bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3701: Transcriptomic consequences of MDMX (MDM4) oncoprotein expression knockdown in MDMX-amplified breast cancer cells
Authors: Ho Yi-hsuan , Hutton Claire , Newell Herbie , Lunec John 
Published: July 2016

Abstract
The tumour suppressor p53 is activated by cellular stress to induce cell cycle arrest and/or apoptosis. Although the TP53 gene is frequently mutated in cancer, approximately half of human cancers express wild type and functional p53. However, p53 activity is often suppressed by its negative regulators, MDM2 and MDMX. Small molecule antagonists have been developed to inhibit p53-MDM2 binding to release the growth inhibitory and/or pro-apoptotic functions of p53. Previous studies have indicated that MDMX amplification and/or increased protein expression may be associated with resistance to MDM2-p53 binding antagonists. However, specific inhibitors for MDMX have yet to be developed and an MDM2/MDMX-p53 co-inhibitor (RO-5963) does not show better efficacy against high MDMX expressing cells than single target MDM2 inhibitors. To better understand the cellular function and therapeutic potential of targeting MDMX, we have investigated the downstream transcriptomic consequences of knocking down MDMX expression.
Knockdown of MDMX protein expression, demonstrated by Western blot analysis, was achieved in MRK-nu-1 MDMX amplified and TP53 wild-type breast carcinoma cells using both lentiviral shRNA and siRNA. MRK-nu-1 cell growth suppression was observed after knockdown of MDMX. Affymetrix Human Transcriptome Array 2.0 was used to detect differences in the expression of full genes and alternatively spliced forms between negative control and MDMX knockdown groups. Transcriptome Analysis Console 3.0 software was used to analyse the microarray data to identify significant changes in gene expression, alternative splicing and associated functional pathways. Alterations in mRNA expression for a selected panel of genes was confirmed by qRT-PCR.
A greater degree of MDMX expression knockdown was achieved with the siRNA (&gt;95%) than the lentiviral shRNA (&gt;50%) This was reflected by increased suppression of growth and larger changes in gene expression patterns with the siRNA knockdown. Although a similar set of genes was affected by both the siRNA and shRNA knockdown, the magnitude of changes was greater following the more pronounced knockdown with siRNA. The expression of a number of p53 transcriptional target genes was found to be altered, including CDKN1A, MDM2, CCNG2, RRM2B, BTG2, ZMAT3 and FAS consistent with a role for MDMX in suppression of p53 function in these MDMX amplified cells.
Citation Format: Yi-hsuan Ho, Claire Hutton, Herbie Newell, John Lunec. Transcriptomic consequences of MDMX (MDM4) oncoprotein expression knockdown in MDMX-amplified breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3701.
Abstract 3708: Targeting synthetic lethality with PARP inhibition in colorectal cancer
Authors: Augustine Titto , Maitra Radhashree , Zhang Jinghang , Nayak Jay , Goel Sanjay 
Published: July 2016

