bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5385: Anticancer effects of a novel histone deacetylase inhibitor, SNUCH-1, in glioblastoma
Authors: Choi Seung Ah , Kwak Phi Ae , Lee Young Eun , Phi Ji Hoon , Choi Jung Won , Wang Kyu-Chang , Park Chul-Kee , Kim Seung-Ki 
Published: August 2015

Abstract
Histone deacetylase inhibitors (HDACi) have been evaluated as promising anticancer drugs against glioblastoma cells. However, there are still lack of animal experiments and new HDAC inhibitors for clinical trials. In this study, we demonstrated the therapeutic efficacy of novel pan-HDACi, SNUCH-1, comparing with other traditional pan-HDACi such as trichostatin A (TSA) and vorinostat (SAHA) in vitro and vivo. We performed cell viability, proliferation, cell cycle, apoptosis, HDAC enzyme activity and western blot assay using the three glioblastoma cell lines and two primary cultured cells. Furthermore, we examined the effects of SNUCH-1 by intracisternal administration on the orthotopic human xenograft glioblastoma mice model. We showed that SNUCH-1 decreased cell viability in a dose-dependent manner and suppressed proliferation with a stronger apoptotic activity than TSA and SAHA. SNUCH-1 inhibited HDAC enzyme activity and blocked cell cycle progression at G2/M, regulating cell cycle related protein expression more effectively than TSA and SAHA. In addition, SNUCH-1 significantly reduced tumor volume and revealed more powerful anti-tumor effect in vivo than TSA. Our results suggest that the novel HDAC inhibitor, SNUCH-1, is a potent therapeutic candidate for glioblastoma.
Key words: Histone deacetylase inhibitor, glioblastoma, intracisternal administration
Citation Format: Seung Ah Choi, Phi Ae Kwak, Young Eun Lee, Ji Hoon Phi, Jung Won Choi, Kyu-Chang Wang, Chul-Kee Park, Seung-Ki Kim. Anticancer effects of a novel histone deacetylase inhibitor, SNUCH-1, in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5385. doi:10.1158/1538-7445.AM2015-5385
Abstract 5387: ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin's lymphoma
Authors: Talekar Mala Kiran , Dicker David , Allen Joshua , El-Deiry Wafik 
Published: August 2015

Abstract
Outcome for non-Hodgkin's lymphoma (NHL) patients using conventional treatment standards remains unsatisfactory, particularly in advanced stage/ relapsed disease creating an imminent need for investigating novel treatment strategies. ONC201/TIC10 is a small molecule (Allen et al, 2013) that induces p53-independent cell death in tumor cells while sparing normal cells through inactivation of the prosurvival kinases Akt and ERK. ONC201 is currently entering Phase I/II clinical trials as a monoagent in adult advanced cancers. We have previously shown that ONC201 induces significant cytotoxicity in preclinical models of human lymphomas (Talekar et al, ASPHO 2014). Here, we show that ONC201 is not only effective as a monoagent across several NHL cell lines, but that it also synergizes with several chemotherapeutic agents to cooperatively induce cell death in vitro.
We found that ONC201 induces significant apoptosis in a diverse panel of human NHL cell lines at low micromolar concentrations (1.3 to 5.06 uM). Increased surface TRAIL and surface DR5 expression was noted in a dose-dependent manner across representative cell lines. The increase in surface TRAIL correlated with increase in sub-G1 DNA content, which suggests that TRAIL may serve as a potential biomarker of response to ONC201. ONC201-induced apoptosis was inhibited using a pan-caspase inhibitor and was blocked by an anti-TRAIL antibody RIK-2, which indicate induction of TRAIL-dependent cell death. Western blot analysis of ONC201-treated NHL cells suggests ERK inhibition and Foxo3a activation as a potential mechanism of cytotoxicity via TRAIL induction. In agreement with this notion, we also observed upregulation of PARP & DR5 and caspase-3 activation in response to ONC201 treatment.
We further found that ONC201 synergizes to potentiate cytotoxicity with several chemotherapeutic agents approved for NHL treatment, particularly anthracyclines (doxorubicin), nitrogen mustard (bendamustine), antimetabolite (cytarabine) and proteasome inhibitor (bortezomib) via cell viability experiments that were corroborated by apoptosis assays. Together these results suggest that ONC201 is a potent antitumor agent in NHL as monoagent and in combination with several approved therapies that may be explored in phase Ib/II trials.
Citation Format: Mala Kiran Talekar, David Dicker, Joshua Allen, Wafik El-Deiry. ONC201/TIC10 is effective as a monoagent and synergizes with chemotherapy to induce cell death in non-Hodgkin's lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5387. doi:10.1158/1538-7445.AM2015-5387
Abstract 5412: Lysosome disruption rapidly and effectively induces necrosis in aggressive thyroid carcinomas
Authors: Champa Devora , Di Cristofano Antonio 
Published: August 2015

