bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A242: R-spondin 2 drives Wnt signaling and tumor formation in breast and liver cancer.
Authors: Conboy Caitlin B. , Tschida Bobbi R. , Hu Hsiangyu , Burns Michael B. , Temiz Nuri A. , Kuka Timothy , Keng Vincent W. , Toffanin Sara , Harris Reuben S. , Llovet Josep , Starr Timothy K. , Largaespada David A. 
Published: August 2014

Abstract
Background: R-spondins are secreted agonists of Wnt signaling that function in development and promote tissue stem cell proliferation. Rspo2 was identified as a candidate oncogene in intestinal tumors via a Sleeping Beauty transposon insertional mutagenesis screen in mice (1). Further, oncogenic activation of RSPO2 and RSPO3 mediated by recurrent genomic rearrangements has been identified in human colorectal cancer (2). The purpose of the current study was to determine if R-spondins function as oncogenes in other cancer types characterized by active Wnt signaling.
Methods: R-spondin mRNA expression was determined in primary human breast tumors and adjacent normal tissue by quantitative RT-PCR. Affymetrix microarrays were used to assay gene expression and classify by molecular subtype human hepatocellular carcinomas compared to pre-malignant lesions and normal livers. RSPO2 was depleted or overexpressed in breast cell lines by stable transduction with anti-RSPO2 shRNA or RSPO2 cDNA. Resulting changes in gene expression and proliferation were measured by qRT-PCR and MTS assay respectively. RSPO2 was somatically overexpressed in murine liver by hydrodynamic injection and Fah selection in an Fah-null model. Subsequent gene expression studies were conducted by qRT-PCR and immunohistochemistry.
Results: RSPO2 was highly expressed in 12% of primary human breast tumors compared to adjacent normal tissue. Similarly, RSPO2 expression was elevated in the subset of primary human liver cancers with activated Wnt/beta-catenin signaling. In human breast cancer cells with elevated RSPO2 expression, RSPO2 knockdown decreased Wnt signaling and proliferation, while RSPO2 overexpression in a non-tumorigenic breast epithelial cell line potentiated Wnt signaling. Overexpression of RSPO2 in the mouse liver increased Wnt signaling and promoted an enlarged liver phenotype and tumor formation.
Conclusions: These data strongly suggest that RSPO2 is a driver of human breast and liver cancer. Future work will further characterize signaling pathways implicated in RSPO-driven phenotypes, and develop targeted therapy to inhibit RSPO signaling.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A242.
Citation Format: Caitlin B. Conboy, Bobbi R. Tschida, Hsiangyu Hu, Michael B. Burns, Nuri A. Temiz, Timothy Kuka, Vincent W. Keng, Sara Toffanin, Reuben S. Harris, Josep Llovet, Timothy K. Starr, David A. Largaespada. R-spondin 2 drives Wnt signaling and tumor formation in breast and liver cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A242.
Abstract A249: Navitoclax and veliparib yield cytotoxicity with lower doses than used for single agents in women's cancers.
Authors: Lee Jung-Min , Stacy Alyssa , Yu Minshu , Kohn Elise C. 
Published: August 2014

