bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4413: Mnk activity in diffuse large b-cell lymphoma: targeting translation
Authors: Landon Ari , Muniandy Parameswary A. , Gartenhaus Ronald B. 
Published: May 2015

Abstract
Augmentation of protein translation has been observed in a number of human malignancies. We have previously demonstrated that cap-dependent protein translation is dysregulated in diffuse large B-cell lymphoma (DLBCL). This cancer-associated phenomenon may result in the deregulation of many proto-oncogenes and tumor suppressors leading to multiple cellular abnormalities. A major rate-limiting step in cap-dependent translation is the binding of eIF4E to the 7-methyl guanosine cap in the 5′ untranslated region of mRNA thus, bridging the eIF4F pre-initiation complex with the ribosome and initiating translation. eIF4E has been widely implicated as a proto-oncogene contributing to cancer development in numerous published reports. In addition to the mTOR signaling network, there is a potential for eIF4E to be modulated by the mitogen-activated protein kinases via map kinase interacting kinases (MNK). MNK proteins (MNK1 or MNK2) exert their effect on eIF4E through phosphorylation of eIF4E at serine 209. This phosphorylation is believed to promote B-cell lymphomagenesis. However, the physiologically relevant regulatory mechanisms and potential for targeting eIF4E phosphorylation in human B-cell lymphoma is largely unexplored. This study aims to elucidate the mechanistic and therapeutic effects of MNK regulation of eIF4E phosphorylation in DLBCL.
Counter-intuitively, we have found differential expression of MNK2 over MNK1 in activated B-cell (ABC) lymphoma versus germinal center B-cell (GCB) lymphoma subtypes even though both are known to converge to phosphorylate eIF4E. Interestingly, ERK does not play a significant role in activating MNK1/2 or affect the downstream phosphorylation of eIF4E in DLBCL, however, p38 plays an important role in eFI4E phosphorylation via MNK1. We show that phosphorylation of eIF4E by MNK is critical for malignant cell survival in both ABC and GCB DLBCL. The inhibition of p38 resulted in a significant and selective killing of DLBCL via inactivation of MNK1 and down-regulation of MCL1. Therefore, p38 inhibition may be a useful targeted approach in DLBCL through its suppression of MNK mediated eIF4E phosphorylation.
Citation Format: Ari Landon, Parameswary A. Muniandy, Ronald B. Gartenhaus. Mnk activity in diffuse large b-cell lymphoma: targeting translation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4413. doi:10.1158/1538-7445.AM2014-4413
Abstract 4414: Neuropilin2 is a novel target gene of Wnt signaling pathway regulating angiogenesis, metastasis and growth of osteosarcoma
Authors: Ji Tao , Guo Yi , Lin Carol , Chen Cheng-Fong , Zi Xiaolin , Hoang Bang H. 
Published: May 2015

Abstract
Objective: Multivascularity of osteosarcoma (OS) rendered the anti-angiogenesis is a promising therapeutics. Neuropilin 2 (NRP2), a coreceptor of vascular endothelial growth factor (VEGF), has been implicated in tumor angiogenesis, growth, and metastasis of many cancers. Its act in osteosarcoma still remains poorly understood. In order to explore the role of NRP2 in modulating tumor growth, angiogenesis, invasion, and lung metastasis of osteosarcoma, we conduct the current study.
Methods: Cell culture, RNA interference, stable transfection, real time PCR, western blot, motility and invasion assay, in vivo tumorigenesis model, tube formation assay, ChIP.
Results: By microtissue array assay, the expression of NRP2 is implicated in metastasis and poor prognosis of osteosarcoma patients. The in vitro data showed NRP2 knockdown has an inhibitory effect on OS tumor cell growth, both anchoragedependent and anchorageindependent way. Xenograft model showed silencing of NRP2 expression in OS cells has an extraordinary inhibitory effect. Both migration and invasion were significantly impaired in two NRP2 knockdown OS cell lines in vitro. Again, a lung metastasis mice model was used to verify the antimetastasis effect after NRP2 silencing and the results showed metastasis was inhibited. The blood vessels and capillaries in the xenograft samples were evaluated by immunohistochemistry staining for CD31. The capillaries in NRP2 knockdown tumors were rarely seen compared with the intact capillaries in control tumors. In order to explore the mechanism underlying the anti angiogenesis effect, we conducted the coculture of tumor cells and HUVEC cells in both contact and noncontact way. The ability of recruiting HUVEC cells by OS cells were dramatically inhibited by NRP2 knockdown. Also NRP2 silencing caused the tumor cells to behave less involved in tube formation. ChIP assay revealed TCF4, wnt effector, bound all the five binding sites in NRP2 promoter region.
