bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3698: The effect of epigenetic silencing and p53 mutation on DLL4 expression in human cancer stem cell disorder: The Li-Fraumeni syndrome
Authors: Yao Zhixing , Sherif Zaki A. 
Published: July 2016

Abstract
Tumorigenesis results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome that can provide powerful insights into our understanding of the somatic mutations present in sporadic cancers. LFS is currently linked to heterozygous mutation in the tumor suppressor gene p53 (TP53), which encodes a transcription factor that responds to diverse cellular stresses through the regulation of target genes that induce apoptosis, cell cycle arrest, DNA repair, and senescence. We previously showed a balanced reciprocal chromosomal translocation t(11;15)(q23;q15) in the non-cancerous skin fibroblasts of a bilateral breast cancer patient in LFS family. This prompted us to investigate the breakpoint region of the translocation, which uncovered a gene that encodes DLL4, (Delta-like ligand 4; locus at 15q15.1), a Notch ligand that is a key target in tumor vasculature. DLL4 regulates T-cell lineage thymopoiesis and further affects cancer immunosurveillance. In the breakpoint region of chromosome 15q15, we examined THBS1, DNAJC17, Rad51, DLL4, CHAC1 and INO80 gene expression levels. We found that specifically DLL4 is abrogated in all the LFS cell lines as well as MDA231 breast cancer cell line, and drastically down-regulated in MCF7 breast and IMR32 brain cancer cell lines and several human organ-specific tumor samples. Furthermore, DNA methylation studies revealed that DLL4 promoter is silenced only in MCF7 and MDA231 but not in LFS cell lines. ChIP and siRNA knockdown assays demonstrated that p53 binds to DLL4 promoter through its association with CTCF, a chromosomal networking protein CCCTC binding factor. These results imply a possible karyotype-phenotype correlation with respect to DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in normal skin fibroblasts of LFS patients as well as breast and brain cancer cells is significant and supports the concept that this ligand may also play a role in cancer immune-surveillance; and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth.
Citation Format: Zhixing Yao, Zaki A. Sherif. The effect of epigenetic silencing and p53 mutation on DLL4 expression in human cancer stem cell disorder: The Li-Fraumeni syndrome. [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 3698.
Abstract 3702: Src phosphorylated Mdm2 requires MdmX to act as a neddylating ligase
Authors: Hauck Paula M. , Mayo Lindsey D. 
Published: July 2016

Abstract
Mdm2 is an oncoprotein and, along with its family member MdmX, have been shown to be elevated in human cancers. Like Mdm2, MdmX, is a RING containing protein, yet it lacks intrinsic E3 ligase function. Mdm2 has been shown to facilitate ubiquitination as a monomer, a homodimer, and as a heterodimer with MdmX depending on the cellular stress. Our recent report establishes that under growth conditions that activate Src, Mdm2 functions as a neddylating enzyme. Whether MdmX is necessary for Mdm2 to neddylate p53 has yet to be shown. Here we demonstrate that Src phosphorylation results in increased levels of MdmX, increased binding between Mdm2 and MdmX, and increased neddylation of MdmX and p53. Interestingly, the lack of MdmX (in transient assays or in shRNA cell lines) results in decreased neddylation of p53. These data support a critical role for MdmX as part of the Mdm2 neddylating complex.
Citation Format: Paula M. Hauck, Lindsey D. Mayo. Src phosphorylated Mdm2 requires MdmX to act as a neddylating ligase. [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 3702.
Abstract 3703: MDM2 regulation of MYC and MYCN in pediatric neural cancers
Authors: Tran Hung N. , Qi Donglai , Cobrinik David 
Published: July 2016