Abstract
Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are very aggressive and lethal neoplasms for which there is currently no effective therapy. By activating Kras and deleting p53 in the mouse thyroid we have generated a mouse model of PDTC progressing to ATC. These tumors are characterized by elevated levels of anti-apoptotic members of the Bcl2 family. Tumor cell lines established from this model as well as similarly aggressive human thyroid cancer cell lines undergo cell death upon treatment with Obatoclax, an inhibitor of the anti-apoptotic Bcl2 family members. Even though several studies have suggested that Obatoclax induces apoptosis or necroptosis by binding to its designated targets in a number of different cancer models, our studies show that Obatoclax induces necrosis in both human and mouse thyroid cancer cell lines. By exploiting its autofluorescence, we show that Obatoclax is found in association with lysosomes, but not with mitochondria as it would be expected given the location of its known Bcl2-family targets, and that it causes rapid lysosome disruption. Obatoclax was also able to induce a block in the later stages of autophagy, as shown by an accumulation of autophagosomes upon treatment, likely as a result of lysosome impairment. Furthermore, Bafilomycin A1, an inhibitor of lysosomal acidification, counteracts the effect of Obatoclax and allows for cell survival. These findings suggest a novel mechanism of action for Obatoclax, in which direct lysosome disruption leads to necrosis. Strikingly, human and mouse thyroid cancer cell lines are also sensitive to other lysosome-destabilizing agents.
Importantly, transformed human thyroid cell lines are much more sensitive to Obatoclax than non-transformed thyroid cells, suggesting the existence of a useful therapeutic window. Even though Obatoclax has been removed from clinical trials due to low anti-tumor activity and toxic side effects, its efficacy in killing thyroid cancer cells otherwise refractory to treatment, and the alternative mechanism of action involved in this process support a new approach for targeting aggressive thyroid neoplasms. In conclusion, our data show that aggressive thyroid cancer cells are intrinsically sensitive to lysosome destabilization, and this characteristic can be exploited for the development of novel therapeutic approaches.
Citation Format: Devora Champa, Antonio Di Cristofano. Lysosome disruption rapidly and effectively induces necrosis in aggressive thyroid carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5412. doi:10.1158/1538-7445.AM2015-5412
Abstract 5419: Structure elucidation of G-quadruplex within the mid-region of the kRAS promoter and identification of stabilizing small molecules as promising transcriptional silencers
Authors: Morgan Rhianna K. , Brooks Tracy A. , Rahman Khondaker M. 
Published: August 2015

Abstract
Over 60% of pancreatic cancers harbor mutations in the kRAS oncogene, whose promoter has three distinct guanine-rich regions (near, mid, and far) capable of forming higher order G-quadruplexes (G4s). These important structures have transcriptional silencing potential and stabilizing compounds cause selective apoptosis in kRAS-addicted cells. Previous works in our laboratory have identified the mid-G4 region as having the highest silencing capacity, with little apparent roles for the near- or far-G4 regions. The structure of this mid-region G4 is being elucidated by electromobility shift assay, DNA polymerase stop assay, DMS footprinting, and circular dichroism (CD). In addition, small molecules are being screened by the Förster Resonance Energy Transfer (FRET) melt assay and confirmed by CD for their stabilization potential. We have identified multiple, equilibrating, intramolecular G4s forming within the mid-region of the kRAS promoter. Varying buffer conditions (cations, dehydration, and molecular crowding) affect these formations; the predominating isoform is a tetra-stacked mixed parallel and antiparallel structure with an 8:15:7 loop configuration. Over 1,600 compounds have been screened and several are being pursued as leads. Several compounds selectively stabilized the mid-G4 and suppress kRAS transcription. Our work highlights the mid-G4-forming region of the kRAS promoter a therapeutic target with the utmost promise for pancreatic cancer, and further features the stabilizing potential of targeted compounds. Studies are ongoing to vet the potential of other “hit” compounds from the FRET screen, as well as to elucidate the structure of the kRAS mid-G4 in chromosomal DNA.
Brooks Lab startup funds, DoD, Rhianna Morgan GSC Grant, University of Mississippi School of Pharmacy
Citation Format: Rhianna K. Morgan, Tracy A. Brooks, Khondaker M. Rahman. Structure elucidation of G-quadruplex within the mid-region of the kRAS promoter and identification of stabilizing small molecules as promising transcriptional silencers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5419. doi:10.1158/1538-7445.AM2015-5419
Abstract 5450: Naturally occurring mutations in the MPS1 gene predispose cells to kinase inhibitor drug-resistance
Authors: Gurden Mark D. , Westwood Isaac , Faisal Amir , Naud Sébastien , Cheung Jack , McAndrew Craig , Wood Amy , Schmitt Jessica , Boxall Kathy , Mak Grace , Workman Paul , Burke Rosemary , Hoelder Swen , Blagg Julian , Van Montfort Rob , Linardopoulos Spiros 
Published: August 2015

