and cell cycle. The combination of calcium blockers with chemotherapeutic agents may be a new alternative strategy to overcome the steroid resistance of ALL.
Citation Format: Hyun Joo Jung. Calcium blockers modulate the steroid resistance 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 2843.
Abstract 2866: Anticancer effect of a new cyclic peptide ALOS4 is associated with its systemic anti-inflammatory activity
Authors: Nesher Elimelech , Pinhasov Albert , Becker Maria , Kirby Michael , Harazi Raichel Cohen , Yakobovich Shiri , Agranyoni Oryan , Shoval Bar , Elbaz Shany I. , Udartseva Olga , Gitlin Ilya , Leonova Katerina , Gurova Katerina , Gudkov Andrei , Koman Igor 
Published: August 2018

Abstract
The association of chronic inflammation with cancer development and progression has been well recognized. Here, we report a synthetic cyclic peptide, ALOS4, capable of suppressing tumor growth following systemic administration and possessing anti-inflammatory properties. Although ALOS4 was initially isolated by phage display for its ability to bind avb3 integrin and demonstrated tumor-suppressor activity in preclinical xenograft and syngeneic models of melanoma, it surprisingly showed no functional activity resembling RGD peptides in functional in vitro assays. Remarkably, ALOS4 displayed no signs of toxicity in treated animals, even at doses exceeding &gt;100-fold beyond the efficacious dose. To identify the mechanisms underlying profound antitumor activity of this safe peptide, we used a large panel of cell-based repeater assays designed to detect modulators of a variety of signaling pathways including p53, NF-kB, and different types of stress responses including heat shock and hypoxia. We also tested the effects of ALOS4 on tumor cell growth, adhesion, clonogenicity, morphology and other in vitro properties. ALOS4 showed no detectable activity in any of these numerous assays with one exception: it suppressed the ability of treated cells to induce interferon type I signaling in response to mimics of double-stranded RNA (Poly I:C). Based on this observation, we hypothesized that the antitumor effect of ALOS4 is driven by a systemic anti-inflammatory effect rather than by a direct effect on tumor cells. Consistently, ALOS4 treatment dramatically altered both the abundance and content of the immunocyte population infiltrating subcutaneous melanomas in mice. These results suggest that ALOS4 may be an anticancer agent with a new mechanism of action that targets the tumor-supporting interferon-driven mechanism of tumor-host interaction.
Citation Format: Elimelech Nesher, Albert Pinhasov, Maria Becker, Michael Kirby, Raichel Cohen Harazi, Shiri Yakobovich, Oryan Agranyoni, Bar Shoval, Shany I. Elbaz, Olga Udartseva, Ilya Gitlin, Katerina Leonova, Katerina Gurova, Andrei Gudkov, Igor Koman. Anticancer effect of a new cyclic peptide ALOS4 is associated with its systemic anti-inflammatory activity [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 2866.
Abstract 2869: Nintedanib abrogates the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients
Authors: Alcaraz Jordi , Gabasa Marta , Ikemori Rafael , Hilberg Frank , Reguart Noemí 
Published: August 2018

Abstract
Nintedanib is a clinically-approved multikinase receptor inhibitor that, in combination with docetaxel, provides clinical benefits to advanced lung adenocarcinoma (ADC) patients but not to lung squamous cell carcinoma (SCC) patients. However, the mechanisms underlying the selective therapeutic effects of Nintedanib in ADC remain poorly understood. Of note, Nintedanib is also approved to treat patients with idiopathic pulmonary fibrosis (IPF), a rare disease characterised by an abundant desmoplastic stroma rich in pathologically activated fibroblasts. Since the tumor stroma in lung cancer is also desmoplastic, and we recently showed that tumor-associated fibroblasts (TAFs) derived from ADC and SCC patients exhibit different phenotypes in vitro, we hypothesized that TAFs may underlie the selective effects of Nintedanib in ADC. To test this hypothesis we activated TAFs in culture with the pro-fibrotic cytokine TGF-β1 in the presence of increasing concentrations of Nintedanib, and collected the corresponding conditioned medium. Remarkably SCC-TAFs showed very modest inhibition of a panel of fibrotic markers including α-SMA, P4HA2 and fibrillar collagens (COL1A1, COL3A) in response to Nintedanib, in striking contrast to ADC-TAFs and paired lung parenchyma fibroblasts, which were markedly affected. This was matched by a significant reduction in the abilities of the conditioned medium of ADC-TAFs but not SCC-TAFs to promote cancer cell growth and invasion in a panel of lung cancer cell lines after Nintedanib treatment. These results reveal that Nintedanib is an effective inhibitor of stromal fibrosis and its associated tumor-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to Nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that TGF-β signalling and aberrant TAF-carcinoma cross-talk are regulated by different mechanisms in ADC and SCC. In addition they support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to Nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumors.
Citation Format: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Frank Hilberg, Noemí Reguart. Nintedanib abrogates the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients [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 2869.
Abstract 2892: EGLN1 is a synthetic lethal target in ARID1A-mutant ovarian cancer
Authors: Briggs Kimberly J. , Min Chengyin , Zhang Hongxiang , Huang Alan 
Published: August 2018

