bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2670: Natural compound tetrocarcin-A downregulates junctional adhesion molecule-A in conjunction with erα, her2 and inhibitor of apoptosis proteins and inhibits tumor cell growth
Authors: Vellanki Sri Harikrishna , Hudson Lance , Jahns Hanne , Cruz Rodrigo G.B. , Sette Giovanni , Eramo Adriana , Hopkins Ann M. 
Published: August 2018

Abstract
Overexpression of the tight junction protein Junctional Adhesion Molecule-A (JAM-A) has been linked to aggressive disease in breast and several other cancers, but JAM-targeting drugs remain elusive. Screening of a natural compound library identified the cytotoxic antibiotic Tetrocarcin-A as a novel downregulator of JAM-A protein expression in breast cancer cells. Specifically, Tetrocarcin-A-induced cytotoxicity was accompanied by downregulation of JAM-A protein expression in conjunction with that of estrogen receptor alpha (ERα) and human epidermal growth factor receptor 2 (HER2) in MCF7-HER2-overexpressing breast cells. Lysosomal inhibition partially rescued the downregulation of JAM-A, HER2 and ERα caused by Tetrocarcin-A, and attenuated its cytotoxicity. Interestingly, Tetrocarcin-A repressed the transcriptional activity of c-FOS by inhibiting ERK1/2-mediated phosphorylation at Threonine-232, and downregulated protein expression of the inhibitor of apoptosis proteins (IAP). Investigation of cell death pathways revealed that Tetrocarcin-A induced caspase-dependent apoptosis. To begin testing the potential clinical relevance of our findings, we extended our studies into various other models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused cytotoxicity in primary breast cancer and lung cancer stem cells, and inhibited the growth of model human breast tumors in an in vivo model involving invasion across the chicken egg chorioallantoic membrane. Taken together, our data suggest that Tetrocarcin-A merits future evaluation as a novel cancer therapeutic by virtue of its ability to downregulate JAM-A expression, induce apoptosis and reduce tumorigenic signalling. This work was financially supported by Science Foundation Ireland (grant 13/IA/1994 to AMH). Tetrocarcin-A was provided by the NCI/DTP Open Chemical Repository https://dtp.cancer.gov. (NSC 333856)
Citation Format: Sri Harikrishna Vellanki, Lance Hudson, Hanne Jahns, Rodrigo G.B. Cruz, Giovanni Sette, Adriana Eramo, Ann M. Hopkins. Natural compound tetrocarcin-A downregulates junctional adhesion molecule-A in conjunction with erα, her2 and inhibitor of apoptosis proteins and inhibits tumor cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2670.
Abstract 2672: Phyllanthusmins induce apoptosis and reduce tumor burden in high grade serous ovarian cancer by late-stage autophagy inhibition
Authors: Young Alexandria N. , Herrera Denisse , Huntsman Andrew , Lantvit Daniel D. , Korkmaz Melissa A. , Aldrich Leslie N. , Kinghorn A. Douglas , Fuchs James R. , Burdette Joanna E. 
Published: August 2018

Abstract
High grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We developed potent synthetic analogues of a class of compounds known as the phyllanthusmins, inspired by natural products isolated from Phyllanthus poilanei Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines in vitro and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its effects by initially inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition was required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly reduced cancer cell lines grown in hollow fibers as well as ovarian tumor burden. We show that PHY34 is a new late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single-agent against HGSOC in vivo. This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating the disease.
Citation Format: Alexandria N. Young, Denisse Herrera, Andrew Huntsman, Daniel D. Lantvit, Melissa A. Korkmaz, Leslie N. Aldrich, A. Douglas Kinghorn, James R. Fuchs, Joanna E. Burdette. Phyllanthusmins induce apoptosis and reduce tumor burden in high grade serous ovarian cancer by late-stage autophagy inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2672.
Abstract 2673: Securidaca1 and 2 induced apoptosis: A PI3K-AKT dependent pathway in cervical cancer
Authors: Obasi Titus C. , Braicu Cornelia , Noack Heiko , Berindan-Neagoe Ioana , Junker Bjorn , Oprean Radu N. 
Published: August 2018

Abstract
Background: Securidaca1 and 2 are plant-derived substances isolated from African medicinal plant S. longipedunculata, using new bioactivity-guided method partly described in Obasi et al. (2017). Our previous report suggested that certain fractions from this plant root were able to activate apoptosis in cervical cancer cell lines. Generally, over 90% of cervical cancer has been associated with high-risk human papilloma virus (HPV), whose etiologic molecule E6 oncoprotein is involved in the process of carcinogenesis. The purpose of this study, therefore, is to investigate the proapoptotic potentials of these substances and their ability to block cell survival mechanism, via antiapoptotic effectors of PI3K-AKT downstream.
Experimental Procedure: Two cervical cancer cell lines (Caski and BU25TK), positive with HPV were used for the investigation. Cells were treated with the plant-derived substances and the IC50 was determined by MTT assay. Fluorescence microscopy (Annexin V-FITC, MPC and PI staining) was used to investigate autophagy/apoptosis, while relevant genes were analyzed by RT-qPCR.
Results: Reduced cell proliferation was earlier achieved in dose- and time-dependent manner by fractions retaining Securidaca1 and 2, with IC50 of 7.03 and 16.39 (μg/mL) respectively on Caski cells. Late apoptosis was also activated on cells treated with securidaca1 fraction, while the securidaca2 in contrast indicated early apoptosis. Analysis by RT-qPCR revealed a fold-change expression of antiapoptotic proteins, MCL-1 and BCL2L1, more pronounced in securidaca1. Interestingly, the AKT-3 was significantly inhibited, correlating with low expression of MCL-1, BCL2L1, VEGFA and CDH-1. Data analysis suggests the most likely activation of apoptosis via PTEN regulated PI3K-AKT pathway and respondent downstream (mTOR/ NF-kB).
Conclusion: The ability of Securidaca1 and 2 to kill tumor cells and induce apoptosis in manner involving multiple regulatory pathways enhances their potential against possible resistance and makes them attractive as candidates for anticancer development.
Citation Format: Titus C. Obasi, Cornelia Braicu, Heiko Noack, Ioana Berindan-Neagoe, Bjorn Junker, Radu N. Oprean. Securidaca1 and 2 induced apoptosis: A PI3K-AKT dependent pathway in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2673.
Abstract 2686: Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs
Authors: Beni Yousef , Alhamed Samiyah , Alnakhli Jawzah , Karim Kaleh , Boadi William 
Published: August 2018