Abstract
Acquired resistance is the greatest challenge to the effectiveness of targeted anti-cancer therapies in the clinic. With several MPS1 inhibitors under pre-clinical development, we aimed to investigate how cancer cells will develop resistance against these inhibitors; therefore we modeled acquired resistance using a range of MPS1 inhibitors. We identified and characterized five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed that several MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. One mutation in particular, p.C604W, which is close to the gatekeeper residue, rendered MPS1 resistant to all the inhibitors we tested. However, we were able to design new compounds to specifically overcome this mutation, which in fact targeted the mutant with more potency than the wild-type MPS1 protein. Importantly, we show that these mutations are present in untreated cancer cell lines and primary tumour samples, and also pre-exist in normal lymphoblast and breast tissues. Furthermore, to confirm this is not specific to MPS1, we show that the EGFR p.T790M mutation is also pre-existing in cancer cell lines and normal tissue. Our data therefore suggest that mutations conferring resistance to targeted therapy are naturally occurring mutations in normal and cancer cells that are not introduced due to cancer cells being more mutagenic.
Citation Format: Mark D. Gurden, Isaac Westwood, Amir Faisal, Sébastien Naud, Jack Cheung, Craig McAndrew, Amy Wood, Jessica Schmitt, Kathy Boxall, Grace Mak, Paul Workman, Rosemary Burke, Swen Hoelder, Julian Blagg, Rob Van Montfort, Spiros Linardopoulos. Naturally occurring mutations in the MPS1 gene predispose cells to kinase inhibitor drug-resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2015-5450
Abstract 5452: Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors
Authors: Damaraju Vijaya L. , Kuzma Michelle , Cass Carol E. , Sawyer Michael B. 
Published: August 2015

Abstract
Inhibition of nucleobase transport activities by tyrosine kinase inhibitors (TKIs) has not been studied to date. Since many targeted TKIs are often combined with either capecitabine or 5-fluorouracil (5-FU) in treatment of various advanced cancers, we examined TKI effects on both equilibrative nucleobase transport (ENBT) and sodium-dependent nucleobase transport (SNBT) activities. Our goal was to study effects of TKIs on human ENBT and SNBT activities to explore potential TKI interactions with nucleobase chemotherapy drugs. Effects of TKIs on ENBT activities were investigated in normal human renal proximal tubule epithelial cells (hRPTECs). TKI effects on SNBT activities were assessed in a pig kidney cell line (LLC-PK1). We showed that TKIs inhibited both ENBT and SNBT activities to different extents. Gefitinib inhibited ENBT activity with an IC50 value of 0.7 μM thus indicating high sensitivity of ENBT to inhibition by gefitinib in hRPTECs. Erlotinib &gt; sorafenib &gt; imatinib &gt; sunitinib inhibited ENBT with IC50 values of 15, 40, 60, 78 μM, respectively whereas dasatinib, lapatinib and vandetanib were not inhibitory at concentrations &gt;100 μM. Similar studies in LLC-PK1 cells, which exhibit SNBT activity, showed that vandetanib was the most potent inhibitor followed by sorafenib &gt; erlotinib &gt; gefitinib &gt; sunitinib &gt; imatinib with IC50 values of 14, 25, 28, 40, 47 and 94 μM, respectively whereas dasatinib and lapatinib were not inhibitory at concentrations &gt;100 μM. These results indicate inhibition of both ENBT and SNBT activities by exposure of cells to TKIs. These effects on nucleobase transport activities, which could be direct or indirect, suggest why regimens combining gefitinib and 5-FU have failed. Further studies should test all TKI classes for such inhibitory activities to assess potential effects on combination regimens using TKIs with nucleobase drugs such as 5-FU in cancer treatment.
Citation Format: Vijaya L. Damaraju, Michelle Kuzma, Carol E. Cass, Michael B. Sawyer. Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5452. doi:10.1158/1538-7445.AM2015-5452
Abstract 5454: Wogonin overcomes cisplatin resistance of head and neck cancer by targeting antioxidant defense mechanisms
Authors: Kim Ji Won , Kim Eun Hye , Park Jin Young , Kwon Minsu , Roh Jong-Lyel 
Published: August 2015

