tbuckley/cabot-search huggingface dataset:
Abstract 4303: Vopp1 physically interacts with Wwox and inhibits its apoptotic function in breast cancer
Authors: François Lallemand, Florian Bonin, Rosette Lidereau, Keltouma Driouch
Journal: Cancer Research (2017)

Abstract WWOX is a tumor suppressor gene spanning the fragile site FRA16D and targeted by loss of heterozygosity or homozygous deletion in several tumor types. Wwox protein consists of two N-terminal WW domains that mediate protein-protein interactions and a C-terminal short-chain Dehydrogenase/Reductase domain (SDR). The WW1 module acts as a versatile platform linking WWOX with numerous multiprotein complexes. Thus, Wwox suppressor activity relies on its binding capacities to various partners. Wwox has been shown to interact with known proto-oncogenes such as p73, deltaNp63, AP2γ, c-jun, Erbb4, c-Met, Runx2 and Dvl-2. At the cellular level, Wwox has been shown to be a pro-apoptotic protein that induces cell death by acting in both the nucleus and cytoplasm. More recently, emerging evidence also suggest an important role of WWOX in DNA damage response. By using a yeast two-hybrid system and co-immunoprecipitation assays, we characterized Vopp1 (Vesicular Over-expressed in cancer Pro-survival Protein 1) as a new molecular partner of the tumor suppressor Wwox. VOPP1 gene localizes at the frequently amplified 7p11.2 locus and is often co-amplified with EGFR. It is overexpressed in multiple malignancies such as glioblastoma, gastric, head and neck and lung cancers. In this study, we demonstrate that VOPP1 physically interacts with Wwox in breast cancer cells. Upon binding, Wwox is recruited to the Vopp1-containing lysosomal compartment. This recruitment inhibits Wwox-mediated apoptosis at least in part by preventing Wwox-p73 interaction. In addition, Vopp1 acts as an oncogene as shown by its capacity to potentiate cellular transformation. Moreover, in breast cancer clinical samples, VOPP1 overexpression was detected predominantly in tumors retaining Wwox expression. Vopp1 overexpression is associated to a reduced survival of breast cancer patients, especially patients with luminal B tumor types. Remarkably, the VOPP1/WWOX expression ratio showed a significantly worst prognosis outperforming either gene alone. These findings highlight the importance of Wwox compartimentation in addition to Wwox loss in human cancer pathogenesis and define Vopp1 as a novel negative regulator of Wwox whose overexpression induces breast carcinogenesis by affecting the tumor suppressive activity of Wwox. Citation Format: François Lallemand, Florian Bonin, Rosette Lidereau, Keltouma Driouch. Vopp1 physically interacts with Wwox and inhibits its apoptotic function in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4303. doi:10.1158/1538-7445.AM2017-4303
Abstract 5832: Rho-associated kinase is a therapeutic target in neuroblastoma
Authors: Cecilia H. Dyberg, Susanne Fransson, Teodora Andonova, Baldur Sveinbjörnsson, Jessika Lännerholm-Palm, David Forsberg, Eric Herlenius, Tommy Martinsson, Per Kogner, John Inge Johnsen, Malin Wickström
Journal: Cancer Research (2017)