Abstract
The successful use of PARP inhibitors for the treatment of BRCA-mutant ovarian cancer underscores the importance of synthetic lethality as a therapeutic opportunity for tumors with loss-of-function mutations in tumor suppressor genes. Ovarian cancer ranks as the fifth deadliest cancer among women, and one ovarian cancer subtype, clear cell carcinoma, is particularly underserved. The most frequent genetic alteration in ovarian clear-cell carcinoma is loss-of-function mutation of the SWI/SNF-A complex subunit, ARID1A. We interrogated the data published by Project Achilles to determine candidate synthetic lethal partners with ARID1A in ovarian cancer, and identified EGLN1, a member of the EglN-family of prolyl hydroxylases. Inhibition of EGLN1, either genetically or pharmacologically, leads to decreased viability in ovarian cancer cell lines. Pharmacological inhibition of EGLN1 is clinically achievable as evidenced by several well-tolerated, small molecule inhibitors currently in clinical trials for the treatment of anemia in the context of chronic kidney disease. The synthetic lethal interaction of ARID1A and EGLN1 may provide a therapeutic opportunity for patients diagnosed with ovarian clear-cell carcinoma.
Citation Format: Kimberly J. Briggs, Chengyin Min, Hongxiang Zhang, Alan Huang. EGLN1 is a synthetic lethal target in ARID1A-mutant ovarian 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 2892.
Abstract 2905: Deciphering and blocking the mechanisms of cadmium induction of TCTP in prostate cancer cells
Authors: Saad Rama , Munirathinam Gnanasekar , Kucynda Theresa , Ribeiro Marta , Lindholm Paul , Balla Andre 
Published: August 2018

Abstract
While cadmium is a well-known lung carcinogen, its role in prostate cancer is yet to be understood. Recently, a meta-analysis study showed that cadmium did not increase the risk of prostate cancer. It is not known whether cadmium exposure at environmentally relevant concentrations increases aggressiveness of already existing prostate cancer. Although our lab previously showed that the 75th percentile of cadmium concentration in prostate cancer was associated with biochemical recurrence, more evidence is needed to substantiate this finding. We also showed evidence that cadmium promotes prostate cancer cells migration and invasion via inducing the expression of translationally controlled tumor protein (TCTP). Furthermore, it was demonstrated that cadmium induces the phosphorylation of p38, and that the p38 inhibitor SB203580 (SB) blocks the effects of cadmium on migration and invasion. In this study, we aimed to delineate the signaling events upon cadmium treatment; whether p38 or TCTP is upstream. We addressed this via inhibition of p38 using SB203580 and by inducing TCTP degradation via dihydroartemisinin (DHA) followed by measurement of TCTP expression and phosphorylation of p38 respectively. p38 inhibition led to the increased expression of TCTP on both mRNA and protein levels. Pretreatment with DHA led to less TCTP expression and less phosphorylation of p38. We also aimed to understand the effect of cadmium on cell proliferation, survival and migration. While DHA lowered the colony count and EdU incorporation, cadmium did not alter these functions. In addition, DHA abrogated the cadmium-mediated migration of PC3-Inv prostate cancer cell line. Furthermore, we aimed to determine the effect of nanomolar cadmium concentrations on the phosphorylation of PlK1, which is well established to be upstream of TCTP. Our results demonstrated that nanomolar concentrations of cadmium resulted in increased phosphorylation of PlK1 in both PC3 and LNCaP cells. Altogether, our results suggest that environmentally relevant exposures of cadmium induce TCTP expression through several pathways, and that there is a feedback mechanism between p38 and TCTP.
Citation Format: Rama Saad, Gnanasekar Munirathinam, Theresa Kucynda, Marta Ribeiro, Paul Lindholm, Andre Balla. Deciphering and blocking the mechanisms of cadmium induction of TCTP in prostate cancer 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 2905.
Abstract 2922: The utility of BET inhibition in the sensitization and re-sensitization of pancreatic cancer cells to paclitaxel
Authors: Hamdan Feda H. , Kutschat Ana P. , Sen Madhobi , Wang Xin , Johnsen Steven A. 
Published: August 2018

