bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4507: SL-501, a next-generation targeted therapy directed to IL-3R, inhibits the growth of tyrosine kinase inhibitor-resistant CML cells
Authors: Brooks Christopher , Hoberman Kenneth , Bergstein Ivan , Rowinsky Eric 
Published: May 2015

Abstract
Although imatinib and other tyrosine kinase inhibitors (TKIs) achieve high response rates in patients with chronic myeloid leukemia (CML), patients can fail these therapies or develop specific mutations that render TKIs ineffective. Moreover, TKIs have limited effectiveness against CML cancer stem cells (CSCs). It was previously shown that SL-401, a novel targeted therapy directed to the interleukin 3 receptor (IL-3R), inhibits the growth of CML tumor bulk and CSCs, both of which over express IL-3R. SL-501 is a next-generation targeted therapy also directed to IL-3R. SL-501 has approximately 4-fold increased binding affinity for IL-3R and a more than 30-fold increase in potency against acute myeloid leukemia (AML) cells compared to SL-401. In this study, we assessed the activity of SL-501 against a panel of TKI-sensitive and TKI-resistant CML cell lines. KBM5, KBM5-STI, K562, and BV173 cells were treated with SL-501 (range: 5 - 21,000 pg) for 24 or 48 hours and assessed for viability and apoptosis. We found that SL-501 reduced the absolute cell number of all cell lines tested in a dose-dependent manner with IC50s of 20 pM, 21 pM, 31.5 nM, and 3.9 nM, respectively; these concentrations are readily achieved at tolerable doses in the clinic. Moreover, SL-501 significantly reduced the number of imatinib-resistant KBM5-STI viable cells by more than 5-fold after 48 hours. Using caspase and lactate dehydrogenase (LDH) release assays, we also found that SL-501 alone induced apoptosis of all cell lines tested by more than 40% after 24 hours. The combination of SL-501 with TKIs (imatinib, dasatinib, or nilotinib) had an enhanced effect on apoptosis in KBM5, K562, and BV173 cells 24 hours post-treatment. Taken together, these findings indicate that SL-501, a novel next-generation IL-3-targeted therapeutic, may be effective at treating TKI-resistant CML. These promising results together with the IL-3R expression pattern on CML blasts and CSCs warrant further development of SL-501 in CML and, in particular, TKI-resistant CML.
Citation Format: Christopher Brooks, Kenneth Hoberman, Ivan Bergstein, Eric Rowinsky. SL-501, a next-generation targeted therapy directed to IL-3R, inhibits the growth of tyrosine kinase inhibitor-resistant CML 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 4507. doi:10.1158/1538-7445.AM2014-4507
Abstract 4510: RG7787 - a novel de-immunized PE based fusion protein for therapy of mesothelin-positive solid tumors
Authors: Niederfellner Gerhard , Bauss Frieder , Imhof-Jung Sabine , Hesse Friederike , Kronenberg Sven , Staak Roland , Lechmann Martin , Krippendorff Ben , Richter Wolfgang , Mateus Rita , Kollmorgen Gwendlyn , Brinkmann Ulli , Onda Masanori , Pastan Ira , Bosslet Klaus 
Published: May 2015