Abstract
Background: Cisplatin is a first-line chemotherapeutic agent for head and neck cancer (HNC). However, the main limitation to clinical usefulness of cisplatin is the high incidence of chemoresistance causing one of major failures in cancer management. This may suggests the necessity of combination therapies of cisplatin with other drugs to circumvent chemoresistance. Wogonin, one of major natural flavonoids, is known to reverse multidrug resistance in several types of cancers, however, which has been rarely tested in HNC cells. Therefore, the present study investigated the ability and molecular mechanisms of wogonin overcoming cisplatin resistance in HNC cells.
Methods: Two cisplatin-resistance HNC cell lines (AMC-HN4R and -HN9R) and their parental and other human HNC cell lines were used. The effect of wogonin, alone and in combination with cisplatin, was assessed in HNC cells and normal cells by measuring cell viability, cell cycle and death assays, reactive oxygen species (ROS) production, and protein expression, and in preclinical tumor xenograft mouse models.
Results: Wogonin selectively killed HNC cells but spared normal cells. It inhibited NF-E2-related factor 2 (NRF2), P-glycoprotein, and glutathione S-transferase P (GSTP), overexpressed in cisplatin-resistant HNC cells, resulting in the increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Wogonin also induced selective cell death by targeting the antioxidant defense mechanisms enhanced in the resistant HNC cells and subsequently, effectively activating cell death pathways involving PUMA and PARP. Therefore, wogonin significantly sensitized the resistant HNC cells to cisplatin in vitro and in vivo.
Conclusions: Wogonin might be the promising anticancer candidate by inducing ROS accumulation and selective killing HNC cells, thus contributing to overcome the cisplatin-resistance of HNC cells.
Citation Format: Ji Won Kim, Eun Hye Kim, Jin Young Park, Minsu Kwon, Jong-Lyel Roh. Wogonin overcomes cisplatin resistance of head and neck cancer by targeting antioxidant defense mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5454. doi:10.1158/1538-7445.AM2015-5454
Abstract 5488: Utilizing a pathway based analysis of genome wide association data to identify biomarkers of toxicity in breast cancer patients
Authors: Bidadi Behzad , Kalari Krishna R. , Rubner Matthias , Hein Alexander , Beckmann Matthias W. , Fasching Peter A. , Rack Brigitte , Janni Wolfgang , Weinshilboum Richard , Wang Liewei 
Published: August 2015