Abstract
Background: The apoptosis inhibitor Bcl-XL is upregulated in recurrent ovarian (Ov) and breast (Br) cancer(Ca)s. Modest clinical activity with navitoclax, Bcl-2, Bcl-XL inhibitor, was observed in hematologic malignancies, although a significant grade 3/4 thrombocytopenia has been a challenge for the further development of navitoclax. Our phase I/Ib study of olaparib (PARP inhibitor) and carboplatin (NCT00647062) in Ov and BrCa patients with BRCA1/2 mutation showed a change in Bim and Bcl-2 tissue protein quantities measured before and after 1 cycle correlated with the duration of response (r2=-0.86, p=0.007). We hypothesized combination of PARP inhibitor, veliparib, with navitoclax will yield clinical synergy at doses lower than used for single agents in women's cancers, thus with the potential to minimize the thrombocytopenia.
Materials and Method: We have examined cell injury in Ov (SKOV3, OVCAR8) and triple negative breast cancer (MDA-MB231) cell lines. Cell injury was measured with XTT assays. The clinically attainable dosage of navitoclax and veliparib were compared to the IC50 and a physiologically attainable dose was obtained. Protein expression of Bcl-2, Bcl-XL, Mcl-1, an anti-apoptotic protein of the Bcl-2 family, BAG3, a chaperone protein stabilizing and preventing degradation of Mcl-1 were examined using immunoblot to identify potential biomarkers.
Results: Veliparib (up to 50uM) had little single agent activity, up to 11% inhibition of control growth in all cell lines; navitoclax also had limited single agent activity in doses attainable clinically, up to 31% inhibition of control growth at 5uM. Concurrent administration of the two agents yielded a dose dependent increase in cell injury in all cell lines (up to 49% inhibition; p&lt;0.05). Protein expression of Bcl-2 and Bcl-XL was reduced by navitoclax and combination of navitoclax and veliparib showed further reduction in all cell lines. Mcl-1 protein expression was reduced by the combination in all cell lines, although BAG3 was reduced by the combination, only in SKOV3. Further analysis of protein expression, drug effects in soft agar density-independent cultures, and survival assays are in progress in other Br and OvCa cell lines.
Conclusions: These preliminary results suggest that the combination of PARP inhibition and Bcl2/Bcl-XL neutralization may be cooperative in yielding better results than either agent alone. Further studies are ongoing to complete credentialing this novel drug combination.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A249.
Citation Format: Jung-Min Lee, Alyssa Stacy, Minshu Yu, Elise C. Kohn. Navitoclax and veliparib yield cytotoxicity with lower doses than used for single agents in women's cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A249.
Abstract A266: Leucovorin rescue of high dose pralatrexate in mesothelioma xenografts.
Authors: Tedeschi Philip M. , Farooqi Iqra , Kathari Yamini , Bertino Joseph R. 
Published: August 2014

Abstract
Pralatrexate is a second generation antifolate that targets dihydrofolate reductase. It was found to have a higher affinity to reduced folate carrier type 1 (RFC-1), the primary folate transporter, and has high intracellular retention via enhanced polyglutamylation. Mucositis, rather than bone marrow toxicity, is the dose limiting toxicity (DLT) in patients. In this study, we examine whether the use of leucovorin (folinic acid) can reduce pralatrexate DLT when used in mouse xenografts, and possibly enable high dose pralatrexate treatment. Nude mice bearing H2052 mesothelioma xenografts were treated with pralatrexate at normal and toxic doses with or without leucovorin administration 24 hours later. Tumors were measured three times weekly and toxicity monitored through weight loss. Leucovorin was found to abrogate pralatrexate toxicities at high doses without sacrificing efficacy. These results demonstrate that high dose pralatrexate with subsequent leucovorin rescue may be a viable treatment strategy in mesothelioma and other cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A266.
Citation Format: Philip M. Tedeschi, Iqra Farooqi, Yamini Kathari, Joseph R. Bertino. Leucovorin rescue of high dose pralatrexate in mesothelioma xenografts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A266.
Abstract A27: Proteomic study of the of posttranslational modifications (phosphorylation and glycosylation) and its significance in human breast cancer.
Authors: Kaur Navkiran , Jauhari Parul 
Published: August 2014