Abstract
Background
MYC and MYCN have critical roles in a wide range of cancers and can be deregulated through diverse transcriptional and post-transcriptional mechanisms. Recent studies have shown that the high-level MYCN expression needed to drive retinoblastoma and MYCN-amplified neuroblastoma proliferation depends upon efficient MYCN translation mediated by highly expressed MDM2 and acting via a p53-independent mechanism. Here, we assessed MDM2-mediated regulation of MYC as well as MYCN in other pediatric neural tumors, specifically in Group 3 medulloblastoma and in MYC-overexpressing neuroblastoma. We also assessed MDM2-mediated regulation of MYCN in small cell lung cancer (SCLC), which has genetic and morphologic features in common with retinoblastoma.
Methods
MDM2, MYCN, and MYC expression were defined in Group 3 medulloblastoma lines D283, D425, D341; in MYC-overexpressing neuroblastoma lines CHLA 255 and SY-5Y; and in p53-wild type and p53-mutant SCLC lines H69 and H526 by western blotting. Cells were infected with shMDM2 and scrambled control lentivirus and effects on MDM2, MYC, and MYCN protein expression defined using western blot and effects on cell growth defined using Cell Titer-Glo. In neuroblastoma cells, MDM2 knockdown effects were defined with or without p53 co-knockdown.
Results
Group 3 medulloblastoma lines D283, D341, D425 highly expressed MYC but not MYCN. MDM2 knockdown did not decrease MYC expression in these cells. MDM2 knockdown decreased MYC expression In CHLA 255 and SY5Y neuroblastoma cells, along with p53 induction and cell death, and MYC down-regulation and cell death were mitigated by co-knockdown of p53. MDM2 knockdown decreased MYCN expression and impaired viability in p53-wild type H69 SCLC cells and in p53-mutant H526 SCLC cells.
Conclusions
MDM2 is not needed to sustain high-level MYC expression in three Group 3 medulloblastoma cell lines. MDM2 sustains high-level MYC in two MYC-overexpressing neuroblastoma cell lines via a p53-dependent mechanism distinct from the p53-independent MYCN regulation in MYCN-amplified neuroblastomas. In SCLC, MDM2 sustains high-level MYCN expression and viability in a p53-independent manner, similar to MDM2 effects in retinoblastoma and in MYCN-amplified neuroblastoma. These findings suggest that MDM2 selectively sustains MYCN but not MYC expression through a p53-independent mechanism and raise the possibility that cis-acting elements specific to MYCN-RNA mediate MDM2 regulation.
Citation Format: Hung N. Tran, Donglai Qi, David Cobrinik. MDM2 regulation of MYC and MYCN in pediatric neural cancers. [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 3703.
Abstract 3707: Semiconductor-based next-generation sequencing analysis of 409 cancer-related genes for mutations and copy-number variations in oral squamous cell carcinoma
Authors: Nakagaki Takafumi , Sasaki Yasushi , Idogawa Masashi , Koyama Ryota , Kobashi Kenta , Tamura Miyuki , Ohashi Tomoko , Ogi Kazuhiro , Hiratsuka Hiroyoshi , Tokino Takashi 
Published: July 2016

Abstract
Somatic mutation analysis is standard of practice for human cancers in order to identify therapeutic sensitizing and resistance mutations. To better understand the molecular pathogenesis of oral squamous cell carcinoma (OSCC) patients, we performed comprehensive genomic analyses that use PCR target enrichment and next-generation sequencing on the Ion Torrent semiconductor sequencers (PGM and Proton). DNA (40 ng) was extracted from 45 human OSCC specimens and their corresponding non-cancerous tissues including FFPE samples. Using the Ion Ampliseq Comprehensive Cancer Panel, we sequenced 15992 loci from 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers (covered regions = 95.4% of total, 1.5 megabases of target sequence). We also detected copy number variations (CNVs) in which segments of the genome can be duplicated or deleted from sequencing data.
Each sample underwent on average 5.9 million sequencing reads after quality filtering. The mean read depths were 367.8 x, and &gt;95% of targeted bases were represented .The number of somatic mutations (SNVs and indels) in 45 patients with OSCC ranged from 1 to 36 with a median of 7.33 (6.40/Mb). The most frequent mutations were detected on TP53 (28 of 45; 62.2%). Many of the mutations on TP53 were detected in the DNA-binding domain (23 of 28; 82.1%). NOTCH1 mutations were identified in 10 cases (8 missense, 1 coding frameshift, and 1 essential splice site mutations). CDKN2A mutations were observed in 8 cases; and PIK3CA were mutated 3 cases. Although the most common mutations in OSCC were C/G&gt;T/A transitions, which are consistent with previous reports on head and neck, lung and oesophageal SCCs, the second most frequent mutations were C/G&gt;A/T transversions. We also identified a median of 100 significant CNVs (range of 0-481) per sample. Pathway assessment has shown that somatic aberrations within OSCC genomes are mainly involved in several important pathways, including cell cycle regulation (p53 pathway, 84.4%) and RTK-MAPK-PI3K (62.2%). This targeted next generation sequencing using low amounts of FFPE DNA is a valuable tool for high-throughput genetic testing in research and clinical settings.
Citation Format: Takafumi Nakagaki, Yasushi Sasaki, Masashi Idogawa, Ryota Koyama, Kenta Kobashi, Miyuki Tamura, Tomoko Ohashi, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino. Semiconductor-based next-generation sequencing analysis of 409 cancer-related genes for mutations and copy-number variations in oral squamous 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 3707.
Abstract 3714: Optimisation of quinazolinedione sulphonamides as novel inhibitors of poly(ADP Ribose) glycohydrolase (PARG)
Authors: Smith Kate , Acton Ben , James Dominic , Jones Cliff , Jones Stuart , Jordan Allan , Hamilton Nicola , McGonagle Alison , Mould Daniel , Small Helen , Stowell Alex , Tucker Julie , Waddell Ian , Waszkowycz Bohdan , Ogilvie Donald 
Published: July 2016

