bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5593: Cigarette smoke and therapeutic response to chemotherapy and radiotherapy in cancer cells
Authors: Warren Graham W. , Romano Michelle , Sobus Samantha , Balasubramanian Sundaravadivel 
Published: August 2015

Abstract
Background: The 2014 Surgeon General's Report concludes that cigarette smoke (CS) causes increased cancer specific mortality. Clinical data support that the effects of CS are reversible, but there are no extant biologic models that have shown therapeutic response profiles for cancer cells exposed to CS.
Methods: An acute, subacute, and chronic dose escalated CS exposure model was developed to test the hypothesis that CS decreases therapeutic response to chemotherapy (CT, cisplatin) and radiotherapy (RT, 0, 2, 4, and 6 Gy) in a reversible manner in cancer cells.
Results: H460, A549, and FaDu cancer cells were treated with single and multiple exposure CS for up to 12 weeks. Subacute and prolonged exposure to CS significantly decreased response to CT and RT. CS increased survival fraction following CT or RT between 30-157% across all cell lines. Exposure of cancer cells to CS for 6 or 9 weeks followed by removal of CS for 3 and 6 weeks resulted in a partial to complete restoration of baseline therapeutic response in a cell specific manner; however, all cell lines required several weeks to achieve a partial or full restoration of therapeutic response. Dose response curves for CS exposure demonstrate that H460 and A549 cells had a decreased therapeutic response profile at higher CS concentrations while FaDu cells were more sensitive to lower concentrations to CS. Dose response curves further demonstrated that high dose CS exposure was cytotoxic in all cell lines. Results were verified in all cell lines using 2 additional repeated experiments with freshly thawed cancer cells purchased from ATCC over 10 months.
Conclusions: CS exposure reproducibly decreases therapeutic response to CT and RT in a dose dependent and reversible manner, reflective of clinical observations. Dose specific effects may vary between cancer cells. Data suggest that the biologic effects of CS removal, such as with acute smoking cessation in cancer patients, may not manifest in an immediate restoration of cancer cell response to CT or RT.
Citation Format: Graham W. Warren, Michelle Romano, Samantha Sobus, Sundaravadivel Balasubramanian. Cigarette smoke and therapeutic response to chemotherapy and radiotherapy in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2015-5593
Abstract 568: Fibroblast growth factor receptors 2 is a novel therapeutic target in esophagogastric junction adenocarcinoma
Authors: Tokunaga Ryuma , Imamura Yu , Nakamura Kenichi , Ishimoto Takatsugu , Iwagami Shiro , Kurashige Junji , Izumi Daisuke , Kosumi Keisuke , Higashi Takaaki , Taki Katsunobu , Hiyoshi Yukiharu , Baba Yoshifumi , Sakamoto Yasuo , Miyamoto Yuji , Yoshida Naoya , Hiroshi Saeki , Oki Eiji , Maehara Yoshihiko , Baba Hideo 
Published: August 2015