Conclusion: We demonstrated that NRP2 plays an important role in modulating tumor growth, angiogenesis, invasion, and lung metastasis of osteosarcoma.
Citation Format: Tao Ji, Yi Guo, Carol Lin, Cheng-Fong Chen, Xiaolin Zi, Bang H. Hoang. Neuropilin2 is a novel target gene of Wnt signaling pathway regulating angiogenesis, metastasis and growth of osteosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4414. doi:10.1158/1538-7445.AM2014-4414
Abstract 4494: A clinical candidate anti-mesothelin-MMAE antibody-drug conjugate (ADC) for therapy of mesothelin-expressing cancers
Authors: Scales Suzie J. , Gupta Nidhi , Pacheco Glenn , Firestein Ron , French Dorothy M. , Chuh Josefa , Zhang Yin , Berry Leanne , Bostrom Jenny , Luis Elizabeth , O'Donohue Aimee Fourie , Kozak Katherine R. , Ross Sarajane , Dennis Mark S. , Tibbitts Jay , Spencer Susan D. 
Published: May 2015

Abstract
Mesothelin (MSLN) is a cell surface glycoprotein widely expressed in a variety of cancers, with prevalence levels by IHC of 85% in ovarian, 75% in pancreatic and 45% in mesothelioma, and normal expression limited to the mesothelia, suggesting it could be an ideal target for antibody-drug conjugate therapy of these cancers. We have generated a high affinity (subnanomolar), humanized antibody to MSLN and conjugated it to auristatin anti-mitotic drugs (monomethylauristatin E and F, Seattle Genetics) via an uncleavable linker (anti-MSLN-mc-MMAF) or a cathepsin-cleavable valine-citrulline linker (anti-MSLN-mc-vc-PAB-MMAE/F) for comparison. The in vivo efficacy obtained in an ovarian transplant model was superior with the anti-MSLN-MMAE ADC. Anti-MSLN-MMAE was specifically internalized by MSLN-expressing cells in vitro, resulting in cell death compared to control ADCs. Pancreatic, ovarian and mesothelioma tumor cell lines endogenously expressing physiological levels of MSLN were identified and established as xenografts in mice. A single dose of anti-MSLN ADC was sufficient to inhibit or shrink tumor growth in models of each of the three indications in vivo, as well as inducing complete regressions in primary human pancreatic models, even those expressing low levels of MSLN typical of most human pancreatic tumors. Additionally, anti-MSLN-MMAE (at suboptimal doses) appeared to synergize with gemcitabine at clinically relevant doses in an HPAC xenograft model. Furthermore, anti-MSLN-MMAE was well tolerated in non-clinical toxicity studies (see accompanying abstract by Gupta et al.). Our data suggest that anti-MSLN-vc-MMAE is a promising clinical candidate for the treatment of several types of mesothelin-positive cancers.
Citation Format: Suzie J. Scales, Nidhi Gupta, Glenn Pacheco, Ron Firestein, Dorothy M. French, Josefa Chuh, Yin Zhang, Leanne Berry, Jenny Bostrom, Elizabeth Luis, Aimee Fourie O'Donohue, Katherine R. Kozak, Sarajane Ross, Mark S. Dennis, Jay Tibbitts, Susan D. Spencer. A clinical candidate anti-mesothelin-MMAE antibody-drug conjugate (ADC) for therapy of mesothelin-expressing cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4494. doi:10.1158/1538-7445.AM2014-4494
Abstract 4526: BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma
Authors: Patwardhan Parag P. , Musi Elgilda , Ivy Kathryn S. , Giovino Natalie , Schwartz Gary K. 
