bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5174: Phosphodiesterase 10A inhibition as a novel approach to suppress β-catenin signaling in ovarian cancer cells
Authors: Silva Luciana Madeira Da , Gavin Elaine , Lee Kevin J. , Ramírez-Alcántara Veronica , Berry Kristy L. , Taylor Holly T. , Musiyenko Alla , Aragon Ileana V. , Keeton Adam B. , Scalici Jennifer , Rocconi Rodney P. , Piazza Gary A. 
Published: July 2017

Abstract
Canonical Wnt/β-catenin signaling is known to be associated with platinum resistance in ovarian cancer in which inhibitors hold promise for the treatment of refractory disease. Phosphodiesterase 10A (PDE10A) is a dual cyclic AMP and cyclic GMP phosphodiesterase isozyme recently implicated in colon cancer. PDE10A inhibition in colon cancer cells by siRNA or small molecule inhibitors increased cGMP levels and activated PKG to inhibit β-catenin signaling. A novel PDE10 inhibitor, ADT-061, was identified by screening a library of indene derivatives, and showed strong antineoplastic activity in the Apc+/min-FCCC mouse (Lee K et al., unpublished data). Cyclic GMP and phosphodiesterases participate in the ovarian follicular development, although little is known about PDE10A expression in ovaries, especially with regard to a potential role in ovarian tumorigenesis. PDE10A protein was found to be expressed in various established ovarian cancer cell lines at higher levels than immortalized or primary ovarian surface epithelial cell lines. Pf-2545920, a known PDE10A inhibitor, and ADT-061 inhibited the growth of multiple ovarian tumor cell lines with IC50s around 20µM and 0.5µM, respectively. Both compounds induced apoptosis after 24h treatment, as measured by PI/Annexin-V staining and PARP cleavage. Pf-2545920 and ADT-061 induced phosphorylation of VASP at Ser157 and Ser239 in various ovarian cancer cell lines, indicating activation of cyclic AMP and cyclic GMP signaling, respectively. Treatment also decreased levels of β-catenin and downstream targets of TCF-dependent transcription, including c-MYC, survivin and cyclin-D1. Homozygous knockout PDE10A clones of OV-90 ovarian cancer cells obtained using CRISPR/Cas9 showed decreased clonogenic potential, decreased Pf-2545920-mediated VASP phosphorylation and β-catenin, c-MYC and survivin expression. Ongoing efforts are focused on the development of more potent ADT-061 analogs. These observations support further study of a role of PDE10 in ovarian tumorigenesis and the development of ADT-061 or analogs for the treatment of refractory ovarian cancer as well as the prevention of malignant recurrence.
Citation Format: Luciana Madeira Da Silva, Elaine Gavin, Kevin J. Lee, Veronica Ramírez-Alcántara, Kristy L. Berry, Holly T. Taylor, Alla Musiyenko, Ileana V. Aragon, Adam B. Keeton, Jennifer Scalici, Rodney P. Rocconi, Gary A. Piazza. Phosphodiesterase 10A inhibition as a novel approach to suppress β-catenin signaling in ovarian cancer cells [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 5174. doi:10.1158/1538-7445.AM2017-5174
Abstract 5181: Targeted knockdown of MYC in AML cells using G-quadruplex interacting small molecules
Authors: Turnidge Megan A. , Patel Apurvi , Montoya Justin J. , Lee David W. , Wai Daniel H. , Gokhale Vijay , Hurley Laurence , Arceci Robert J. , Azorsa David O. 
Published: July 2017

Abstract
Acute Myeloid Leukemia (AML) is a disease that occurs when genomic changes alter expression of key genes, causing cells to resume an undifferentiated state, proliferate, and maintain tumor growth throughout the body. Recently, there has been an increase in efforts toward developing therapies that specifically target the protein products of these aberrantly expressed genes. However, many of the proteins are difficult to target because of structural challenges, protein overexpression that requires high drug doses, or mutations that confer resistance to therapy. One potential type of targeted therapy that circumvents these issues is the use of small molecules that stabilize DNA secondary structures called G-quadruplexes. G-quadruplexes are present in the promoters of many potential oncogenes, and have regulatory roles in their transcription. This study analyzes the therapeutic potential of compounds that target the regulatory G-quadruplex in the MYC oncogene, which is commonly misregulated in AML. Treatment of the MYC expressing AML cell lines KG-1 and UT-7epo with the compound GQC-05 resulted in decreased expression of MYC mRNA, as determined by qPCR. Moreover, GQC-05 treatment induced a more significant decrease in c-Myc protein expression than similar treatment with JQ-1(+), as shown by western blot analysis. Treatment of AML cells with GQC-05 also decreased cell viability and increased apoptosis. Concurrent treatment of AML cells with GQC-05 and JQ-1(+) showed an antagonistic effect, indicating potential competition in the silencing of MYC. These results demonstrate that targeting the MYC promoter G-quadruplex in AML cells leads to knockdown of MYC expression and induces apoptosis. These results further support the development of a novel mechanism for targeting key genetic drivers in AML, and lay the groundwork for advances in treatment of other cancers driven by G-quadruplex regulated oncogenes.