Abstract
Background: The prognosis of esophagogastric junction (EGJ) adenocarcinoma remains poor, though it is increasing worldwide. The fibroblast growth factor receptors (FGFRs) play critical roles in various human cancers, especially FGFR2 amplification has been implicated as a key genetic alteration in EGJ adenocarcinoma. In this study, we confirmed that FGFR2 can be a therapeutic target for EGJ adenocarcinoma.
Methods: Utilizing 200 cases with EGJ adenocarcinoma (Siewert types I-III), FGFR2 copy number was assayed by Real-time PCR (using RNaseP as a referent), and FGFR2 expression was detected by immunohistochemistry. We examined whether FGFR2 amplification correlates with FGFR2 expression. The associations between FGFR2 expression and clinicopathological factors, and prognostic impact of FGFR2 expression were examined. We investigated the role of FGFR2 in cell proliferation, invasion, apoptosis and cell cycle, using OACM 5.1C (FGFR2 overexpressing cell line), by siRNA technique targeting FGFR2.
Results: FGFR2 amplification was detected in 33 (22%) cases, and FGFR2 expression was observed in 112 (58%) cases. FGFR2 amplification significantly correlated with FGFR2 expression (p = 0.045). FGFR2 expression was significantly associated with tumor depth of invasion, nodal involvement, distant metastasis, lymphatic invasion, and vascular invasion (all, p &lt; 0.001). In survival analysis, tumors harboring FGFR2 expression experienced significantly unfavorable outcome (p = 0.039). We observed that si-FGFR2 significantly suppressed phosphorylation of Akt and Erk, resulting in suppressing cell proliferation and invasion; and inducing apoptosis and cell-cycle arrest (p&lt;0.001). We also confirmed that FGF 7 promoted the proliferation and AZD4547 inhibited the proliferation through RAS-ERK and PI3K-AKT pathways.
Conclusion: FGFR2 can be a therapeutic target for EGJ adenocarcinoma.
Citation Format: Ryuma Tokunaga, Yu Imamura, Kenichi Nakamura, Takatsugu Ishimoto, Shiro Iwagami, Junji Kurashige, Daisuke Izumi, Keisuke Kosumi,, Takaaki Higashi, Katsunobu Taki, Yukiharu Hiyoshi, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Saeki Hiroshi, Eiji Oki, Yoshihiko Maehara, Hideo Baba. Fibroblast growth factor receptors 2 is a novel therapeutic target in esophagogastric junction adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 568. doi:10.1158/1538-7445.AM2015-568
Abstract 58: 5-HT promotes hepatocellular carcinoma by influencing β-catenin
Authors: Fatima Sarwat , Xiaoki Shi , Zesie Lin , Guo Chen , Ho John W. , Lee Nikki P. , Zhao Xiang Bian 
Published: August 2015

Abstract
5-hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived human hepatocellular carcinoma cells (HCC) but the detailed intracellular mechanism is still unknown. As Wnt/β-catenin signaling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signaling by 5-HT. 5-HT promoted proliferation of serum-deprived HuH-7 and HepG2 cells and also increased total β-catenin levels, and active β-catenin protein levels compared to just control cells under serum free medium without 5-HT. Furthermore, 5-HT increased β-catenin levels in the presence of cycloheximide, a protein synthesis inhibitor, suggesting increased β-catenin levels due to inhibition of β-catenin degradation. Quantitative real-time polymerase chain reaction (qPCR) showed increased β-catenin downstream target genes, Axin1, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS), in serum-deprived HCC cell lines treated with 5-HT. We next studied the expression of various 5-HT were receptors (5-HT1D, 5-HT2A, 5-HT2B, 5-HT5 and 5-HT7) by qPCR in 33 pairs of HCC tumors and corresponding adjacent non-tumor tissues. Receptors 5-HT1D (21/33, 64%), 5-HT2B (12/33, 36%) and 5-HT7 (15/33, 45%) were overexpressed in HCC tumour tissues whereas receptor 5-HT5 was reduced (30/33, 91%) in HCC tumour tissues. Receptor 5-HT2A did not show any significant statistical difference between HCC tumour and corresponding non-tumour tissues. We further investigated whether antagonists of the 5-HT receptors attenuated the activity of 5-HT both in vitro and in vivo and we narrowed our study to 5-HT7 antagonist as the expression of 5-HT7 was found to be significantly associated to liver histology and venous infiltration. Antagonist of receptor 5-HT7, SB258719, attenuated growth of serum-deprived HCC cell lines and primary tumor tissues in the presence of 5-HT. Furthermore, SB258719 reduced tumor growth in a xenograft mouse model accompanied by reduced β-catenin and increased GSK-3β levels as observed by immunohistochemical analysis. Conclusion: This study provides evidence of Wnt/β-catenin signaling activation in 5-HT induced proliferation of serum-deprived HCC cells. The proliferation is inhibited by 5-HT7 antagonist, SB258719, which may represent a potential therapeutic target for hepatocarcinogenesis.
Citation Format: Sarwat Fatima, Shi Xiaoki, Lin Zesie, Chen Guo, John W. Ho, Nikki P. Lee, Xiang Bian Zhao. 5-HT promotes hepatocellular carcinoma by influencing β-catenin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2015-58
Abstract 581: Mutational landscape of PIK3CA gene and its association with oral squamous cell carcinoma in Indian population
Authors: Shah Sejal , Shah Siddharth , Padh Harish , Kalia Kiran 
Published: August 2015