Published: May 2015

Abstract
BIBF1120 (Nintedanib), an investigational potent small molecule angiokinase inhibitor, selectively binds to and blocks receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor, (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). Nintedanib has shown promising results in preclinical as well as clinical studies of non-small cell lung cancer, colorectal, ovarian cancer and other solid tumors. We tested the in vitro anti-proliferative activity of BIBF1120 in a panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), synovial (SYO-I), Ewing's (CHP100), osteo (SaOS2) and liposarcoma (LS141). Our results indicate that when compared to other potent RTK inhibitors such as Imatinib and Pazopanib, BIBF1120 is highly efficient at nanomolar to low micromolar concentrations in blocking proliferative activity of sarcoma cell lines, specifically, SYO-I and MPNST, which are highly dependent on PDGFR signaling. Western blot analysis to test the efficacy of BIBF1120 confirmed significant blockade of RTK signaling pathways. Ras activation and/or activation of mitogen activated protein kinase (MAPK) pathway has been shown to be critical in sarcomas including MPNST and synovial sarcomas. Unlike Imatinib and Pazopanib, BIBF1120 also blocked MAPK signaling pathway as demonstrated by p-ERK1/2 blockade. In addition to the RTKs, mTOR (mammalian Target of Rapamycin) protein plays a key role in AKT activation and downstream survival signaling. Combination of RTK blockade by BIBF1120 and mTOR blockade by TORC1 inhibitor rapamycin resulted in significantly stronger inhibition of in vitro cellular proliferation compared to single agent treatments. Taken together, our data strongly supports further clinical research of BIBF1120 in sarcoma. Combining potent inhibitors of tyrosine kinase signaling, MAPK signaling and inhibitors of mTOR pathway such as rapamycin could provide a new therapeutic approach in this disease.
Citation Format: Parag P. Patwardhan, Elgilda Musi, Kathryn S. Ivy, Natalie Giovino, Gary K. Schwartz. BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4526. doi:10.1158/1538-7445.AM2014-4526
Abstract 4528: Comparison of anti-proliferation activity of BEZ 235, a multi-step inhibitor of mTOR pathway, vs. BKM120, a pan PI3K inhibitor, in lung cancer cell lines (LCCL)
Authors: Huang Chao H. , Beaudoin Christopher , Veldhuizen Peter Van , Farassati Faris 
Published: May 2015

Abstract
Background: PI3K/AKT/mTOR(Mammalian target of rapamycin) signal transduction pathway is over-activated in many cancers including lung cancers. The activation of cell surface receptors i.e.EGFR (Epidermal Growth Factor Receptor) signals through PI3K/AKT/mTOR pathway which then results in increase cell proliferation, angiogenesis and anti-apoptosis process. BEZ 235 is a multi-step inhibitor of PI3K and mTORC 1 / 2. BKM 120 is a novel pan class I PI3K inhibitor of all class I PI3K isoforms (α, β, Υ, δ). Inhibition of multiple steps of PI3K/AKT/mTOR pathway would be advantageous and could yield higher activity and overcome over activation of PI3K/AKT, a potential mechanism of resistance to mTOR inhibitors. Docetaxel (D) is an approved agent used in the treatment of lung cancer. We previously demonstrated that the sequence of D followed by mTOR inhibitor temsirolimus (T) in lung cancer cell lines (LCCL) had increased suppression of cell proliferation as compared to reverse sequence of T→D due to suppression of over-activation of PI3K/AKT resistance mechanism. We studied the anti-proliferation effect of each compound in LCCL and also compared the activity of sequential docetaxel followed by BKM 120 vs. D followed by BEK235. Methods: Adenocarcinoma LCCL H2122 and A549 were treated with increasing concentrations of BEZ 235 (50nM, 75 nM, 100 nM) and BKM 120 at same concentrations. Both agents were provided by Novartis.We assessed the cell proliferation by optical density. In the sequential treatment study, we incubated LCCL with D 100nM for 24h then added BKM 120 or BEZ235 at 50nM, 75nM and 100nM. We then assessed the anti-proliferation effect at 48h and 72h.
Results: BEZ 235 single had greater inhibitory effect in LCCL proliferation as compared to BKM120. The sequential treatment of D followed by BEZ235 or BKM120 did not yield higher anti-proliferation effect compared to single agent treatment in both LCCL.