Abstract
The macrodomain protein poly(ADP ribose) glycohydrolase (PARG) has been shown to be a critical component in the repair of single stand DNA breaks and counteracts the function of the ARTD family of poly(ADP ribose) polymerases, commonly known as the PARPs. As PARG exists as a single protein, it presents an attractive target for therapeutic intervention in cancer cells with enhanced dependence upon DNA repair.
Inhibitors of this enzyme have proved difficult to discover and develop. Moreover, intact cell-active tool compounds which have the propensity to be used as robust chemical probes to understand PARG pharmacology, are absent from the literature.
This poster will describe our work in this emerging area, optimising a series of drug-like quinazolinedione derivatives to deliver molecules with the correct physicochemical and biochemical properties to function as in vitro cell probe compounds. These unprecedented agents display potent on-target biochemical (5 nM) and cell (10 nM) activity with a significant window to acute 3-day cytotoxicity. Moreover, these agents are selective against PARP family members and the close glycohydrolase homologue ARH3. The medicinal chemistry optimisation of the scaffold will be described, alongside the outline pharmacology demonstrating on-target, selective inhibition of PARG in cells. Such tool compounds will be of value in revealing the detailed mechanisms of action of PARG in DNA repair and other PAR chain-mediated cellular processes, with the ultimate goal of delivering novel and clinically relevant therapeutic agents.
Citation Format: Kate Smith, Ben Acton, Dominic James, Cliff Jones, Stuart Jones, Allan Jordan, Nicola Hamilton, Alison McGonagle, Daniel Mould, Helen Small, Alex Stowell, Julie Tucker, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. Optimisation of quinazolinedione sulphonamides as novel 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 3714.
Abstract 373: Discovery of selective PI3Kb inhibitors for PTEN-deficient tumors and other indications
Authors: Chowdhury Arnab R. , Athisayamani Jeyaraj D. , Mitra Sayan , Maddi Srinivas , Adluri Ram Sudheer , Bethi Sridhar R. , Joshi Hemant , Tirunagaru Vijaya G. , Gupta Jang B. 
Published: July 2016