Abstract
Oral Squamous Cell Carcinoma (OSCC) - the subset of Head and Neck Cancer is the sixth most common cancer worldwide and leading cancer in India. Western part of India (Gujarat) is a prime tobacco growing belt, henceforth, has a high tobacco consumption and increased occurrence of oral cancer. Phosphatidylinositol- 3- kinase (PI3K) is heterodimeric protein kinase composed of catalytic subunit, p110α, and a regulatory subunit, p85α; which regulates cell proliferation, apoptosis, and metastasis. The PIK3CA gene, encodes p110α catalytic subunit, when somatically mutated gets highly deregulated in number of cancers. Canonical mutations E542K, E545K and H1047R in p110α have proven to have higher oncogenic potential, subsequently activating downstream pathways. However, this observation has been reported in limited ethnicity in OSCC. Therefore, we have analyzed mutation profile of exon9 and 20 of PIK3CA gene in 50 OSCC primary tumors and corresponding control samples by direct sequencing in Indian population. We have observed two hot spots mutations E542K and E545K in exon 9, which were earlier reported to activate downstream signaling pathways and two synonymous mutations C3075T and C2985T in exon 20 in fourteen and one OSCC patients, respectively. Patients harboring oncogenic mutations were at advanced stage of OSCC having tobacco chewing history more than ten years. Additionally, we observed two Single Nucleotide Polymorphism rs114587137 (C&gt;T) and rs17849071 (T&gt;G) in intron 9 of PIK3CA gene, which was found germ line mutated in fifteen and three OSCC patients respectively.
In summary, we found 4% (2/50) oncogenic mutation frequency of PIK3CA gene, which may play a crucial role through PI3K downstream signaling pathway in oral neoplasia. Our study supports the notion that lower oncogenic mutation frequency of PIK3CA gene has been found in Asian populations but comparable to that seen in western countries. The knowledge of the involvement of PIK3CA mutations in OSCC is of importance, because a specific kinase inhibitor of PIK3CA may potentially serve as an effective therapeutic target against OSCC as a personalized medicine.
Citation Format: Sejal Shah, Siddharth Shah, Harish Padh, Kiran Kalia. Mutational landscape of PIK3CA gene and its association with oral squamous cell carcinoma in Indian population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 581. doi:10.1158/1538-7445.AM2015-581
Abstract 589: Expression levels of ABCA6 or ABCA7 predict primary Ewing sarcoma progression at diagnosis
Authors: Pasello Michela , Fanelli Marilù , Mularoni Valentina , Ciotti Sonia , Picci Piero , Serra Massimo , Scotlandi Katia 
Published: August 2015

Abstract
Introduction:
Ewing Sarcoma (EWS), the second most common bone tumor occurring in children and young adults, is a clinically very aggressive tumor with high metastatic tendency. EWS therapy is still firmly based on chemotherapy and development of chemoresistance is a major cause of disease progression. The mechanisms of chemoresistance are, however, still poorly defined. In this study, we analyzed the prognostic value of 21 ABC transporters with different mechanisms of action.
Materials and methods:
Gene expression of 21 ABC transporters was determined by RT-PCR in two different series of EWS patients with primary localized tumor at diagnosis (training set: 30 pts; validation set: 109 pts) and in human EWS cell lines. Association with patient outcome was determined by log-rank test and Kaplan-Meier survival curves (EFS and OVS). Sensitivity to conventional chemotherapeutic agents, such as Doxorubicin, Vincristine, Etoposide, Actinomicin-D and Ifosfamide, was tested in a representative panel of human EWS cell lines.
Results:
Among the 21 ABC transporters that were analyzed in the training set, expression of ABCA2, ABCA6, ABCA7, ABCB9 and ABCC4 was found to be associated with differential prognosis. Of these genes, only ABCA6 and ABCA7 were confirmed to be significant indicators of EWS progression when the analysis was extended to a new series of 109 patients with localized primary tumor (validation set): high expression of ABCA6 or ABCA7 was associated with a better prognosis. Correlative in vitro studies on EWS cell lines showed that the high expression of ABCA7 was not associated with higher response to conventional drugs, indicating a more complex role in the regulation of EWS aggressiveness.
Conclusions:
The study validated the impact of ABCA6 or ABCA7, the still poorly understood members of ABC transporters, on EWS progression. However, since high expression of these two transporters is related to better prognosis rather that worse, a different role from the canonical function of drug extruders should be supposed. We are currently testing the association between ABCA7 expression and ceramide levels, which are known to induce cell apoptosis, and macrophage-mediated phagocytosis as indicated in the literature (Kielar D. et al. J Invest Dermatol. 2003 Sep;121(3):465-74; Jehle AW et al. J Cell Biol. 2006 Aug 14;174(4):547-56).
Funded by: AIRC to KS IG 14049.
Citation Format: Michela Pasello, Marilù Fanelli, Valentina Mularoni, Sonia Ciotti, Piero Picci, Massimo Serra, Katia Scotlandi. Expression levels of ABCA6 or ABCA7 predict primary Ewing sarcoma progression at diagnosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 589. doi:10.1158/1538-7445.AM2015-589
Abstract 6: Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199)
Authors: Jin Sha , Tapang Paul , Osterling Donald J. , Gao Wenqing , Albert Daniel H. , Souers Andrew J. , Leverson Joel D. , Phillips Darren C. , Chen Jun 
Published: August 2015