Conclusion: Single agent BEZ235 had greater anti-proliferation effect than BKM120 in both LCCL. The sequential treatment of D followed by BEZ235 or BKM120 did not lead to increased anti-proliferation effect. The potential explanation of lack of synergistic effect may due to suppression of PI3K by pretreatment with D.
Note: This abstract was not presented at the meeting.
Citation Format: Chao H. Huang, Christopher Beaudoin, Peter Van Veldhuizen, Faris Farassati. Comparison of anti-proliferation activity of BEZ 235, a multi-step inhibitor of mTOR pathway, vs. BKM120, a pan PI3K inhibitor, in lung cancer cell lines (LCCL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4528. doi:10.1158/1538-7445.AM2014-4528
Abstract 4534: In vivo antitumor activity of PM060184 in patient-derived xenografted tumors (avatar)
Authors: Hidalgo Manuel , Guillén M. José , López-Casas Pedro Pablo , Sarno Francesca , Cataluña Oscar , Palomares Mandy , Cuevas Carmen , Aviles Pablo M. 
Published: May 2015

Abstract
Background: PM060184 is a synthetic marine-derived compound originally isolated from the marine sponge Lithoplocamia lithistoides. PM060184 induces disorganization and disruption of the microtubule network as well as aberrant mitotic spindle multipolarization and chromosome missegregation. These effects give rise to prometaphase arrest and formation of multinucleated cells. Then, cells enter to caspase-driven apoptosis or are arrested in a pseudo-senescent state. PM060184 is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases.
Material and Methods: Athymic female nu/nu mice were subcutaneously implanted with different patient-derived tumors: NSCLC (N=4)), pancreas (N=5), colon (N=4) and gastric (N=2). Tumor (ca. 300 mm3) bearing animals (N=6-10/group) were randomly allocated to receive PM060184 (16 mg/kg) or placebo. Treatments were administered weekly for 5 consecutive weeks. Antitumor effect was calculated using ΔT/ΔC (%), defined as a percentage of the change in tumor size for treated (T) and placebo (C) groups during the placebo-treated survival time (D). Complete tumor regression (CR) was defined when tumor volume &lt; 63 mm3 for 2 or more consecutive measurements.
Results: The treatment with PM060184 produced lowest ΔT/ΔC values summarized as follows:
TumorMinimal ΔT/ΔC (%)on Day NSCLCPulm-0052.232Pulm 00920.414Pulm-0160.045Pulm-02114.738PancreasPanc-21537.335Panc-26512.126Panc-35429.532JH-02450.039ColonCCR-02051.628CCR-02535.639CCR-02933.535CCR-03034.328GastricGastric-00853.331Gastric-0102.538
During the treatment, complete remissions (CR) of tumors were also seen in animals bearing the following xenografts: Pulm-005 (7 CR/7 mice), Pulm-016 (10 CR/10 mice) and Gastric-010 (9 CR/9 mice).
Conclusion: The treatment with PM060184 demonstrated significant in vivo antitumor activity in patient-derived xenografts of human NSCLC, pancreas, colon and gastric tumors.
Citation Format: Manuel Hidalgo, M. José Guillén, Pedro Pablo López-Casas, Francesca Sarno, Oscar Cataluña, Mandy Palomares, Carmen Cuevas, Pablo M. Aviles. In vivo antitumor activity of PM060184 in patient-derived xenografted tumors (avatar). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2014-4534
Abstract 4535: Inhibition of cell proliferation by (R,R')-4′-methoxy-1-naphthylfenoterol in breast cancer cell lines
Authors: Paul Rajib K. , Wnorowski Artur , Bernier Michel , Wainer Irving W. 