Abstract
PTEN somatic mutations occur in a large percentage of human cancers, from breast to prostate. Deletions of PTEN e.g. in prostate cancers are associated with tumor aggression and poor outcome, and up to 70 percent of prostate cancer patients have lost one copy of the PTEN gene at the time of diagnosis. Recent pharmacologic and genetic studies have identified the β isoform of PI3K to be required for growth of PTEN-deficient tumors in vivo and highly potent compounds are currently being explored in the clinic. These clinical candidates, however, are either limited by poor bioavailability or moderate selectivity against the delta isoform, thus warranting more selective compounds with better exposure. We have undertaken a comprehensive knowledge-based discovery of selective inhibitors of PI3Kβ with admissible pharmacokinetic and drug like properties. We have successfully identified a chemical series with potency ranging as low as 2.5 nM for PI3Kβ with &gt;100 - fold selectivity for PI3Kδ. The α and γ isoform selectivity was around 1000 and 500 fold respectively. Compounds did not decrease insulin sensitivity and T cell proliferation thus mitigating the PI3Kα and PI3Kδ mediated side effects of nonselective inhibitors. In vitro biochemical potency translated into cell survival assay and pAKT target engagement in recombinant and wild type mammalian cell lines. In vivo tumor regression was observed in xenograft models of prostate cancer. The series did not show any observable hERG or CYP liabilities. The considerable potency, high selectivity and good bioavailability of this novel class of compounds not only makes them attractive for prostate cancer, but also for rare disease indications like hamartoma and other drug resistant cancers that are dependent on PTEN deletions.
Citation Format: Arnab R. Chowdhury, Jeyaraj D. Athisayamani, Sayan Mitra, Srinivas Maddi, Ram Sudheer Adluri, Sridhar R. Bethi, Hemant Joshi, Vijaya G. Tirunagaru, Jang B. Gupta. Discovery of selective PI3Kb inhibitors for PTEN-deficient tumors and other indications. [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 373.
Abstract 3731: TSC deficiency unmasks a novel protective role of RIP1/RIP3 signaling against mitochondrial and oxidative stress-induced cell death
Authors: Filipczak Piotr T. , Thomas Cindy , Chen Wenshu , Salzman Andrew , McDonald Jacob D. , Lin Yong , Belinsky Steven A. 
Published: July 2016

Abstract
Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach. The presented study shows that simultaneous inhibition of two major pathways regulating redox homeostasis using L-Buthionine-sulfoximine (BSO, glutathione synthesis inhibitor) and auranofin (thioredoxin reductase inhibitor) induces oxidative burst, mitochondrial damage and necrotic cell death in TSC2 deficient cells in a highly synergistic and cell context-specific manner. Furthermore, blocking RIP1/RIP3-dependent signaling using chemical inhibitors necrostatin-1 and necrosulfonamide (NSA), reported by others to protect from some cytotoxic stimuli, synergizes with BSO and auranofin in killing TSC2 deficient cells. Expression analysis demonstrated that RIP1 and RIP3 protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitochondrial dysfunction. Finally, supplementation with the mitochondrial metabolite alpha-ketoglutarate, whose synthesis is regulated by RIP1/RIP3, rescues cells from the sensitizing effect of necrostatin-1 and NSA. Together, this study identifies a novel TSC context-dependent role of RIP1/RIP3 signaling in regulating mitochondrial and oxidative homeostasis, and substantiates glutathione, thioredoxin and RIP1/RIP3 pathways targeting as a promising therapeutic approach against TSC-associated tumors.
Citation Format: Piotr T. Filipczak, Cindy Thomas, Wenshu Chen, Andrew Salzman, Jacob D. McDonald, Yong Lin, Steven A. Belinsky. TSC deficiency unmasks a novel protective role of RIP1/RIP3 signaling against mitochondrial and oxidative stress-induced cell death. [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 3731.
Abstract 3741: Antimetastatic activity of ISTH0047, a potent and selective TGF-beta 2 antisense oligonucleotide, in syngeneic lung metastatic model of mouse 4T1 mammary carcinoma
Authors: Wosikowski Katja , Hasenbach Kathy , Petschenka Jutta , Barea Roldan Diana , Kreiter Sebastian , Sahin Ugur , Serin Guillaume , Redon Julie-Orlane , Hillairet de Boisferon Marc , Bichat Francis , Kohonen Hanna , Janicot Michel 
Published: July 2016