Citation Format: Megan A. Turnidge, Apurvi Patel, Justin J. Montoya, David W. Lee, Daniel H. Wai, Vijay Gokhale, Laurence Hurley, Robert J. Arceci, David O. Azorsa. Targeted knockdown of MYC in AML cells using G-quadruplex interacting small molecules [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 5181. doi:10.1158/1538-7445.AM2017-5181
Abstract 5182: Targeting abnormal metabolism downstream of MYC in atypical teratoid/rhabdoid tumors
Authors: Wang Sabrina , Rubens Jeffrey , Allen Sariah , Orr Brent , Eberhart Charles , Raabe Eric 
Published: July 2017

Abstract
Atypical teratoid rhabdoid tumors (AT/RT) are deadly infantile brain tumors in dire need of new, targeted therapies. Recent molecular analysis revealed considerable tumor heterogeneity subdividing AT/RT into 3 distinct groups. The MYC subgroup has a dismal 5 year survival of 18.5%. MYC is known to drive reliance on glutamine for cellular metabolism suggesting that high-MYC expressing neoplasms may be sensitive to glutamine metabolic inhibitors. 6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist that decreases the tumorigenicity of high MYC expressing models of medulloblastoma and neuroblastoma . We hypothesize that DON will reduce the tumorigenicity of the MYC subgroup of AT/RT. High levels of c-MYC protein are expressed in about 1/3 of human AT/RT (Immunohistochemistry for c-MYC on 22 human AT/RT, H-score &gt; 1 standard deviation over the median considered high c-MYC expression). Similarly two of six of AT/RT cell lines expressed high levels of c-MYC protein by western blot. DON treatment slowed cell growth of high c-MYC expressing AT/RT cell lines BT12 and CHLA06 (MTS assay p&lt;0.005 10uM DON vs DMSO control; t-test), whereas cell lines BT37 and CHLA05, which had low c-MYC expression were not affected. Cell cycle analysis demonstrated that DON caused cell cycle arrest in the G2/M phase for the high c-MYC expressing lines BT12 and CHLA06 (31.2% of BT12 DMSO controls in G2/M phase vs 54.5% after 10uM DON treatment and 27.4% vs 48.9% in CHLA06). In contrast the cell cycle was not affected by DON treatment in the cell lines with low c-MYC expression (21.3% DMSO vs 20.2% after 10uM DON in BT37). DON also increased apoptosis in cell lines with high c-MYC and induced DNA strand breaks (Western blot for c-PARP and p-H2A.X respectively). DON significantly improved survival in BT-12 high c-MYC expressing orthotopic mouse xenografts (median survival increased from 21 to 36 days, p&lt;0.005; log-rank test). These data develop the framework for future clinical trials using glutamine antagonists to target the MYC subgroup of AT/RT.
Citation Format: Sabrina Wang, Jeffrey Rubens, Sariah Allen, Brent Orr, Charles Eberhart, Eric Raabe. Targeting abnormal metabolism downstream of MYC in atypical teratoid/rhabdoid tumors [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 5182. doi:10.1158/1538-7445.AM2017-5182
Abstract 5183: The radioenhancer NBTXR3 brings anticancer efficacy to the cisplatin-based chemoradiation in vitro and in vivo
Authors: Pottier Agnès , Vivet Sonia , Paris Sébastien , Lu Bo 
Published: July 2017

Abstract
NBTXR3 is a radioenhancer composed of functionalized hafnium oxide nanoparticles, designed to enhance the radiation dose deposit within the cancer cells when activated by ionizing radiations. NBTXR3 is intended for single intratumor administration and is currently evaluated in cancer clinical trials including soft tissue sarcoma, head and neck (H&N), prostate, liver and rectum.