Abstract
Attaching toxic payloads to antibodies has recently been established as a breakthrough in cancer therapy. Most of the currently developed antibody drug conjugate programs represent targeted chemotherapy with microtubule polymerization inhibiting drugs and hence share resistance mechanisms and side effects with classical chemotherapeutics like Taxol. Inhibition of protein synthesis by Pseudomonas Exotoxin (PE) is a more powerful mode of action that interferes with all hallmarks of cancer cells, not just with proliferation. However, its clinical use has been limited by immunogenicity as shown for SS1P, a mesothelin targeted immunotoxin. We have developed a novel de-immunized PE fusion protein (RG7787) for treatment of mesothelin-positive tumors.
In order to de-immunize PE, point mutations have been introduced into domain III and the entire domain II has been deleted reducing the size of the effector moiety to approximately 24 kD. PE24 fusions with a disulfide-stabilized Fv fragment have previously been shown to be much better tolerated in rodents, but this could, at least in part, also be attributed to a much reduced serum half-life and exposure. In order to also de-immunize the targeting moiety of RG7787 and restore PK parameters similar to those of SS1P, we substituted the mouse dsFv moiety by a humanized Fab fragment. We show that RG7787 has indeed similar PK properties to SS1P in mouse and cyno.
Cell viability assays show that RG7787 has similar cytotoxic potency as SS1P on different cell lines. In-vivo equipotency to SS1P in different xenograft models has been achieved at ∼3 fold higher doses indicating that tumor penetration of SS1P might be slightly better. However, RG7787 is up to tenfold better tolerated in rodents and cynomolgus monkeys, indicating that the therapeutic window is improved. RG7787 achieves potent tumor growth inhibition and even tumor regressions in several xenograft models. We also observed clearly synergistic efficacy with Taxol treatment in different tumor models making this a promising combination for clinical trials.
Citation Format: Gerhard Niederfellner, Frieder Bauss, Sabine Imhof-Jung, Friederike Hesse, Sven Kronenberg, Roland Staak, Martin Lechmann, Ben Krippendorff, Wolfgang Richter, Rita Mateus, Gwendlyn Kollmorgen, Ulli Brinkmann, Masanori Onda, Ira Pastan, Klaus Bosslet. RG7787 - a novel de-immunized PE based fusion protein for therapy of mesothelin-positive solid tumors. [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 4510. doi:10.1158/1538-7445.AM2014-4510
Abstract 4523: Chaetoglobosin K, a dual Akt and JNK inhibitor, modulates Akt phosphorylation in an mTORC2 independent manner
Authors: Ali Amna , Matesic Diane F. 
Published: May 2015

Abstract
Chaetoglobosin K (ChK) is a natural indolylcytochalasin that has been reported to inhibit the proliferation of human lung and ovarian carcinoma cells in vitro. We have previously shown that ChK concomitantly down-regulates Akt and JNK activation, and have recently determined that the inhibition of Akt by ChK is not via direct inhibition of the upstream enzyme PI3 kinase. The reduction in Akt activation after ChK treatment is also not related to changes in phosphorylation of the upstream modulators PDK1 or PTEN. The mammalian target of rapamycin (mTOR) is a kinase that regulates cell growth and protein synthesis and can be both upstream (mTORC2) and downstream (mTORC1) of Akt. The purpose of this study was to determine whether ChK: 1) decreases the activation of upstream mTORC2, as this may lead to a decrease in Akt phosphorylation; 2) alters the phosphorylation of downstream mTORC1 mediators 4E-BP1 and p70 S6 kinase. In these studies, ras-transformed rat liver epithelial cells were treated with either a non-cytotoxic dose of ChK or vehicle. Western blot analysis was performed using phosphorylation site-specific antibodies to monitor changes in 4E-BP1, p70 S6 kinase, and mTOR protein activation levels. The results of this study indicate that ChK treatment did not decrease mTORC2 activation levels and suggest that ChK decreases Akt phosphorylation through an alternate mechanism. ChK treatment decreased the phosphorylation of 4E-BP1 and p70 S6 kinase, confirming that ChK modulates downstream Akt/mTOR pathway effectors. Further investigations are warranted to determine the exact mechanism by which ChK down-regulates Akt, as well as JNK, activation in tumorigenic cells.
This project was funded by NIH grant 1R15CA135415
Citation Format: Amna Ali, Diane F. Matesic. Chaetoglobosin K, a dual Akt and JNK inhibitor, modulates Akt phosphorylation in an mTORC2 independent manner. [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 4523. doi:10.1158/1538-7445.AM2014-4523
Abstract 4525: mTOR complex inhibition as a novel therapeutic strategy in high-grade papillary serous ovarian cancer
Authors: Musa Fernanda , Alard Amandine , David-West Gizelka , Giuroiu Iulia , Blank Stephanie , Pothuri Bhavana , Curtin John P. , Schneider Robert 
Published: May 2015