Abstract
Transforming growth factor beta (TGF-β) isoforms are the primary mediators for TGF-β signaling via TGF-β receptors and downstream phosphorylation/dephosphorylation cascade. TGF-β is associated with a wide range of biological processes in oncology, including tumor cell invasion, migration, angiogenesis, immunosuppression, as well as regulation of tumor stem cell properties. Mouse 4T1 mammary carcinoma cell line is a transplantable tumor cell line that is highly tumorigenic and invasive and, unlike most tumor models, can spontaneously metastasize from the primary tumor in the mammary gland to multiple distant sites including lymph nodes, blood, liver, lung, brain, and bone. Considering rather challenging preclinical evaluation of antitumor activity in tumor models, mouse 4T1 mammary carcinoma model has been widely used in the literature for evaluation of TGF-β antagonists. In this report, we describe the efficacy of ISTH0047 - a potent and selective TGF-β2 antisense oligonucleotide - in murine 4T1 primary tumors and lung metastasis following tumor cell injection into the mammary fat pad (orthotopic tumor model) of syngeneic Balb/c mice. Consistent with literature data generated with other classes of TGF-β antagonists (e.g., small-molecule kinase inhibitors, antibodies or TGF-β trap agents), although limited antitumor activity was demonstrated on primary tumor growth, marked and statistically significant decrease of lung metastasis number was observed upon subcutaneous administrations of ISTH0047. In addition, side by side comparison with murine surrogates of CTLA-4 or PD-1 antibodies indicated similar efficacy of all test items on lung metastasis in this model. Taken together, these encouraging results pave the way for in-depth preclinical evaluation of both ‘seed and soil’ theory and efficacy of combination regimen (immunomodulation) for better clinical outcome.
Citation Format: Katja Wosikowski, Kathy Hasenbach, Jutta Petschenka, Diana Barea Roldan, Sebastian Kreiter, Ugur Sahin, Guillaume Serin, Julie-Orlane Redon, Marc Hillairet de Boisferon, Francis Bichat, Hanna Kohonen, Michel Janicot. Antimetastatic activity of ISTH0047, a potent and selective TGF-beta 2 antisense oligonucleotide, in syngeneic lung metastatic model of mouse 4T1 mammary 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 3741.
Abstract 3771: Discovery of a covalent inhibitor of ERK docking-interactions that inhibits A375 melanoma cells proliferation
Authors: Kaoud Tamer S. , Johnson William H. , Ebelt Nancy D. , Piserchio Andrea , Warthaka Mangalika , Cano Micael , Sammons Rachel , Wang Qiantao , Ren Pengyu , Ghose Ranajeet , Dalby Kevin N. 
Published: July 2016

Abstract
Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Several ERK inhibitors have already entered clinical trials.
Most of the available ERK inhibitors are reversible inhibitors that either act through an allosteric mechanism, or by targeting the ATP binding site. Taking advantage of our understanding of ERK-docking interactions we tried to discover an irreversible substrate-selective inhibitor that targets the protein-binding site of ERK. Here, we report the discovery of a covalent inhibitor of ERK that targets its protein-docking site. Protein NMR, Mass spectroscopy, mutagenesis and molecular docking studies indicate a covalent interaction of the inhibitor with a conserved cysteine residue, Cys-159. Extensive biochemical studies provide an estimate of its kinetic parameters and its kinase-selectivity profile. The new ERK inhibitor inhibits ERK activation, as well as its ability to phosphorylate downstream substrates (e.g. p90RSK and Elk-1) in HEK293T and A375 melanoma cells. The targeting of ERK in HEK293T cells was confirmed using a chemical-genetic approach where the ERK2 C159A mutant was used to rescue the effects of this compound on ERK2 signaling and cell proliferation. Currently, we are testing the effect of the compound on tumor growth inhibition in an A375 melanoma cancer xenografts model. This covalent inhibitor represents a potentially valuable lead molecule whose development may result in a novel class of pharmacologically useful ERK inhibitors for targeting resistant forms of melanoma.
Citation Format: Tamer S. Kaoud, William H. Johnson, Nancy D. Ebelt, Andrea Piserchio, Mangalika Warthaka, Micael Cano, Rachel Sammons, Qiantao Wang, Pengyu Ren, Ranajeet Ghose, Kevin N. Dalby. Discovery of a covalent inhibitor of ERK docking-interactions that inhibits A375 melanoma cells proliferation. [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 3771.