Abstract
Post translational modifications are the biochemical modifications introduced into the protein after translation (or during translation in case of co-translational modification). Various changes that occur are in the form of chemical groups added to various residues of the target protein by specific enzymes like glycosyltransferase, kinase, methyltransferase, etc. Various studies have shown that cancer cells differ from non-neoplastic cells not only in expression of proteins and their related function, but they also have major differences in the pattern of post-translational modification. These changes may be direct result of difference in expression levels of PTM-responsible enzymes, or differences in the functioning of the same. In the same manner, differences in PTM pattern of cancer proteins leads to many structural and functional changes in the target proteins, many of which may be responsible in furthering the neoplastic characteristics and survival of the cancer cell. Since PTM leads to change in functionality in target proteins, this study aims to find a direct relation between change in function of both pro-apoptotic and anti-apoptotic proteins and cancer cell immortality. Theoretically, pro-apoptotic proteins need to be non-functional for the cell to skip apoptosis, as is often seen in cancer cells. Also, the activity of anti-apoptotic proteins needs to be subdued by PTM to reach the same results. Differential PTM of various proteins in cancer cells with respect to non-neoplastic cells has been seen to be of great significance. This upregulation or downregulation of certain type of specific PTM can be a factor for the overall progression and development of cancer. Present study was desined with an aim to identifying the proteome exclusive to breast cancer cells, and also to study the differential PTM pattern of the same and determine the significance of this difference in various aspects of cancer occurrence, pathogenesis and progression. We found that the there is a significant change in the expression profiling of phosphorylation and glycosylation patterns of various proteins associated with breast cancer as assessed by using various bioinformatic based tools.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A27.
Citation Format: Navkiran Kaur, Parul Jauhari. Proteomic study of the of posttranslational modifications (phosphorylation and glycosylation) and its significance in human breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A27.
Abstract A283: PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance.
Authors: Chang Lei , Graham Peter , Hao Jingli , Ni Jie , Bucci Joseph , Cozzi Paul , Kearseley John , Li Yong 
Published: August 2014

Abstract
Purpose: Radioresistance is a major problem in prostate cancer (CaP) radiotherapy (RT). The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway plays a central role in cancer metastasis and radioresistance. This study aimed to evaluate the effects of combination of dual or single inhibitors targeting PI3K/Akt/mTOR pathway proteins with RT in CaP radioresistant (RR) cells in vitro.
Experimental Design: Three CaP-RR cell lines (PC-3RR, DU145RR, and LNCaPRR) were established in our laboratory by radiation treatment and their radioresistance was confirmed by colony assay. The half maximal inhibitory concentration (IC50) values of four inhibitors including two dual inhibitors (BEZ235 and PI103) and two single inhibitors (BKM120 and Rapamycin) were tested by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in CaP RR cells. Combination of 1/2 IC50 doses of each inhibitor with RT was examined to decide which inhibitor has a better capability to improve radiosensitivity of CaP-RR cells by cologenic assay and apoptosis assays.
Results: We found that CaP-RR cells are associated with epithelial-mesenchymal transition (EMT) and enhanced cancer stem cell phenotypes, and the activation of PI3K/Akt/mTOR signaling pathway. We also found that the combination of single inhibitor either BKM120 (targeting PI3k) or rapamycin (Targeting mTOR) with RT had limited capability to improve radiosensitivity, including less regression of colony formation and inducing less apoptosis in CaP RR cells, whereas dual inhibitor BEZ235 or PI103 combined with RT could effectively improve radiosensitivity, obviously inhibit CaP RR cells in colony ability (P&lt;0.05), and induce more apoptosis (P&lt;0.05).
Conclusions: Our findings suggest that PI3K/Akt/mTOR pathway is actively involved in CaP radioresistance and the dual PI3K/Akt/mTOR inhibitors (BEZ235 and PI103) have obvious advantages over single inhibitors in sensitizing radiation therapy and overcome CaP radioresistance. Using a PI3K/mTOR dual inhibitor with RT is a promising modality for the treatment of CaP to overcome radioresistance and this combination approach is worthwhile for future animal study and clinical trials.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A283.
Citation Format: Lei Chang, Peter Graham, Jingli Hao, Jie Ni, Joseph Bucci, Paul Cozzi, John Kearseley, Yong Li. PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A283.
Abstract B237: CD105: A therapeutic target for sarcomas.
Authors: Fritchie Karen , Attia Steven , Okuno Scott , Arndt Carola , Robinson Steven 
Published: August 2014