Abstract Background: Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. The non-canonical Wnt/planar cell polarity (PCP) signaling pathway regulates cytoskeletal organization, migration and maturation of neural crest cells during neuritogenesis. Here we show that neuroblastoma harbors frequent mutations of genes controlling the PCP signaling pathway and Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. The majority of these mutations were detected in GTPase activating proteins and guanine nucleotide exchange factors genes, which may result in inhibition of Rac and activation of Rho and was associated with aggressive high-stage neuroblastomas. Methods: We performed whole-exome sequencing of neuroblastoma samples of all clinical subgroups to search for mutations and genetic aberrations. Cytotoxic activity of Rho-associated kinases (ROCK) inhibitors was studied in cell viability assays. Morphology and invasion were studied with microscopy. The molecular mechanisms were characterized using cell- and molecular biology techniques. In vivo studies (xenografts and the transgenic mouse model TH-MYCN) in mice were carried out to validate the therapeutic effects and toxicity. Results: Exome sequencing detected frequent mutations and gene aberrations in genes controlling the activity of PCP signaling. Analysis of gene signatures and immunohistochemistry showed that high expression of ROCK1 and ROCK2 correlated with poor patient survival. Several mediators of Rac/Rho were differentially expressed in cell lines and patient samples. Pharmacological or genetic inhibition of ROCK, a key molecule in Rac/Rho signaling resulted in differentiation, inhibition of neuroblastoma cell growth and migration and degradation of MYCN protein. Finally, ROCK inhibition reduced the growth of established neuroblastoma xenografts in nude mice and repressed tumor progression in a MYCN-driven mouse model of neuroblastoma (T-MYCN) Conclusions: These results provide evidence that inhibition of the non-canonical/PCP signaling cascade using ROCK inhibitors suppress the growth of neuroblastoma in preclinical models and suggest possibilities for improved treatment of high-risk neuroblastomas. Citation Format: Cecilia H. Dyberg, Susanne Fransson, Teodora Andonova, Baldur Sveinbjörnsson, Jessika Lännerholm-Palm, David Forsberg, Eric Herlenius, Tommy Martinsson, Per Kogner, John Inge Johnsen, Malin Wickström. Rho-associated kinase is a therapeutic target in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5832. doi:10.1158/1538-7445.AM2017-5832
Abstract 4297: ADCs inhibiting the all-powerful osmotic transducer
Authors: James R. Prudent, David Marshall, Fabio Malavasi, Antonella Chillemi
Journal: Cancer Research (2017)

Abstract Purpose Extracellular drug conjugates (or EDCs) are a new type of ADC that selectively inhibit the all-powerful Na,K-ATPase, an extracellular membrane ion pump required for life . To determine if EDCs may be valuable clinical candidates, we further assessed their safety, efficacy and mode of action. Experimental Design Cynomolgus monkeys were infused with EDCs at various levels and monitored by heart telemetry, blood cell levels and serum examination. Additionally, cultured cells were subjected to EDCs and monitored in real time and by high resolution dual fluorescent labeling to better understand the mechanism of cell death. Results We tested the efficacy of the EDCs in a number of xenografts models and observed strong activity (regression and cures). Little to no tumor reduction was observed for the free antibodies or with control-EDCs where the antibody target was not expressed. To test for safety, each cynomolgus monkey were infused with one of three EDCs to better understand the MTD of each EDC. In all cases, MTD was determined to be between 5 and 10mgs/kg where EDC serum levels reached between 100 and 200ugs/ml. At the maximum safe dose tested (5mgs/kg), heart beat and other observed parameters were found to be normal with the exception of the blood cells expressing the EDC targets (EDC targeting CD20 at this high level was found to drop all B-cells to a nondetectable level which rebounded to normal on day 58). To further understand the EDC mechanism, cells exposed to the EDCs and monitored visually in real-time or by dual fluorescence microscopies. All cells exposed to the EDCs showed membrane swelling and extracellular localization of the EDC. Conclusion These results show that targeted inhibitors of the Na,K-ATPase ion pump have promise as future anticancer medicines. First, EDCs appear safe in nonhuman primates at efficacious doses in rodent xenografts. In addition, an identified mechanism of extracellular necrotic death is novel in the field of oncology. Our hope is that cancers that up-regulate MDR and/or anti-apoptotic mechanisms will be sensitive to EDCs. Continuing efforts to identify the full death pathway of this new type of ADC should lead to identifying patients most likely to respond to EDC based therapies. Citation Format: James R. Prudent, David Marshall, Fabio Malavasi, Antonella Chillemi. ADCs inhibiting the all-powerful osmotic transducer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4297. doi:10.1158/1538-7445.AM2017-4297
Abstract 17: Anti-metastatic platinum through glycan targeting in breast cancer
Authors: Samantha J. Katner, Erica Peterson J. Peterson, Eriko Katsuta, Stephanie C. DeMasi, Jennifer Koblinski, Kazuaki Takabe, Nicholas P. Farrell
Journal: Cancer Research (2017)