Cisplatin (CDDP) is a cytotoxic agent considered to be a radiosensitizer and inhibits the repair of sublethal damage from irradiation. Concurrent chemoradiation using CDDP is the mainstream treatment for high risk H&N, cervix and non-small cell lung cancer patients. We hypothesized that adding NBTXR3 to radiation treatment (RT) may improve significantly anticancer effect of the chemoradiation combination
In vitro, no specific clonogenic toxicity was observed for the cells exposed only to NBTXR3. For the combined treatment CDDP was used at its IC50 concentrations. A marked and enhanced cell destruction (DEF) was observed with the CDDP combined treatment (added 6h or 16h prior to RT) and NBTXR3 (800µM, added 16h prior to RT) at ≥2Gy when compared to the single agent.
TreatmentCell line (DEF*)CDDPNBTXR3IrradiationFaDuNCI-H460-Luc26h-2 Gy1.0±0.061.2±0.06-16h1.4±0.151.3±0.256h16h1.4±0.141.6±0.1216h-1.0±0.121.9±0.32-16h1.2±0.131.5±0.1716h16h1.8±0.232.6±0.456h-4 Gy1.3±0.082.2±0.16-16h2.2±0.241.9±0.416h16h3.1±0.643.8±0.4816h-1.2±0.192.9±0.52-16h2.1±0.312.8±0.3916h16h5.3±0.977.6±2.76
*For a given radiation dose, the DEF value was obtained by taking the ratio of the survival fraction in the control (radiotherapy alone) and the survival fraction of the treatment.
In vivo, NBTXR3 enhanced the fractionated radiation treatment (5x2Gy) when injected intratumorally at 25% of tumor volume. NBTXR3 activated with ionizing radiation in combination with low dose of CDDP (1mg/kg administered 5 consecutive days, 2 hours prior to RT) delayed tumor growth when compared to single agent CDDP in combination with RT.
These results strongly support the concurrent chemoradiotherapy regimen with NBTXR3 nanoparticles as an effective radioenhancer to increase the anticancer effect. A new phase I/II trial with H&N cancers patient receiving radiotherapy plus CDDP has been started evaluating the optimal dose, safety and preliminary efficacy of NBTXR3.
Citation Format: Agnès Pottier, Sonia Vivet, Sébastien Paris, Bo Lu. The radioenhancer NBTXR3 brings anticancer efficacy to the cisplatin-based chemoradiation in vitro and in vivo [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 5183. doi:10.1158/1538-7445.AM2017-5183
Abstract 5191: A combination of Stat3 inhibitor and radiation for the treatment of malignant pleural mesothelioma
Authors: Matsumoto Seiji , Doi Hiroshi , Fukuda Akihiro , Nakamichi Tohoru , Kuroda Ayumi , Hashimoto Masaki , Takuwa Teruhisa , Kondo Nobuyuki , Hasegawa Seiki 
Published: July 2017

Abstract
Background: Trimodality therapy, including surgery, is the treatment for patients with malignant pleural mesothelioma (MPM). However, the 5-year survival rate remains less than 40%. To improve the survival rate, we investigated Stat3 as a potential therapeutic target for MPM.
Methods:Cell viability was assessed using Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cells (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) were seeded into 96-well plates. After treatment with a Stat3 inhibitor (BBI-608 : napabucasin), Cell Counting Kit-8 solution was added to each well and absorbance was measured using a microplate reader. The level of phosphorylated Stat3 (p-Stat3) in cell lysates was measured by ELISA. ROS level in cells was measured by FACS analysis. In the in vivo study, H226 cells were injected subcutaneously in the flank region of nude mice randomly assigned to four treatment groups (5 mice/group)—(1) treatment with vehicle control, (2) treatment with Stat3 inhibitor, (3) radiation therapy (RT), and (4) Stat3 inhibitor and RT. Tumor size was measured twice/week.
Results: Napabucasin decreased the viability of MPM cells (epithelioid, sarcoma, biphasic) in a dose-dependent manner. p-Stat3 levels decreased by 90% after treatment with 10 μM napabucasin in H226 cells. Napabucasin treatment induced more ROS production in MPM cells than did Pemetrexed. Moreover, combinatorial treatment with napabucasin and radiation (2 Gy, 5 Gy) induced more ROS production than did RT alone. In the mouse model, treatment with napabucasin alone significantly suppressed tumor growth (p &lt; 0.05), but napabucasin and RT completely suppressed tumor growth.