Abstract
Background:
Small molecule poly ADP-ribose (PAR) polymerase (PARP) inhibitors (PARPi) purportedly result in DNA damage and are promising agents in the treatment of cancer. In a quest to identify best “synthetic lethality” for treatment, we have screened various combination therapies in colorectal cancer (CRC) cell lines. In addition, we have interrogated if the presence of microsatellite instability (MSI) status favor susceptibility of cells to synthetic lethality and thus acts as a prognostic marker of combination therapy.
Methods:
Using the SRB assay, the 12 combinations of the PARPi, veliparib (V), rucaparib (R), olaparib (Ol) and PJ34, and the cytotoxic drugs, irinotecan (I), 5-fluorouracil (5-FU) and oxaliplatin (Ox) were screened in HCT116 and LIM2405 cell lines. We assessed the effect of the combination using the CalcuSyn software for combination index (CI). We next evaluated the effectiveness and sequence dependence of combination in an additional 2 cell lines that had MSI status (RKO and HCT15) and 2 that had microsatellite stable (MSS) status (HT29 and SW837) and in 7 HCT116 isogenic lines (mutants of Bax, p21, p53, PTEN, Kras and DNMT and wild type of PIK). The combination of I and R was confirmed by FACS analysis in HCT116 and LIM2405.
Results:
Ol and R showed synergy in combination with I, whereas, V and PJ34 showed antagonism with Ox, including in Ox-sensitive cells. Single agent cytotoxicity was observed at 200nM for R, whereas V required more than 30uM. Early PARP-1 protein upregulation was observed upon Ox administration; but the changes were not reversed with either R or V. Nevertheless, R at 200nM and V 1uM significantly reduced PAR formation in Ox-sensitive cell lines. FACS analysis showed S phase arrest in SW837 (MSS) (p = 0.03) whereas G2-M arrest was observed in LIM2405 (MSI) (non-significant) upon treatment with R 400nM and I 200nM. In addition, studies using isogenic cell lines revealed the importance of p21, p53 and PTEN in exerting synergistic effect while combining R and I. Administration of I prior to R (24h each) was more cytotoxic than vice versa and simultaneous treatment in MSI cell lines.
Conclusion:
Among the various combinations studied, R with I was the most synergistic. The effect appears to be more pronounced when I precedes R, particularly in MSI cell lines. Alteration in cell cycle is MSI status dependent. Further work to identify mechanism of synergy is ongoing.
Citation Format: Titto Augustine, Radhashree Maitra, Jinghang Zhang, Jay Nayak, Sanjay Goel. Targeting synthetic lethality with PARP inhibition in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3708.
Abstract 3715: Benzimidazolone sulphonamides - potent, selective and drug-like inhibitors of poly(ADP Ribose) Glycohydrolase (PARG)
Authors: Jordan Allan , Acton Ben , Hamilton Nicola , Hitchin James , Hutton Colin , James Dominic , Jones Cliff , Jones Stuart , McGonagle Alison , Small Helen , Smith Kate , Stowell Alex , Tucker Julie , Waddell Ian , Waszkowycz Bohdan , Ogilvie Donald 
Published: July 2016

Abstract
In recent years, many proteins involved in DNA repair, such as ATR, ATM and PARP, have received considerable attention as potential points of therapeutic intervention in cancer. Indeed, these efforts have recently delivered several agents into clinical evaluation or FDA regulatory approval. However, the DNA repair protein poly(ADP ribose) glycohydrolase (PARG), which plays an equally critical role in DNA single stand break repair, to successful drug discovery efforts.
Through our innovative collaboration with AstraZeneca, we have discovered a novel PARG-binding pharmacophore and have employed this information to discover drug-like chemotypes, facilitating the development of potent and selective inhibitors.
This poster will describe our emerging results in this area, where a novel benzimidazolone sulphonamide scaffold has been shown potently to inhibit PARG in both biochemical and cellular assays with potencies of 40 nM and 60 nM respectively. Moreover, these agents display pharmacology consistent with the anticipated mode of action, appropriate drug-like properties and are selective against PARP1 and the close glycohydrolase homologue ARH3. The medicinal chemistry optimisation of this scaffold will be described, alongside the recent biological results obtained. Ultimately, this work has helped deliver tool compounds which may help to elucidate the true pharmacology and roles of PARG in cancer and other disease settings.
Citation Format: Allan Jordan, Ben Acton, Nicola Hamilton, James Hitchin, Colin Hutton, Dominic James, Cliff Jones, Stuart Jones, Alison McGonagle, Helen Small, Kate Smith, Alex Stowell, Julie Tucker, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. Benzimidazolone sulphonamides - potent, selective and drug-like inhibitors of poly(ADP Ribose) Glycohydrolase (PARG). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3715.
Abstract 3725: B-Raf inhibition-induced paradoxical activation of MEK/ERK signaling enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells
Authors: Oh You-Take , Deng Jiusheng , Yue Ping , Sun Shi-Yong 
Published: July 2016