Abstract
Purpose: Endoglin/CD105 is a homodimeric transmembrane glycoprotein that is expressed on the proliferating endothelium of solid tumors. TRC105, the chimeric IgG1 antibody with high affinity binding for human CD105, has recently undergone human testing. This exploratory study sought to validate CD105 as a potential therapeutic target in sarcomas.
Methods: We performed immunohistochemical staining for CD105 expression in 146 retrospectively identified paraffin embedded sarcoma patient samples in our tumor registry, utilizing an anti-CD105 antibody (clone 4G11, Novocastra). The diagnoses were verified and samples were examined for CD105 expression in the malignant vasculature as well as tumor cells.
Results: The vast majority of specimen expressed CD105 in the tumor vasculature, 134 of 137 evaluable cases. CD105 expression in the cells of the varied sarcoma histologies themselves were as follows: 19/20 angiosarcomas, 6/7 Ewing sarcomas, 8/20 undifferentiated pleomorphic sarcomas, 6/20 uterine leiomyosarcomas (LMS), 4/20 osteosarcomas, 3/20 non-uterine LMS, 3/20 synovial sarcomas. None of the 19 evaluated chondrosarcoma cells expressed CD105. Thirteen of 19 angiosarcomas showed CD105 expression in &gt;50% of tumor cells, 3 of 19 showed CD105 expression in 25-49% of the tumor cells and 3 of 19 showed CD105 expression in 5-24% of tumor cells.
Conclusions: CD105 targeting appears to be a rational antiangiogenic therapeutic approach in sarcomas, with particular emphasis on angiosarcomas. A clinical trial utilizing TRC105 in soft tissue sarcomas is currently under development.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B237.
Citation Format: Karen Fritchie, Steven Attia, Scott Okuno, Carola Arndt, Steven Robinson. CD105: A therapeutic target for sarcomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B237.
Abstract B61: Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors.
Authors: Wang Wei-Ting , Catto James , Meuth Mark 
Published: August 2014

Abstract
While DNA damage response pathways are well characterized in cancer cells, much less is known about their status in normal cells. These pathways protect tumor cells from DNA damage and replication stress and consequently present potential therapeutic targets. However, a better understanding of the response of normal cells to DNA damage is needed before a role in cancer treatment can be pursued. Here we characterize the response of hTERT-immortalized normal human urothelial (NHU) cells to agents that disrupt DNA replication. In contrast to malignant cells, the ATR-CHK1 signaling cascade is activated late after treatment with a replication inhibitor in hTERT-NHU cells and these cells do not depend upon the ATR-CHK1 signaling cascade for protection from apoptosis during DNA replication stress. Instead ATM signaling is more rapidly activated under these conditions. Intriguingly, an ATM inhibitor not only suppressed checkpoint activation after exposure to replication inhibitors but also stopped entry of cells into S phase suggesting activation of a G1 checkpoint. Consistent with this, cells treated with the ATM inhibitor and thymidine showed increased levels of cyclin-dependent kinase inhibitor p19INK4D and reduced phosphorylation of the retinoblastoma protein. Nevertheless ATM inhibitor-treated hTERT-NHU cells re-entered S-phase upon release into inhibitor-free medium. In contrast, a bladder cancer cell line treated with the ATM inhibitor progressed more slowly through S-phase and showed a dramatic increase in apoptosis following co-treatment with ATM and replication inhibitors. Taken together, our findings suggest that ATM and CHK1 signaling cascades play different roles in tumor and normal epithelial cells, confirming these as promising therapeutic targets.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B61.
Citation Format: Wei-Ting Wang, James Catto, Mark Meuth. Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B61.
Abstract B64: The role of JAK1/2-STAT3 as acute resistance mechanism to MEK inhibition in BRAF mutant colorectal cancer.
Authors: Carson Robbie , Celtikci Basak , Dunne Philip , Johnston Patrick , Van Schaeybroeck Sandra 
Published: August 2014