Abstract The high affinity of polynuclear platinum compounds (PPCs) for heparan sulfate (HS) is mediated through a “sulfate clamp” and PPC interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding.1 Metalloshielding will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation.2 PPCs inhibit cleavage of a model pentasaccharide by heparanase and further modulate bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells.3 The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis.3 Following proof-of-principle of strong in vivo anti-metastatic activity of PPCs in clinically relevant breast cancer models,4 this contribution examines the underlying mechanism of platinums as anti-metastatic agents. We report on the cellular effects of PPC-HS metalloshielding on multiple growth factor signaling pathways (bFGF, HB-EGF) and specific syndecan (Sdc)-dependent signaling in breast cancer. Coupled with previously demonstrated DNA binding, PPCs represent intrinsically dual- function agents combining platinum cytotoxicity with anti-angiogenic effects derived from first principles through glycan targeting. [1] Mangrum, J.B., Engelmann, B.J., Peterson, E.J., Ryan, J.J., Berners-Price, S.J., Farrell, N.P. Chemical Communications 2014, 50, 4056-4058. [2] Chiodelli, P., Bugatti, A., Urbinati, C., Rusnati, M. Molecules 2015, 20, 6342-6388. [3] Peterson, E.J., Daniel, A.G., Katner, S.J., Bohlmann, L., Chang,C., Bezos, A., Parish, C.R., von Itzstein, M., Berners-Price, S.J., Farrell, N.P. Chem. Sci. 2016, DOI: 10.1039/C6SC02515C. [4] E. Katsuta, S. Demasi, S. Katner, H. Aoki, E. Peterson, E., N.P. Farrell and K. Takabe. (2016). Proc. AACR New Orleans, LA. Abstract #3064. DC 1-5 April 2017 Citation Format: Samantha J. Katner, Erica Peterson J. Peterson, Eriko Katsuta, Stephanie C. DeMasi, Jennifer Koblinski, Kazuaki Takabe, Nicholas P. Farrell. Anti-metastatic platinum through glycan targeting in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 17. doi:10.1158/1538-7445.AM2017-17
Abstract 5105: Structure-activity relationship study of pyrrolo[2,3- <i>d</i>]pyrimidines as microtubule targeting antitumor agents
Authors: Aleem Gangjee, Tasdique M. Quadery, Susan L. Mooberry
Journal: Cancer Research (2017)

Abstract Microtubules are cytoskeleton protein polymers composed of αß-tubulin heterodimers which play pivotal roles in cell division, cellular transport and cell signaling. Interfering with microtubule dynamics is a well-established strategy for the treatment of cancer. However, clinical utility of microtubule targeting agents (MTAs) in cancer chemotherapy is often limited by the emergence of drug resistance. Expression of P-glycoprotein (Pgp) or the βIII isotype of tubulin, are two clinically established drug resistance mechanisms. We previously reported that compound AG346 binds to the colchicine site of tubulin and has microtubule depolymerization activity in A-10 cells (EC50 = 365 nM). Molecular modeling and docking studies of this compound in the X-ray crystal structure of tubulin (PDB: 402B) suggested that the pyrrole NH can be substituted with alkyl chains of optimal length to obtain an altered binding conformation which can facilitate interaction with the hydrophobic pocket formed by amino acid Val181 of side chain A, and Lys352 and Thr314 of side chain B. We designed and synthesized a variety of pyrrole NH-alkyl substituted compounds and determined that the compound AG473 shows a 43-fold improved microtubule depolymerization potency (EC50 = 8.4 nM) in A-10 cells, compared to the lead compound. In addition, this compound inhibited the growth of human melanoma cancer cell line MDA-MB-435 in culture with an IC50 of 7.2 nM, which is a 5-fold improvement in potency over the parent compound. These analogs also circumvented resistance mediated by Pgp and βIII-tubulin. These attributes provide the impetus for further preclinical development of these compounds as microtubule targeted antitumor agents in vivo and these studies are currently underway. Citation Format: Aleem Gangjee, Tasdique M. Quadery, Susan L. Mooberry. Structure-activity relationship study of pyrrolo[2,3- d]pyrimidines as microtubule targeting antitumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5105. doi:10.1158/1538-7445.AM2017-5105
Abstract 738: Highly multiplexed and precisely calibrated reference materials for copy number variation detection
Authors: Catherine Huang, Yves Konigshofer, Jessica Dickens, Bharathi Anekella
Journal: Cancer Research (2017)