Conclusion:We showed that napabucasin inhibited proliferation of the MPM cells (epithelial, biphasic, sarcomatoid) and demonstrated that combination therapy with napabucasin and radiation completely suppressed tumor growth in a mouse model. Treatment with the napabucasin alone and the combination of napabucasin and RT induced high ROS production in MPM cells. Collectively, the combination of Stat3 inhibitor with Radiation Therapy (START) is a promising approach for the treatment of MPM.TheA combination of of Stat3 inhibitor and radiation with for the treatment of malignant pleural mesothelioma
Citation Format: Seiji Matsumoto, Hiroshi Doi, Akihiro Fukuda, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa. A combination of Stat3 inhibitor and radiation for the treatment of malignant pleural mesothelioma [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 5191. doi:10.1158/1538-7445.AM2017-5191
Abstract 5192: Selection of radiosensitizers based on HRAS mutation in head and neck cancer
Authors: Fisher Michael M. , Swick Adam D. , Nickel Kwangok P. , Kimple Randall J. 
Published: July 2017

Abstract
Purpose/Objective(s): The ability of activated HRAS to promote radiation resistance and predict for sensitivity to potential radiosensitizers was tested in a head and neck cancer model system.
Materials/Methods: Mutations in HRAS, KRAS, and NRAS were analyzed using cBioPortal in a head and neck cancer cohort. The Illumina TruSeq Amplicon Cancer panel was used to screen a panel of head and neck cancer cell lines for mutations in RAS-family genes. Cell growth and radiation survival was assessed by clonogenic survival assay. Immunoblots were used to confirm target activation/knockdown in overexpression and knockdown studies. A tumor control dose 50% (TCD50) assay was employed to investigate radiosensitization of a mutated-HRAS head and neck cancer cell line in a flank xenograft model in nude mice.
Results: Activating mutations in one of the three RAS genes are seen in 5-10% of head and neck cancer patients. Mutations in HRAS represent over 50% of these. Screening our panel of head and neck cancer cell lines identified a canonical activating mutation in HRAS (i.e. G12V) in SCC22B. Consistent with known roles for activated HRASG12V, SCC22B is relatively insensitive to both cetuximab and radiation. Using both in vitro and in vivo studies, cetuximab exhibited no ability to radiosensitize SCC22B. Cetuximab treatment decreased AKT, but not ERK activation. Direct inhibition pathways downstream of HRAS by selumetinib (MEK/ERK) or BEZ235 (PI3K/MTOR) decreased target protein activation and resulted in significant growth inhibition compared to control (p&lt;0.05). Treatment with either selumetinib or BEZ235 radiosensitized HRASG12V expressing cells (SER 1.3-1.8) but had more modest effects on cells with wildtype HRAS. siRNA knockdown of HRAS radiosensitized SCC22B, but not SCC1 or SCC6 cells relative to non-targeting control. Overexpression of HRASG12V conferred relative radioresistance in wildtype cell lines. In vivo assessment of the radiosensitizing effects of these compounds (TCD50) is pending.
Conclusion: More than 5% of head and neck cancers harbor activating mutations in one of the RAS family of genes. These mutations lead to resistance to cetuximab, either as a single agent, or as a radiosensitizer. Inhibition of downstream targets such as the MEK/ERK and PI3K/MTOR pathways can radiosensitize tumors harboring activating mutations in HRAS. Identification of additional mutation/drug combinations that result in radiosensitization may be valuable to advance the design of personalized radiation therapy.
Citation Format: Michael M. Fisher, Adam D. Swick, Kwangok P. Nickel, Randall J. Kimple. Selection of radiosensitizers based on HRAS mutation in head and neck 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 5192. doi:10.1158/1538-7445.AM2017-5192
Abstract 5215: Time dependent blood-brain barrier modulation by vascular endothelial growth factor to improve CNS drug delivery
Authors: McCord Matthew 
Published: July 2017

Abstract
Introduction:
Efforts to transiently increase blood brain barrier permeability would facilitate improved CNS delivery of chemotherapy agents. Previous studies demonstrated that vascular endothelial factor (VEGF) increases permeability in traumatic brain injury and ischemic brain disease. Exogenously administered VEGF increases barrier permeability in the non-diseased CNS. In our study, we investigated the role for exogenous VEGF therapy to modulate blood-brain barrier permeability
Methods:
For in vitro studies, confluent mouse brain endothelial cells (BEND.3) were treated with VEGF165. Trans-endothelial electrical resistance measured cell impedance changes and immunofluorescence was used to assess qualitative expression of tight and adherens junction proteins at key time points. Western blotting and qPCR were done to evaluate the effect of VEGF on expression of protein and RNA associated with tight and adherens junctions.