Abstract
Background: Oncogenic mutations in BRAF occur in 8% of patients with advanced colorectal cancer (CRC) and have been shown to correlate with poor prognosis. In contrast to BRAF mutant (MT) melanoma, where the BRAF inhibitor PLX4032 has shown significant increases in response rates and overall survival compared to standard Dacarbazine treatment, only minor responses to PLX4032 treatment have been reported in BRAFMT CRC. Clear understanding of the vulnerabilities of BRAFMT CRC is important, and identification of druggable targets uniquely required by BRAFMT CRC tumors has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. The aim of this study was to identify novel resistance mechanisms to MAPK inhibition in BRAFMT CRC.
Methods: Paired BRAFMT/WT RKO and VACO432 CRC cell line models and non-isogenic BRAFMT LIM2405, WiDR and COLO205 CRC cells were used. Changes in protein expression/activity were assessed by Western Blotting. Interaction between MEK1/2 and JAK1/2 inhibition was assessed using the MTT cell viability assays and flow cytometry. Apoptosis was measured using Western blotting for PARP, cleaved caspase 3/8 and caspase 8, 3/7 activity assays.
Results: Treatment with MEK1/2 inhibitors AZD6244, GSK1120212, UO126 and PD98059 resulted in acute increases in STAT3 activity in the BRAFMT RKO and VACO432 cells but not in their BRAFWT clones and this was associated with increases in JAK2 activity. Inhibition of JAK/STAT3 activation using gene specific siRNA or small molecule inhibitors TG101348 or AZD1480, abrogated this survival response and resulted in significant increases in cell death when combined with MEK1/2 inhibitors AZD6244 or GSK1120212 in BRAFMT CRC cells. In addition, combination of MEK1/2 and JAK/STAT3 inhibition resulted in strong synergy with CI values between 0.3 and 0.7 in BRAFMT CRC cells.
Conclusions: We have identified JAK/STAT3 activation as an important escape mechanism for BRAFMT CRC following MEK1/2 inhibition. These data provide a strong rationale for further investigation of combination of MEK1/2 and JAK/STAT3 inhibition in BRAFMT in vivo models.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B64.
Citation Format: Robbie Carson, Basak Celtikci, Philip Dunne, Patrick Johnston, Sandra Van Schaeybroeck. The role of JAK1/2-STAT3 as acute resistance mechanism to MEK inhibition in BRAF mutant colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B64.
Abstract B69: Dynamic reprogramming of signaling following Met inhibition reveals pathways for cell proliferation and negative feedback in gastric cancer.
Authors: Lai Andrea , Cory Sean , Zhao Hong , Sehat Bita , Tofigh Ali , Guiot Marie-Christine , Thompson Crista , Bell Emily S. , Bertos Nicholas , Ferri Lorenzo E. , Hallett Michael , Park Morag 
Published: August 2014

Abstract
The Met receptor tyrosine kinase activates multiple signalling pathways in response to stimulation by ligand. However, the signalling events that occur under chronic Met activation in cancer cells are poorly understood. Utilizing a pharmacological small-molecule inhibitor of Met, we demonstrate that the gastric cancer cell lines, Okajima, MKN45, Snu-5 and KATO II are dependent on Met signalling for proliferation and anchorage-independent growth. We show that short-term inhibition of Met leads to waves of changes in gene expression such as a rapid loss of immediate-early genes, negative regulators, and a more delayed decrease in genes involved in the cell-cycle and proliferation. At the post-translational level, the Ras-Erk, PI3K-Akt and STAT3 pathways were all found to be dependent on Met signalling in these cells, though STAT3 signalling was the key requirement for proliferation, downstream from Met. We also observed the loss of negative regulators of Erk signalling, such as DUSP4 and DUSP6, which allowed for Mek-dependent reactivation of Erk, in the presence of Met inhibitor. As Met inhibitors are currently in clinical trials, it is essential to understand the molecular events that occur upon treatment, such that we can more effectively target sensitive tumours and avoid resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B69.
Citation Format: Andrea Lai, Sean Cory, Hong Zhao, Bita Sehat, Ali Tofigh, Marie-Christine Guiot, Crista Thompson, Emily S. Bell, Nicholas Bertos, Lorenzo E. Ferri, Michael Hallett, Morag Park. Dynamic reprogramming of signaling following Met inhibition reveals pathways for cell proliferation and negative feedback in gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B69.