Abstract Introduction: Genomic instability is a hallmark of cancer, and copy number variation (CNV), including gene duplication and deletion, can be a key driver of oncogenesis. Detection of CNV is needed for personalized treatment, and may involve microarray analysis or Next Generation Sequencing. Often, DNA from patient-derived cell lines is used as positive control material in these assays. However, these materials are often poorly characterized, may change over time, and have additional confounding genetic alterations. Here we describe the development of new reference materials that are highly characterized by digital PCR and can aid in the validation and calibration of new diagnostic assays for CNV. Methods: The GM24385 reference cell line has been extensively characterized by the Genome in a Bottle project1 and originates from a participant in the Personal Genome Project. DNA from this cell line was used to make a library of full-length gene inserts. The library had &amp;gt;12X coverage of the GM24385 genome and an average insert size of ~135 Kb. PCR based screening was used to identify and isolate full length MYC, FGFR3 and ERBB2 genes. Next Generation Sequencing, using Illumina Nextera library preparation kits and a MiSeq instrument, was used to verify the gene of interest. The genomic DNA and gene inserts were then formulated into reference materials, in purified DNA format to amplify the copy numbers of these key genes. Digital PCR was used to control the mixing and verify the number of copies of genes and/or mutations within the reference material. Results: The sequence confirmed genes were formulated into GM24385 genomic DNA at levels consistent with 5X and 10X amplification. Testing on the ArcherDx VariantPlex™ Solid Tumor Kit indicated that each amplification could be detected at the expected level. Conclusions: Highly characterized and consistently manufactured reference materials for copy number detection are currently lacking. The described Seraseq CNV Reference Materials provide proof of concept for a biosynthetic, engineered material that uses digital PCR as an orthologous reference method and provides a “ground truth” copy number level for key oncogenes. Citation Format: Catherine Huang, Yves Konigshofer, Jessica Dickens, Bharathi Anekella. Highly multiplexed and precisely calibrated reference materials for copy number variation detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 738. doi:10.1158/1538-7445.AM2017-738
Abstract 5858: MicroRNA-338-5p regulates radioresistance by directly targeting survivin in esophageal squamous cell carcinoma
Authors: Misun Park, Hyeon-joon Yoon, Moon Chul Kang, Jun Ah Lee, Junhye Kwon, Haewon Lee
Journal: Cancer Research (2017)

Abstract Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and resent studies have reported the miRNA-mediated radiotherapy resistance. However, further research would be necessary to reveal the regulation mechanisms and the treatment strategies using miRNA have yet to be established in ESCC. We compared the miRNA expression profile in ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell line using miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of the miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering the survivin, which is known to play an inhibitor of apoptosis. Over expression of survivin using plasmid vector reversed miR-338-5p induced apoptosis. From tumor xenograft experiments, we found that therapeutic delivery of the miR-338-5p mimics via direct injection to tumor mass increased sensitivity to radiation therapy. In conclusion, these findings suggested that miR-338-5p is a potential radiosensitizer and may be one of the therapeutic biomarkers for radioresistant in ESCC. Citation Format: Misun Park, Hyeon-joon Yoon, Moon Chul Kang, Jun Ah Lee, Junhye Kwon, Haewon Lee. MicroRNA-338-5p regulates radioresistance by directly targeting survivin in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5858. doi:10.1158/1538-7445.AM2017-5858
Abstract 3331: PID1, a candidate tumor suppressor in pediatric and adult brain tumors, is a novel interacting partner for a cell surface receptor
Authors: Anat Erdreich-Epstein, Xiuhai Ren
Journal: Cancer Research (2017)