Abstract
B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers such as melanoma and thyroid cancer. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but lead to a paradoxical activation of MEK/ERK signaling in Ras-mutant cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. Given the critical role of MEK/ERK signaling in the positive regulation of DR5 expression as we have previously demonstrated, this study focuses on determining the impact of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-treatment of Ras-mutated cancer cells with PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells. Our results may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition. (This study was supported by Emory Winship Cancer Institute Robbins Scholar awards to YTO and to JD and Halpern Research Scholar award to SYS. SYS is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar)
Citation Format: You-Take Oh, Jiusheng Deng, Ping Yue, Shi-Yong Sun. B-Raf inhibition-induced paradoxical activation of MEK/ERK signaling enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3725.
Abstract 3760: XCE853 is a promising protein disulfide isomerase (PDI) inhibitor exhibiting a strong inhibitory activity in preclinical tumor models
Authors: Prevost Gregoire P. , Garrido Marine , Serova Maria , Briand Jean François , Gutmann Mathieu , Ladam Patrick , Carniato Denis , Tijeras-Raballand Annemilai , De Grammont Armand , Chauchereau Anne , Pitty Marc-Henry , Foster Paul 
Published: July 2016

Abstract
Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers, including ovarian, prostate, and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target.
XCE853 is a synthetic small molecule displaying an excellent docking with the human PDI. XCE853 inhibits in vitro recombinant PDI activity. In addition, the proliferation of a large panel of human tumor cells is blocked by XCE853 with IC50s in the nanomolar range through an irreversible cytolysis.
XCE853 is also active on a large panel of drug resistant human cancer cells. XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates).
In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) in several tumor types.
Finally, XCE853 displayed excellent oral bioavailability in mice and was able to block the growth of several human cancers using in vivo xenograft models leading to a complete tumor growth arrest even after the cessation of the treatment.
Altogether, these data support further efforts on this drug candidate to initiate the preclinical studies and to define the most relevant human tumor types.
Citation Format: Gregoire P. Prevost, Marine Garrido, Maria Serova, Jean François Briand, Mathieu Gutmann, Patrick Ladam, Denis Carniato, Annemilai Tijeras-Raballand, Armand De Grammont, Anne Chauchereau, Marc-Henry Pitty, Paul Foster. XCE853 is a promising protein disulfide isomerase (PDI) inhibitor exhibiting a strong inhibitory activity in preclinical tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3760.
Abstract 3769: Continuous, low intensity systemic dosing maximizes the therapeutic margin of Eg5/KSP inhibition in an orthotopic model of urothelial cell carcinoma
Authors: Williams Leigh , Ellston Rebecca , Trueman Dawn , Musgrove Helen , Ruston Linette , Aquila Brian , Pease Elizabeth , Klein Stephanie , Davies Barry R. 
Published: July 2016