Abstract
The BCL-2-selective inhibitor venetoclax (ABT-199) binds with high affinity to the BH3-binding groove of BCL-2, thereby competing for binding with the BH3-only protein BIM (Souers et al., 2013). Venetoclax is currently being evaluated in clinical trials for CLL, AML, multiple myeloma and NHL. To facilitate these studies, we developed and validated a 384-well electrochemiluminescent ELISA (MSD, Gaithersburg, MD,USA) that quantifies expression of BCL-2, BCL-XL, and MCL-1protein alone or in complex with BIM. We subsequently quantified expression of BCL-2 and BCL-2:BIM complexes in 16 hematologic tumor cell lines. We found the EC50 of venetoclax in these tumor cell lines to correlate strongly with baseline BCL-2:BIM complex levels. This correlation was superior to the correlation between venetoclax EC50 and absolute BCL-2 expression. We also applied the assay to measure disruption of BCL-2:BIM complexes in vivo. Treatment of the Non-Hodgkin's Lymphoma (NHL) xenograft model SU-DHL-4 with a BCL-2-selective inhibitor resulted in disruption of tumor BCL-2:BIM complexes that aligned with serum and tumor concentrations of inhibitor. Collectively, these data demonstrate that quantifying BCL-2:BIM complexes offers an accurate means of assessing target engagement by venetoclax and, potentially, predicting its efficacy. The utility of this assay is currently being assessed in clinical trials.
Citation Format: Sha Jin, Paul Tapang, Donald J. Osterling, Wenqing Gao, Daniel H. Albert, Andrew J. Souers, Joel D. Leverson, Darren C. Phillips, Jun Chen. Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 6. doi:10.1158/1538-7445.AM2015-6
Abstract 633: Amanitin-based ADCs with an improved therapeutic index
Authors: Hechler Torsten , Müller Christoph , Pahl Andreas , Anderl Jan 
Published: August 2015

Abstract
Antitumoral activity of monoclonal antibodies can be dramatically enhanced by conjugation to toxic small molecules. Beside the recent approval of Kadcyla (T-DM1) and Adcetris (SGN-35) more than 30 antibody-drug conjugates (ADC) have entered clinical trials, promising to strengthen the therapeutic capabilities for cancer treatment in the next decade. Surprisingly most ADCs are based on one of few toxic compounds only and on an even smaller number of toxicity mechanisms: Most antibodies are coupled to the microtubuli-targeting auristatins and maytansins. Toxins that operate through such a mechanism could suffer from limited activity in different cancer indications and in cells expressing resistance mechanisms. Accordingly the use of new drugs that function via alternative toxicity mechanisms could enhance the therapeutic potential of ADCs.
In the present study we evaluated the antitumoral potency of monoclonal antibodies conjugated to small molecules from the amatoxin family. Amanitin, the most well-known toxin of the amatoxin family, binds to the eukaryotic RNA pol II and thereby inhibits the cellular transcription at very low concentrations. In our experiments, we tested random- and site-specific strategies to covalently conjugate amanitin to antibodies and generated conjugates with low aggregation and high affinity for the target antigen. We compared the cytotoxic activity of stable and cleavable linker ADCs and the stability of such constructs in plasma. Overall we observed high stability in plasma after incubation for four days. Moreover we demonstrated superior efficacy of amanitin-based ADCs in cancer xenograft models compared to tubulin-inhibiting toxins. For site-specific conjugation antibodies were engineered at different locations to incorporate cysteines (Thiomabs). Thiomabs with different positions of the engineered cysteine were compared in vitro and in vivo to identify the best position for amanitin-thiomab-conjugates. Safety profiling of the two best Thiomabs in cynomolgous monkey revealed a substantial in improvement in tolerability and of the therapeutic index by using site-specific engineered amanitin-ADCs. The data support the development of amanitin-based ADCs by using a toxin with a new mode of action and with a favorable therapeutic index.
Citation Format: Torsten Hechler, Christoph Müller, Andreas Pahl, Jan Anderl. Amanitin-based ADCs with an improved therapeutic index. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2015-633
Abstract 638: Modulation of antibody-dependent cytokine release using Fc engineering
Authors: Kinder Michelle , Greenplate Allison , Strohl William , Jordan Robert , Brezski Randall 
Published: August 2015