Abstract
While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. As late diagnosis and resistance to conventional therapies are major contributors to high mortality rates, novel treatment options are needed to improve the prognosis of pancreatic cancer patients. Recent findings showed that inhibition of the Bromodomain and Extraterminal Domain (BET) family of epigenetic reader proteins is effective, both alone and in combination with conventional chemotherapy, in decreasing pancreatic tumor growth in patient-derived xenografts. Thus, we aim to evaluate the potential role of and mechanisms of action of BET inhibitors (BETi) as an adjuvant therapy option in pancreatic ductal adenocarcinoma. We established L3.6 pancreatic cells that are resistant to paclitaxel by maintaining them in incrementally higher concentrations for 3 months. Paclitaxel-resistant cells showed a half maximal inhibitory concentration (IC50) 100-fold higher than that of parental cells. Intriguingly, we report that low, non-cytostatic concentrations of the BETi, JQ1, not only sensitized cells to paclitaxel, but also induced significant re-sensitization of chemoresistant cells. In order to elucidate the mechanism by which BETi induces chemo-sensitization, we investigated the differential gene expression profiles of resistant and sensitive cells. Thereby, we uncovered that BETi reverses the regulation of transcriptionally-activated genes in resistant cells. Interestingly, these genes showed a major tendency to gain BRD4 at putative enhancer regions. We anticipate that enhancer RNAs (eRNAs) transcribed at these particular enhancers may provide us with novel biomarkers which can be used to predict chemotherapeutic resistance and the possibility of re-sensitization by BETi. In conclusion, we provide evidence that BETi can potentially be used as adjuvant agents in pancreatic cancer. However, approaches may likely be largely independent of their anti-proliferative effects that require higher concentrations and possibly lead to intolerable adverse effects, but rather to their transcriptional regulatory functions that attenuate the activated programs in chemoresistant cancers.
Citation Format: Feda H. Hamdan, Ana P. Kutschat, Madhobi Sen, Xin Wang, Steven A. Johnsen. The utility of BET inhibition in the sensitization and re-sensitization of pancreatic cancer cells to paclitaxel [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 2922.
Abstract 2939: ETC159, a porcupine inhibitor, exhibits synergism with PI3K inhibitors in 3-dimensional cell culture
Authors: Sepramaniam Sugunavathi , Chew Xin Hui , Ngeow Kao Chin , Lee May Ann 
Published: August 2018

Abstract
Aberrations in WNT signaling, a pathway regulated by a family of secreted glycoproteins known as WNTs, is implicated as a cause for cancer. Post-translational modification of WNTs by porcupine is critical for their activity and eventual activation of the WNT pathway. ETC-159 is an orally available, potent porcupine inhibitor. Addition of ETC-159 suppresses cancer proliferation in several cell lines by blocking the secretion and activity of all WNTs. Nevertheless, tumor growth is driven by complex molecular interactions that dysregulate several pathways at any one time. Thus, early drug discovery studies have increasingly evolved to target multiple molecules or pathways. As therapeutic approaches using combinations of drugs directed at multiple targets can improve treatment response, in this study we explored the possibility of identifying compounds that are synergistic with ETC-159. Unlike conventional two-dimensional combination drug screening, we used the three-dimensional soft agar colony formation assays for the study. Dose-response curves were first independently established to obtain the EC50 ranges for each drug, before proceeding to combination treatments. Using the Chou-Talalay Drug Combination Software, CompuSyn, we identified several inhibitors, which target the PI3K pathway, to act synergistically with ETC-159 in pancreatic cell lines HPAF-II, ASPC-1 and CFPAC-I. Similar treatments in nonpancreatic cell lines indicated that the observed synergism was not cell-line specific, hence highlighting the applicability of such combination treatments for different cancers.
Citation Format: Sugunavathi Sepramaniam, Xin Hui Chew, Kao Chin Ngeow, May Ann Lee. ETC159, a porcupine inhibitor, exhibits synergism with PI3K inhibitors in 3-dimensional cell culture [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 2939.