Published: May 2015

Abstract
(R,R')-4′-methoxy-1-naphthylfenoterol (MNF) is a bitopic ligand that acts as an agonist of the β2-adrenergic receptor and an antagonist of the orphan G-protein-coupled receptor GPR55. Activation of GPR55 is pro-oncogenic through cannabinoid-related signal transduction and MNF treatment inhibits proliferation of different tumor cell lines, representing cancers of the liver, pancreas and brain. Of significance, MNF exerts antitumor activity in a xenograft glioma model in nude mice. In the current study, the anti-proliferative response mediated by MNF has been examined in human breast cancer cell lines. In this study, MCF-7 and MDA-MB-231 cells were screened for the presence of epidermal growth factor receptor (EGFR) and GPR55 proteins by Western blotting. The EGFR in such cancer cells plays a key role in the control of growth and proliferation. When compared to MCF-7 cells, MDA-MB-231 cells contained high levels of EGFR and GPR55 and showed exquisite sensitivity to MNF as evidenced by the significant reduction in constitutive phosphorylation of the extracellular signal-regulated kinase (ERK1/2), with an IC50 of 0.08 nM. [3H]-Thymidine incorporation assay was performed and revealed that MNF elicited a 2-fold higher growth inhibition in MDA-MB-231 cells as compared to MCF-7 cells (50% vs. 24.9% inhibition at 10 µM of MNF; p&lt;0.001). Evidence for the altered expression and/or signaling pathway activation triggered by EGFR and GPR55 in response to MNF will be presented. We conclude that MDA-MB-231 cells represent a suitable model for the study of possible crosstalk between two classes of pro-oncogenic cell surface receptors and the analysis of MNF as novel therapeutic agent for the management of cancer. This work was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH.
Citation Format: Rajib K. Paul, Artur Wnorowski, Michel Bernier, Irving W. Wainer. Inhibition of cell proliferation by (R,R')-4′-methoxy-1-naphthylfenoterol in breast cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4535. doi:10.1158/1538-7445.AM2014-4535
Abstract 4536: ABT-737 and ABT-199 complement the multikinase inhibitor TG02 to induce apoptosis in acute myeloid leukemia cells
Authors: Abdul-Aziz Amina , Burrows Francis , Yu Ning , Russell Nigel H. , Seedhouse Claire H. , Pallis Monica 
Published: May 2015

Abstract
TG02 is a novel multikinase inhibitor currently in Phase 1 trials for AML and CLL, with a unique spectrum of molecular targets. We have previously shown that TG02 significantly downregulates MCL1 but not BCL2 or BCL2L2 in AML cells at nanomolar concentrations. ABT-737 is a BH3 mimetic which inhibits BCL2, but its effects are impaired in cells which over-express MCL1. Both these agents are documented to target dormant as well as proliferating leukaemia cells and thus have the potential to reduce relapse risk, but cellular responses are heterogeneous. In primary AML samples, BCL-2 expression correlated with that of BCL-XL but not of MCL-1. The response at 48 hours to 100 nM TG02 was measured in primary samples. (This concentration did not inhibit clonogenic growth of haematopoietic stem cells from healthy donors). We show that resistance to TG02 is significantly associated with BCL2 over-expression (P=0.001) but not with MCL1. In CD34+CD38- KG1-a cells, using TG02 with ABT-737 or with the novel and more specific BCL-2 inhibitor ABT-199 at a fixed dose ratio of 1(TG02):20, the combination indices for drug interactions were calculated. For TG02 with ABT-737 and ABT-199 respectively these were IC50 0.59 and 0.26; IC90 0.13 and 0.14, indicating strong synergy, particularly at the IC90. We also show that the OCI-AML-3 cell line, which is resistant to both ABT compounds, was sensitive to TG02 (TG02 IC50 43 nM, IC90 97 nM; ABT-737/199 IC50&gt;4,000nM). All three agents exposed activation-specific epitopes of bax, reduced mitochondrial membrane potential, cleaved caspase 3 and induced phosphatidylserine exposure. 50 nM TG02 + 50 nM ABT199 or ABT-737 was significantly (P&lt;0.05) more toxic than 100 nM of any of the 3 agents individually in a cohort of 12 patient samples treated in vitro for 48 hours. Moreover samples which were sensitive to ABT-199 alone clustered separately from samples sensitive to TG02 alone (p=0.03), indicating that in this heterogeneous disease, the combinatorial approach broadens the range of samples that can be targeted as well as enhancing individual toxicities. We conclude that the cytotoxic actions of TG02 and ABT-737 /ABT-199 are complementary.
Citation Format: Amina Abdul-Aziz, Francis Burrows, Ning Yu, Nigel H. Russell, Claire H. Seedhouse, Monica Pallis. ABT-737 and ABT-199 complement the multikinase inhibitor TG02 to induce apoptosis in acute myeloid leukemia cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4536. doi:10.1158/1538-7445.AM2014-4536