Abstract
Urothelial Cell Carcinoma (UCC) is the fifth most common cancer, but no new generation molecularly targeted therapies have been registered to treat this disease. Non muscle-invasive bladder cancer can be treated by systemic or intravesical dosing routes. However, the urothelium is one of the most formidable permeability barriers in nature, and may limit the penetration of small molecules into tumour tissue from the intravesical location. Inhibitors of mitosis, including spindle proteins such as Eg5, are attractive targets for cancer therapy, but their efficacy when dosed systemically is severely limited by bone marrow toxicities such as neutropenia and thrombocytopenia. AZ9814, a very potent and selective small molecule inhibitor of Eg5, induces apoptosis and inhibits proliferation of UCC cells in culture with a GI50 of &lt; 1 nM. We have developed an orthotopic model of bladder cancer in the nude rat coupled with a programmable mini-pump system to continuously infuse AZ9814 into the bladder, and compared the therapeutic index of this delivery route with systemic dosing schedules using intraperitoneal injection and continuous subcutaneous infusion using an osmotic mini-pump. Continuous intravesical infusion resulted in severe bladder toxicity including hydropic degeneration and ulceration of urothelium, mucosal erosion and bilateral hydronephrosis, with limited penetration of compound into the tumour, and no significant impact on tumour pharmacodynamics and growth. In contrast, continuous low intensity systemic dosing resulted in significant tumour pharamacodynamic activity and control of tumour growth, albeit with significant but non-lethal effects on bone marrow toxicity. Daily intraperitoneal injection of AZ9814 resulted in very modest anti-tumour effects which were limited by bone marrow toxicity. It is concluded that Eg5 inhibitors have potential to treat UCC, but continuous systemic infusion is the best dosing schedule to maximize therapeutic index.
Citation Format: Leigh Williams, Rebecca Ellston, Dawn Trueman, Helen Musgrove, Linette Ruston, Brian Aquila, Elizabeth Pease, Stephanie Klein, Barry R. Davies. Continuous, low intensity systemic dosing maximizes the therapeutic margin of Eg5/KSP inhibition in an orthotopic model of urothelial cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3769.
Abstract 3770: HEXIM1 as a pharmacodynamic marker for monitoring target engagement of ABBV-075
Authors: Huang Xiaoli , Lin Xiaoyu , Li Leiming , Wang Rongqi , Roberts Lisa , Hessler Paul , Uziel Tamar , Lam Lloyd , Magoc Terry , Albert Daniel H. , Elmore Steven W. , Fang Guowei , Rosenberg Saul H. , McDaniel Keith , Kati Warren , Shen Yu 
Published: July 2016

Abstract
Bromodomain and extra-terminal (BET) family are dual bromodomain-containing proteins that play an important role in transcription regulation. ABBV-075 is a small molecule BET bromodomain inhibitor currently in phase 1 clinical trials. Here we report the identification of Hexim1 and other BET-responsive genes as robust pharmacodynamic markers for monitoring ABBV-075 target engagement in tumors and in surrogate tissues such as whole blood and skin. Transcription profiling of cancer cell lines for their responses to BET inhibitors identified a set of 9 BET-regulated genes, including Hexim1, that responded to BET inhibition across cancer cell lines and in xenograft tumors. Further characterization of BET-responsive genes in surrogate tissues such as mouse skin, mouse/human PBMCs and whole blood revealed that the mRNA level of Hexim1 exhibited the best response to BETi treatment across different settings. A dose-dependent increase of Hexim1 expression was detected in the whole blood of ABBV-075 treated tumor bearing mice, and the Hexim1 response was closely correlated with the plasma drug concentration and largely reflected the anti-tumor efficacy at various dose levels of ABBV-075. Hexim1 is part of a protein/RNA complex that sequesters pTEFb and prevents its recruitment by BRD4. It also reportedly mediates the anti-proliferative activity of BRD4 in AML. Taken together, Hexim1 could serve as a functional relevant pharmacodynamic marker for monitoring ABBV-075 target engagement in animal models and in the clinical setting.
Citation Format: Xiaoli Huang, Xiaoyu Lin, Leiming Li, Rongqi Wang, Lisa Roberts, Paul Hessler, Tamar Uziel, Lloyd Lam, Terry Magoc, Daniel H. Albert, Steven W. Elmore, Guowei Fang, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen. HEXIM1 as a pharmacodynamic marker for monitoring target engagement of ABBV-075. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3770.
Abstract 3794: Novel therapeutic targets in head and neck cancer
Authors: Kondratyev Maria , Pesic Aleksandra , Marastoni Stephano , Ketela Troy , Moffat Jason , Virtanen Carl , Sayad Azin , Bashkurov Mikhail , Dati Alessandro , Ailles Laurie , Grenman Reidar , Koritzinsky Marianne , Wouters Brad 
Published: July 2016