Abstract
Breast cancer is the most common invasive cancer in women worldwide and treatment related toxicity has high inter-patient variability. Our goal was to identify additional genetic predictors of toxicity by completing a pathway based analysis taking advantage of the genotyping results obtained through a GWAS of the same patients. For our analysis, we have utilized GWA data from the SUCCESS-A trial in which 3,754 breast cancer patients were treated with adjuvant chemotherapy. We have included SNPs associated with 112 genes involved in drug disposition and 375 genes in selected cancer pathways.
We identified 35 SNPs associated with neutropenia (P-value &lt;1×10−4). These patients initially received three cycles consisting of 5-fluorouracil (5-FU), cyclophosphamide, and epirubicin. Currently we are characterizing the function of three SNPs located within an intron of the hyaluronan mediated motility receptor (HMMR) gene that are associated with the neutropenia phenotype (P-value &lt;1×10−4). These SNPs are highly associated with the expression of a gene encoding a B-cell survival factor, TNFSF13B, (P-value &lt;1×10−5).
Our in vitro studies using lymphoblastoid cell lines (LCLs) selected based on the genotypes of HMMR gene showed that heterozygous and homozygous variant cells (n = 6) have an increased sensitivity to 5-fluorouracil, but not cyclophosphamide or epirubicin when compared with homozygous wild-type cells (n = 6). LCLs exposed to the previously mentioned chemotherapeutic agents resulted in an upregulation of TNFSF13B gene expression and downregulation of HMMR gene expression.
We have utilized a pathway based approach to analyzing GWA data to identify several SNPs in the HMMR gene highly associated with the expression of one of the top signals in the cytopenia GWAS. Our goal is to further characterize the role of HMMR gene variants in chemotherapy response by assessing whether combinations of these agents in vitro (including 5-FU) also have a genotype dependent response to cytotoxicity.
Citation Format: Behzad Bidadi, Krishna R. Kalari, Matthias Rubner, Alexander Hein, Matthias W. Beckmann, Peter A. Fasching, Brigitte Rack, Wolfgang Janni, Richard Weinshilboum, Liewei Wang. Utilizing a pathway based analysis of genome wide association data to identify biomarkers of toxicity in breast cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5488. doi:10.1158/1538-7445.AM2015-5488
Abstract 5512: Preclinical evaluation of the recombinant human arginase PEG-BCT-100 leading to arginine deprivation in sarcomas
Authors: Choy Chi Tung , Cheong Hio Teng , U Kin Pong , Wong Chi Hang , Loong Herbert Ho Fung 
Published: August 2015

Abstract
Background: Arginine deprivation is a novel approach to limit arginine-dependent tumour growth. The presence of enzymes involved in the de novo synthesis of arginine from citrulline, argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and ornithine transcarbamylase (OTC), can influence the sensitivity of tumour to arginine depletion. We studied the preclinical efficacy of PEG-BCT-100 (also known as rhArg1peg5000), a PEGylated recombinant human arginase 1 on sarcoma cell lines. In this study, ASS, ASL and OTC expression were established in sarcoma cell lines and the sensitivity of each cell line to PEG-BCT-100 treatment was determined in order to establish their suitability as predictive markers to determine responsiveness to PEG-BCT-100 treatment.
Methods: Cells from 5 representative soft-tissue sarcoma (STS) cell lines (RD, GCT, HT-1080, SW872, SW982) and 1 osteosarcoma cell line (SJSA-1), either incubated in full culture medium (control), arginine free medium or PEG-BCT-100 (1U/ml) treated medium. They were monitored by live cell imaging for 72 hours. Their corresponding IC50 were determined by cell viability assay. The expression of ASS, ASL and OTC were determined by Western blotting.
Results: All sarcoma cell lines were sensitive to PEG-BCT-100 and demonstrated significant cell proliferation inhibition. Their IC50, as determined by cell viability assay were 0.023 U/ml, 0.028 U/ml, 0.023 U/ml, 0.026 U/ml, 0.20 U/ml, 0.053 U/ml, and 0.03 U/ml for GCT, HT-1080, RD, SJSA-1, SW872 and SW982 respectively. Western blot analysis confirmed strong basal protein expression of ASL and low OTC expression in all sarcoma cell lines, suggesting sensitivity to PEG-BCT-100 is not determined by ASL but rather, OTC. On the contrary, low ASS basal protein expression was revealed in all sarcoma cell lines except for RD. A strongly expressed ASS was observed in RD despite of its sensitivity to PEG-BCT-100, implying that ASS might be less important in the response towards PEG-BCT-100.
Conclusion: Arginine deprivation by PEG-BCT-100 is effective in suppressing STS cell growth in vitro, suggesting arginine auxotrophism in STSs. Moreover, arginase treatment can be an effective strategy against STS. Low expression of OTC, instead of ASS and ASL, may be a more important predictive biomarker for response to treatment. Further in-vivo and clinical studies are warranted.
Citation Format: Chi Tung Choy, Hio Teng Cheong, Kin Pong U, Chi Hang Wong, Herbert Ho Fung Loong. Preclinical evaluation of the recombinant human arginase PEG-BCT-100 leading to arginine deprivation in sarcomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5512. doi:10.1158/1538-7445.AM2015-5512