Abstract
Antibodies can elicit multiple functions through its Fc region, including cell-killing through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxity (CDC) and antibody-dependent cellular phagocytosis (ADCP). In addition to the cell-killing functions, antibodies also mediate antibody-dependent cytokine release (ADCR). In this study, we demonstrate that ADCR is regulated differentially in PBMC and macrophages. ADCR is FcγRIII-dependent in PBMC and mediated by NK cells. In contrast, ADCR in macrophages is FcγRI-dependent. In PBMC, ADCR is characterized by expression of primarily pro-inflammatory cytokines including IFN-γ, IL-1α, IL-1ß, TNF-α. Meanwhile in macrophages, ADCR results in a mixture of the anti-inflammatory cytokine IL-10 and pro-inflammatory cytokines including IFN-γ, IL-1α, IL-1ß, TNF-α, and RANTES. Using an Fc engineering approach, we generated antibody variants lacking FcγRI binding while maintaining binding to FcγRIIa and FcγRIII. These variants retain ADCC and ADCR in PBMC, but modulate ADCP without eliciting cytokine release in macrophages, separating the two processes. Ultimately, a better understanding of how cytokine release is regulated by antibodies and of strategies to modulate cytokine release through Fc engineering could be used to influence immune cell fate decisions in vivo.
Citation Format: Michelle Kinder, Allison Greenplate, William Strohl, Robert Jordan, Randall Brezski. Modulation of antibody-dependent cytokine release using Fc engineering. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 638. doi:10.1158/1538-7445.AM2015-638
Abstract 656: Discovery of MAbs against difficult GPCRs, ion channels, and transporters using the MPS Discovery Engine®
Authors: Willis Sharon H. , Mattia Kimberly , Payne Riley , Hall Moniquetta , Mabila Manu , Rettew Christine , Couto Joseph , Keshwara Rohan , Paes Cheryl , Doranz Benjamin J. , Rucker Joseph 
Published: August 2015

Abstract
Integral membrane proteins are important drug targets and monoclonal antibodies (MAbs) directed against them are highly sought for therapeutic purposes. However, the complex structure of membrane protein targets makes the discovery of these MAbs especially challenging. To address this need, we have developed the MPS Discovery Engine® to enable the isolation, characterization, and engineering of monoclonal antibodies for challenging membrane protein targets, including GPCRs, ion channels, and transporters. MPS harnesses the strength of Integral's 10+ years of expertise in membrane protein expression and analysis, as well as proprietary technologies including Lipoparticles for high concentration membrane protein presentation and Shotgun Mutagenesis for comprehensive epitope mapping and MAb optimization. Integral Molecular currently has a pipeline of several dozen MAbs against complex membrane proteins that are involved in a variety of diseases, including cancer, inflammation, pain, and infectious diseases. There are currently no FDA-approved MAbs that target GPCRs, ion channels, or transporters, and MPS provides a pathway to these new and previously intractable targets.
Citation Format: Sharon H. Willis, Kimberly Mattia, Riley Payne, Moniquetta Hall, Manu Mabila, Christine Rettew, Joseph Couto, Rohan Keshwara, Cheryl Paes, Benjamin J. Doranz, Joseph Rucker. Discovery of MAbs against difficult GPCRs, ion channels, and transporters using the MPS Discovery Engine®. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 656. doi:10.1158/1538-7445.AM2015-656