Abstract
Objectives:
To compare mTOR complex 1 inhibition (RAD001) vs. mTOR complex 1/2 inhibition (PP242) as single agents and with Carboplatin (CPP) in a preclinical model of serous ovarian cancer (OVCA).
Methods:
In vitro: OVCAR3 and SKOV3 cell lines were exposed to the following treatment conditions: RAD001 or PP242 as single agents, vehicle, CPP alone, and RAD001 or PP242 followed by CPP. Colony forming assays (CFAs) were performed and quantified. mRNA levels of AKT, downstream targets of mTOR and the DNA repair response (ATR, ATM, BRCA1/2) were quantified by qRTPCR. Immunoblots characterized the protein expression of key components of mTOR and DNA repair pathways. Non-parametric analyses were used to compare results across groups on SPSS. In vivo: OVCAR3 cells expressing F-Luciferase were injected IP into SCID-BG mice. 15 wks post-injection, mice were exposed to the treatment conditions described above for 4 weeks. Tumor growth and response to treatment were assessed using bioluminescence imaging (IVIS). Results were analyzed on Living Image and Prism6.
Results:
In vitro: OVCAR3 and SKOV3 cells are highly sensitive to mTOR inhibition. CFAs showed significantly decreased colony counts and diameter in groups exposed to either PP242 or RAD001 vs. control, an effect that was potentiated by CPP (Fig 1). qRTPCR revealed a significant decrease in 4EBP1 mRNA with mTOR inhibition (p&lt;0.0001), but no change in other biomarkers. Although treatment with both mTOR inhibitors resulted in decreased expression of p-S6 by immunoblots, treatment with the dual inhibitor (PP242) caused a decrease in p-AKT, p-4EBP1, total and p-CHK1, and total and p-BRCA1. The levels of these proteins were not changed by addition of CPP despite the significant effect observed in the functional assay (CFA). In vivo: Treatment with CPP + PP242 was associated with a longer median survival than other treatment groups (Table 1). A decrease in tumor burden was seen on IVIS and tumor flux (photons/sec) at the end of treatment was significantly lower in mice treated with CPP+PP242 compared to other groups (p&lt;0.0001).
Conclusions:
Our preclinical model supports the concurrent use of dual mTOR inhibitors and platinum chemotherapy in the treatment of OVCA. mTOR complex 1/2 inhibition impairs the DNA repair response and correlates with improved survival in a murine model.
Citation Format: Fernanda Musa, Amandine Alard, Gizelka David-West, Iulia Giuroiu, Stephanie Blank, Bhavana Pothuri, John P. Curtin, Robert Schneider. mTOR complex inhibition as a novel therapeutic strategy in high-grade papillary serous ovarian cancer. [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 4525. doi:10.1158/1538-7445.AM2014-4525
Abstract 4542: Regulation of the cell cycle by metformin is p21-dependent in lung cancer
Authors: Templeton Amanda , Ramesh Rajagopal 
Published: May 2015

Abstract
The oral antidiabetic agent metformin has antineoplastic activity that is likely mediated by mechanisms independent of its hypoglycemic effects. Previously reported in human non-small cell lung carcinoma (NSCLC) cell lines, 24 h treatment with metformin induced growth inhibition and G0/G1 phase arrest through induction of the energy sensing kinase AMP-activated kinase (AMPK) and the DNA damage responsive protein ataxia telangectasia mutated (ATM). AMPK and ATM are both known to regulate G0/G1 and G2 phases through modulation of the p53-p21 axis. Therefore, the objective of our study was to elucidate the molecular mechanism of metformin induced cell cycle arrest in NSCLC. Congruent with previous findings, we demonstrate that 5mM metformin treatment for up to 72 h inhibits growth in H1299 and A549 NSCLC cell lines, but not in the non-cancerous fibroblast cell line MRC-9. In H1299 and A549 cells, growth inhibition was associated with an induction of phosphorylation of AMPK and ATM as well as a reduction in phosphorylation of AKT and mTOR. Extending these findings using H1299 cells, metformin consistently induced only a transient G0/G1 phase arrest at 24 h by downregulating cyclin D1 and p27 and upregulating p21 and at 72 h a G2/M-arrest by accumulating cyclin B1 and upregulating p21 and p27. These arrests were associated with ATM and Chk-2 activation and resultant inhibitory phosphorylation of cyclin dependent phosphatase CDC25c. Importantly, p21 knock down in H1299 cells demonstrated the coordinate loss of p27 stabilization, attenuation of the G0/G1 phase arrest at 24 h, and decrease in inhibitory phosphorylation of pan-cyclin dependent kinases. Therefore, we demonstrate for the first time in NSCLC that metformin activates G1 and G2 -checkpoint responses, but the fidelity of the G1-arrest is compromised by the downregulation of p27. However, p21-dependent upregulation of p27 facilitates a G2/M arrest at 72 h. The ability of metformin to control aberrant oncogenic cell-cycle regulation by inducing negative cell-cycle regulators p21 and p27 may provide a novel therapeutic strategy in lung cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Amanda Templeton, Rajagopal Ramesh. Regulation of the cell cycle by metformin is p21-dependent in lung cancer. [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 4542. doi:10.1158/1538-7445.AM2014-4542
Abstract 4546: COX-2 inhibitors arrest prostate cancer cell cycle progression by downregulation of kinetochore/centromere proteins
Authors: Bieniek Jared , Childress Chandra , Swatski Matthew , Yang Wannian 
Published: May 2015