Results:
Confluent endothelial cells treated with rVEGF165 (200ng/mL) evaluated by TEER show a significant drop in cell impedance approximately 6 hours post treatment, compared to control (more than 10-fold) reflecting increased permeability of the monolayer. Treatment with progressively higher doses of VEGF (200, 400, and 600ng/mL) showed a progressively greater drop in cell impedance. Immunofluorescence of endothelial cells treated with rVEGF165 (200ng/mL) shows disassembly of both tight junctions and adherens junctions between 4 and 8 hours post-treatment compared to controls. Western blots and qPCR demonstrate that rVEGF165 treatment induces down-regulation of genes associated with tight junctions, such as Claudin5, beginning as early as 4 hours post treatment and continuing up to 24 hours post treatment.
Conclusion:
Our results suggest that VEGF is capable of inducing transient breakdown of the blood-brain barrier, which may facilitate improved CNS delivery of chemotherapeutic agents. Our in vitro data warrants further investigations of the applicability of VEGF therapy to induce endothelial cell permeability in animal tumor models, potentially improving delivery of chemotherapeutic drugs.
Citation Format: Matthew McCord. Time dependent blood-brain barrier modulation by vascular endothelial growth factor to improve CNS drug delivery [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 5215. doi:10.1158/1538-7445.AM2017-5215
Abstract 522: Expression and functional analysis of signal peptidase complex 18 in bladder cancer
Authors: Shigematsu Yoshinori , Sekino Yohei , Sakamoto Naoya , Sentani Kazuhiro , Oue Naohide , Hayashi Tetsutaro , Teishima Jun , Matsubara Akio , Yasui Wataru 
Published: July 2017

Abstract
Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. In the present study, we built an in-house oligonucleotide array, on which 394 genes were selected based on our SAGE data and previously reported array data, in order to identify the genes of most relevance to gastric carcinogenesis. Among these genes, we focused on SEC11A, because it is frequently overexpressed in gastric cancer (GC). SEC11A encodes the SPC18 protein, which is one of the subunits of the signal peptidase complex (SPC). Most secretory proteins contain amino terminal- or internal signal peptides that direct their sorting to the endoplasmic reticulum (ER). From the ER, proteins are transported to either the extracellular space or the plasma membrane through the ER-Golgi secretory pathway. The ER signal peptides are then cleaved by the SPC. In GC, SPC18 contributes to progression via EGFR pathway associated with TGF-a secretion. However, the expression and function of SPC18 have not been investigated in bladder cancer (BC). In this study, we analyzed the expression and distribution of SPC18 in human BC. Expression of SPC18 was observed in 44 (54.3%) out of 81 BC cases that was associated with T category (p=0.0002), Grade (p=0.0425), vascular invasion (p=0.0112) and CK5/6 positive/ CK20 negative basal type BC (p=0.0004). The univariate analysis indicated that expression of SPC18 (HR, 3.14; 95% CI, 1.47-7.47; P=0.0027) was associated with overall survival. In the multivariate model, SPC18 expression was an independent prognostic indicator (HR, 3.46; 95% CI, 1.35-10.00; P=0.0087). BC cells KMBC2 transfected with SPC18 expression vector significantly induced the cell growth (p&lt;0.01) and invasion (p&lt;0.01) activity. Western blot showed the overexpression of SPC18 induced the phosphorylation of EGFR, Akt and Erk. Real-time reverse transcription PCR analysis revealed the SPC18 forced expression cells induced mesenchymal character. These results suggest that SPC18 might contribute to the progression of BC.
Citation Format: Yoshinori Shigematsu, Yohei Sekino, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Tetsutaro Hayashi, Jun Teishima, Akio Matsubara, Wataru Yasui. Expression and functional analysis of signal peptidase complex 18 in bladder 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 522. doi:10.1158/1538-7445.AM2017-522