Abstract BACKGROUND: PID1 is higher in fat from obese patients and is an inhibitor of insulin receptor signaling. We reported that PID1 is a novel inhibitor of medulloblastoma and glioma cell growth, and its mRNA level is highly correlated with survival across multiple independent datasets of these tumors. PID1 harbors a phosphotyrosine binding domain and is predicted to interact with proteins harboring NPXY motifs. We therefore hypothesized that PID1 will interact with phosphotyrosine-binding (PTB) domain containing protein(s) that may be important in brain tumors, and will modulate its/their signaling. Here we report PID1 interactions with one of these proteins and determine its biological consequences. METHODS: Experiments consisted of immunoprecipitations, transient transfections, and western blotting. Functionally, assays included cell culture, flow cytometry for proliferation using BrdU/7AAD and apoptosis using AnnexinV/7AAD. Plasmids were pCMV-AN-HA-PID1(2) or control or the protein of interest in pcDNA3.1. Cell lines used were glioblastoma, medulloblastoma, atypical teratoid rhabdoid (ATRT), HEK293, and cells deficient or intact in PID1. RESULTS: We demonstrate co-immunoprecipitation of PID1 with a receptor that is considered important in cancer. Immunoprecipitation was both in HEK293T cells overexpressing both proteins and in native brain tumor cell lines with/without overexpression. While tyrosine in the NPXY motifs was not required for the interaction, mutating the kinase domain of the receptor or overall inhibition of tyrosine phosphorylation impaired the interaction with PID1. Different domains in PID1 differentially co-immunoprecipitated with the receptor. Interestingly, mouse embryo fibroblasts without PID1 showed increased growth factor-dependent tyrosine phosphorylation of this protein and increased growth factor-induced proliferation. Identity of the receptor will be disclosed at the meeting. CONCLUSIONS: These data point to PID1 as a novel interacting partner and regulator of this receptor’s biological effects and signaling in brain tumors. Note: This abstract was not presented at the meeting. Citation Format: Anat Erdreich-Epstein, Xiuhai Ren. PID1, a candidate tumor suppressor in pediatric and adult brain tumors, is a novel interacting partner for a cell surface receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3331. doi:10.1158/1538-7445.AM2017-3331
Abstract LB-258: Orphan nuclear hormone receptor, DAX-1, expression during progressive stages of invasive ductal carcimona
Authors: Erin Dishington
Journal: Cancer Research (2017)

Abstract The orphan nuclear hormone receptor DAX-1 (Dosage Sensitive Sex Reversal Adrenal Hypoplasia Congenita on the X Chromosome, gene 1) plays an important role in the development of adrenal and gonadal tissues and functions as a global negative-regulator of steroidogenesis. In addition, it is known to play a role in several cancers including breast. DAX-1 immunoreactivity had been found to directly correlate with androgen receptor (AR), estrogen receptor (ER) expression and lymph node metastasis. Beyond this, DAX-1’s role in breast cancer is relatively poorly understood. In this study we investigated, using fluorescent immunohistochemistry, the expression of DAX-1 and AR during progressive stages of invasive ductal carcinoma with known estrogen receptor ER status. Additionally correlations with patient age, tumor grade, TNM score, progesterone receptor (PR), antigen Ki67 expression and human epidermal growth factor receptor 2 (Her2), were analysed. Comparing both bioinformatic and protein staining methodology we attempted to correlate DAX-1, AR and ER to cancer stage. In order to understand the mechanisms involved in cancer progression we employed epigenetic studies to determine if changes in DAX-1 expression correlated to changes in methylation status. Our data suggests DAX-1 is expressed more frequently in early stage breast cancer. Understanding the time points and mechanisms by which DAX-1 acts in breast cancer could potentially provide a novel target for therapeutic treatments. Citation Format: Erin Dishington. Orphan nuclear hormone receptor, DAX-1, expression during progressive stages of invasive ductal carcimona [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-258. doi:10.1158/1538-7445.AM2017-LB-258