Abstract
Epidemiologic studies likewise revealed a decreased incidence of prostate cancer in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. Previous in vitro studies have shown that inhibition of cyclooxygenase-2 (COX-2) arrests cancer cell growth. However, the molecular mechanism underlying the growth arrest effect of COX-2 inhibition remains elusive. In this study, we demonstrated that treatment with the COX-2 inhibitors celecoxib and CAY10404 significantly inhibited prostate cancer LNCaP cell proliferation. Flow cytometric analysis confirmed the cell cycle arrested at the G2/M phase and immunofluorescent staining indicated that inhibition of COX-2 prevented the cells from entering into mitosis. Further biochemical analysis showed that inhibition of COX-2 induced a dramatic down-regulation of key proteins in the kinetochore/centromere assembly, such as ZWINT, Cdc20, Ndc80, CENP-A, Bub1 and Plk1. Furthermore, the EP1 receptor antagonist SC51322 produced similar effects to the COX-2 inhibitors on LNCaP cell proliferation and down-regulation of kinetochore/centromere proteins, which did not occur in the EP2, EP3 and EP4 receptor antagonists, suggesting the COX-2 inhibitors arrest the cell proliferation and down-regulate kinetochore/centromere proteins through inactivation of the EP1 receptor. Our studies indicate that inhibition of COX-2 can arrest prostate cancer cell growth through inactivation of the EP1 receptor signaling and down-regulation of kinetochore / centromere proteins.
Citation Format: Jared Bieniek, Chandra Childress, Matthew Swatski, Wannian Yang. COX-2 inhibitors arrest prostate cancer cell cycle progression by downregulation of kinetochore/centromere proteins. [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 4546. doi:10.1158/1538-7445.AM2014-4546
Abstract 4558: Resveratrol alters the kinase activity of PKG-Iα and Src family in A2780cp cells (ovarian cancer cell line with mutated p53) resulting in growth inhibition
Authors: Gorjala Priyatham , Wong Janica C. , Constantino Benjamin F.b , Johlfs Mary G. , Coffman Renee , Rosenberg Harry , Fiscus Ronald 
Published: May 2015

Abstract
Epithelial ovarian cancer is a leading cause of death in gynecological cancer patients. One major hurdle in treating ovarian cancer is drug resistance to commonly-used chemotherapy like cisplatin. Resveratrol (3,5,4′-trihydroxy-trans-stilbene), a natural polyphenol found in foods/drinks like grapes, berries, peanuts and red wine, can inhibit tumor growth. Our lab has previously shown that resveratrol down-regulates expression of protein kinase G type-I (PKG-I) in cancer cells, which correlated with decreased cell proliferation and increased apoptosis. For the present study, we used A2780cp cells, which are cisplatin-resistant epithelial ovarian cancer cells with mutated p53. Our data show that resveratrol did not induce apoptosis even at a higher concentration of 500 µM. However, resveratrol caused concentration-dependent decreases (down to 50% of control levels at 100 µM) of both DNA synthesis and cell adhesion. We also observed a concentration-dependent increase in protein expression levels of PKG-I to 3 times of control levels at 50 µM resveratrol, but a drop at 100 µM resveratrol. Though total Src remained fairly unchanged, pSrcY416 (phosphorylation at tyrosine-416) and pSrcS17 (phosphorylation at serine-17), indicators of Src activation, decreased at 50 and 100 µM resveratrol [assessed by ultrasensitive quantitative NanoPro 1000 (ProteinSimple), a new state-of-the-art capillary electrophoresis-based protein analysis system]. Decreased pSrcY416 levels (44% of control levels at 100 µM resveratrol) suggest that the kinase activity of Src family kinases are decreased at the higher concentrations of resveratrol that cause inhibition of ovarian cancer cell proliferation. These results suggest that resveratrol can be effective in decreasing cell proliferation in chemoresistant ovarian cancer cells and that the mechanism of action of resveratrol may involve a down-regulation of the protein expression levels of PKG-I and the typrosine-kinase activity of Src family of kinases.
Citation Format: Priyatham Gorjala, Janica C. Wong, Benjamin F.b Constantino, Mary G. Johlfs, Renee Coffman, Harry Rosenberg, Ronald Fiscus. Resveratrol alters the kinase activity of PKG-Iα and Src family in A2780cp cells (ovarian cancer cell line with mutated p53) resulting in growth inhibition. [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 4558. doi:10.1158/1538-7445.AM2014-4558
Abstract 4561: The antihistamine cyproheptadine induces cell apoptosis through inhibition of β-catenin signaling pathways in urothelial carcinoma
Authors: Hsieh Hsiao-Yen , Wang Yuan-Hung , Shen Cheng-Huang , Chen Shiu-Yi , Chan Michael W. , Hsu Cheng-Da 
Published: May 2015