Abstract
HNSCC is 6th most common malignancy in the world. Despite advances in diagnosis and treatment, the survival rates remain low due to frequent recurrences the biology of which remains unclear. Using functional genomic technologies we identified new therapeutic targets for metastatic disease in HNSCC. Whole genome shRNA screens were conducted in matched sets of cell lines derived from primary tumors and respective metastatic sites, identifying genes essential for cell survival only following metastasis. To test if knockdown of selected targets inhibits metastasis in a therapeutic setting, we established orthotropic model of HNSCC that metastasize to lymph nodes in the mouse. Components of Notch pathway were identified as essential for survival of cells derived from metastatic sites. Whole exome sequencing identified a novel mutation in one of the EGF domains of Notch3 that was acquired only in the metastatic line. Mutations in EGF domains have been reported to influence interaction with specific ligands, dictating which ligand can activate Notch signaling. Our data indicate that metastatic, but not primary tumor cells, undergo apoptosis upon knockdown of Notch3 and that a distinct set of target genes is induced upon interaction between Notch3 and Jag2 ligand. Furthermore, our results indicate that suppression of Notch3 improves survival in mice bearing orthotropic tumors derived from the metastatic HNSCC lines. Our data demonstrate that metastatic cells from head and neck tumors acquire dependency on Notch3 signaling. Novel treatments targeting components of this pathway may prove effective in targeting metastatic cells alone or in combination with conventional therapies.
Citation Format: Maria Kondratyev, Aleksandra Pesic, Stephano Marastoni, Troy Ketela, Jason Moffat, Carl Virtanen, Azin Sayad, Mikhail Bashkurov, Alessandro Dati, Laurie Ailles, Reidar Grenman, Marianne Koritzinsky, Brad Wouters. Novel therapeutic targets in head and neck cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3794.
Abstract 38: The clinical significance of GLUT1 expression in gastrointestinal stromal tumor
Authors: Kuroda Daisuke , Kurashige Junji , Iwatsuki Masaaki , Eto Tsugio , Tamaoki Yuka , Ohuchi Mayuko , Nakamura Kenichi , Tokunaga Ryuma , Shigaki Hironobu , Hayashi Hiromitsu , Ishimoto Takatsugu , Baba Yoshifumi , Sakamoto Yasuo , Yoshida Naoya , Baba Hideo 
Published: July 2016

Abstract
Background: Gastrointestinal stromal tumor (GIST) is, though it is as rare as its incidence is about 7 to 20 cases per million population per year, one of the most common non-epithelial malignant tumors of the gastrointestinal tract. Recently it was reported that Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) is useful in diagnosis and evaluation of malignant grade of GIST. At the same time, expression of glucose transporter 1 (GLUT1), which is a membranous protein facilitates the transport of glucose across the plasma membranes into cells, was reported to be correlated with maximum standardized uptake value (SUVmax) in PET/CT and malignant grade of various kinds of cancers. In this study, the correlation of GLUT1 expression with malignant grade in GIST was investigated.
Methods: We evaluated the protein expression of GLUT1 in immunohistochemistry in the surgically resected specimens in 67 GIST cases, and analyzed the correlation of the other clinicopathological factors.
Results: The number of cases in which the expression of GLUT1 judged to be confirmed in immunohistochemistry was 45 (73.7%). GLUT1 expression group had significantly higher preoperative SUVmax in PET/CT than GLUT1 non-expression group (p = 0.03), had larger tumors in diameter (p = 0.015), and was more malignant by Fletcher classification (p&lt;0.01). Additionally, tumor rupture rate tended to be higher in GLUT1 expression group, though there is no tendency of the correlation with tumor necrosis. Eventually, relapse free survival, as not significantly, tend to be shorter in GLUT1 expression group.
Conclusion: In our study, expression of GLUT1 is correlated with malignant grade in GIST. GLUT1 expression might be a phase of higher metabolic and malignant activity of GIST cells. GLUT1 might be a useful prognostic marker in GIST cases.
Citation Format: Daisuke Kuroda, Junji Kurashige, Masaaki Iwatsuki, Tsugio Eto, Yuka Tamaoki, Mayuko Ohuchi, Kenichi Nakamura, Ryuma Tokunaga, Hironobu Shigaki, Hiromitsu Hayashi, Takatsugu Ishimoto, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. The clinical significance of GLUT1 expression in gastrointestinal stromal tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 38.