Abstract
Recent studies have revealed that the cyproheptadine is a novel therapeutic agent for the treatment of malignancy, such as myeloma, leukemia and HCC. However, its effect on urothelial carcinoma cell is still unknown. The aim of this study was to investigate the effect and underline mechanism of cyproheptadine on UC. We used cell viability assay to investigate the drug effect on two UC cell lines, TSGH8301 and BFTC905, and found the IC50 which was about 55 μM. After treatment of cyproheptadine, cell cycle and apoptosis status of the UC cells were determined by flow cytometry and indicated cell cycle arrest in G0/G1 phase and induction of apoptosis. We further investigated the mechanism of the drug effect using western blot analysis and found that cyproheptadine induced downregulation of cyclin-D1 and c-Myc expression through the inhibition of β-catenin signaling pathway in UC cells. More importantly, Inhibition of β-catenin signaling pathway was related to downregulation of CCRK protein in TSGH8301 cell line, but through activation of IDAX protein leading to inhibition of β-catenin signaling pathway in BFTC905 cell line. These novel results demonstrated that cyproheptadine suppressed the β-catenin signaling pathway and induced UC cell apoptosis.
Citation Format: Hsiao-Yen Hsieh, Yuan-Hung Wang, Cheng-Huang Shen, Shiu-Yi Chen, Michael Wy Chan, Cheng-Da Hsu. The antihistamine cyproheptadine induces cell apoptosis through inhibition of β-catenin signaling pathways in urothelial carcinoma. [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 4561. doi:10.1158/1538-7445.AM2014-4561
Abstract 4563: Mechanism of action of Ibrutinib in mantle cell lymphoma
Authors: Sun Zhijian , Zhou Dongping , Wei Min , Luo Lusong 
Published: May 2015

Abstract
Mantle cell lymphoma (MCL), accounting for about 5-6% of non-Hodgkin lymphoma (NHL), is one of the lymphomas with very poor prognosis (median survival 3-5years).Ibrutinib, a newly approved Bruton's tyrosine kinase (BTK) inhibitor, showed remarkable clinical benefits in MCL. However, the mechanism underlining the clinical activity is not well understood. In this study, we identified MCL cell lines that were sensitive and resistant to ibrutinib. We showed that ibrutinib induced G1 cell cycle arrest in sensitive cell lines at 3-day treatment and eventually led to cell death after prolonged compound incubation. Physiologically relevant low concentration of ibrutinib inhibited phosphorylation of IKB(S32), p65/RelA(S536) and nuclear translocation of NF-κB components. Inhibition of NF-κB signaling decreased IRF4 and c-Myc level, which was accompanied with decrease of CDK6 and phosphor-RB (S807/811) level, meanwhile elevated p27/Kip1. Activation of NF-κB pathway with PKC agonist rescued ibrutinib induced G1 cell cycle arrest and eventually attenuated the cell killing effect. IRF4 phospho-RB and CDK6 level were also rescued by PKC agonist. BTK/PKC/NF-κB pathway and PI3K/AKT/mTOR pathway showed compensatory effect in MCL cell lines. Activating NF-κB pathway with PKC agonist compensated the cell killing effects of idelalisib or everolimus. Additionally, we showed that ibrutinib synergized with idelalisib or everolimus on cell killing of MCL cell lines, suggesting combination therapeutic strategies for MCL.
Citation Format: Zhijian Sun, Dongping Zhou, Min Wei, Lusong Luo. Mechanism of action of Ibrutinib in mantle cell lymphoma. [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 4563. doi:10.1158/1538-7445.AM2014-4563