Abstract
Triptorelin (TRP) and Leuprorelin (LEP) are two synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in mid 80s. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP and LEP in a combination regiment. Therefore, improving of the biological activity of TRP and LEP by increasing the cellular uptake and retention is a remedy to this end.In this research, polyphenolic derivatives were linked to TRP and LEP through hydrophobic linkers to enhance and optimize the hydrophobicity of these drugs with the expectation to improve the cellular uptake. In this regard, several TRP and LEP conjugates of tris(4-methoxyphenyl)methanol (TPM) derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene, anisole, 2-fluoroanisole or 2-methylanisole and 1,3,5-trioxane, followed by the conjugation with TRP or LEP and decanedioic acid or dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields.Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 10-50 µM after 24-72 h of incubation. Similar antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-TRP and TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP or LEP.
Citation Format: Yousef Beni, Samiyah Alhamed, Jawzah Alnakhli, Kaleh Karim, William Boadi. Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2686.
Abstract 2700: Specific cell populations from the primary tumor invasive front and lymph nodes show protein signatures associated with local metastasis in head and neck cancer
Authors: Busso-Lopes Ariane F. , Rivera César , Macedo Carolina C. , Mello Barbara P. , Villa Luisa L. , González-Arriagada Wilfredo A. , Leme Adriana F. Paes 
Published: August 2018

Abstract
Lymph node metastasis is the main prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC), but no molecular markers are currently used in clinical practice. Considering that the invasive front (IF) of the tumor has a prognostic value due to the invasive and metastatic potential of the cells, we explored the mechanisms associated with lymph node metastasis in the primary tumor IF and its paired lymph nodes from HNSCC patients. For that, the proteomic profile was determined for formalin-fixed, paraffin-embedded (FFPE) tissues using mass spectrometry in a 29-patient cohort. Specific cell populations from primary tumor IF (tumor and stroma cells) and lymph nodes (microenvironment cells) were microdissected and HPV genotyping was performed. In total, 27.5% of the cases were positive for HPV16 and 2,154 ± 285 proteins were identified for the three cell populations analyzed. Eighty-one proteins from tumor cells, 36 proteins of stroma cells and 149 proteins of lymph node microenvironment cells were differentially expressed between HNSCC patients positive and negative for lymph node metastasis (Student´s t-test; P-value ≤ 0.05). Specific processes were enriched for the differentially expressed proteins from tumor, stroma and lymph node cells, including post-translational modification, splicing and translation, respectively. Interestingly, differential proteins isolated from primary tumor cells are mainly transported by exosomes. Therefore, our data provide protein signatures related to lymph node metastasis that are expressed by specific cell populations and candidates as prognostic markers in HNSCC.
Financial support: FAPESP (Process number 2015/19191-6).
Citation Format: Ariane F. Busso-Lopes, César Rivera, Carolina C. Macedo, Barbara P. Mello, Luisa L. Villa, Wilfredo A. González-Arriagada, Adriana F. Paes Leme. Specific cell populations from the primary tumor invasive front and lymph nodes show protein signatures associated with local metastasis in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2700.
Abstract 271: Diterpenoid pseudolaric acid B induces M-phase arrest and apoptosis primarily through JNK stress signaling in LNCaP prostate cancer cells
Authors: Pramanik Kartick C. , Gupta Nehal , Ye Min , Lu Junxuan , Jiang Cheng 
Published: August 2018

Abstract
Pseudolaric acid B (PAB) is a major diterpenoid component isolated from the root bark of the traditional Chinese medicinal plant Pseudolarix kaempferi Gordon (Pinaceae). PAB has shown potential as an anticancer agent via inducing cell cycle arrest, apoptosis and DNA damage in several cancer models. To explore potential use of PAB for prostate cancer chemoprevention, we used human LNCaP prostate cancer cells that harbor wild-type p53, functional androgen receptor (AR), and defective PTEN that are characteristic of early stage prostate adenocarcinomas to study cell fates and signaling mechanisms upon PAB exposure in cell culture. Our results show that PAB inhibited LNCaP cell proliferation in a dose- and time-dependent manner (IC50 ~5.4 µM at 24 h and ~ 0.2 µM at 72 h). PAB induced M phase cell cycle arrest as confirmed by increased phosphorylation of histone H3 (p-H3 Ser10). PAB also induced apoptosis evidenced by Annexin V staining and cleavage of the canonical caspase substrate PARP. PAB at lethal exposure concentration decreased AR protein and its best-known target prostate-specific antigen (PSA). Timewise, PAB treatment increased p-H3 (mitosis marker) and the expression of another mitosis/prosurvival protein survivin several hours ahead of PARP cleavage. PAB induced p-H2A.X, which would mark DNA double-strand breaks, and the best-known DNA damage response protein P53 and its target P21Cip1 preceding cPARP. PAB stimulated phosphorylative activation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 decreased PAB-induced p-H2A.X, P53/P21Cip1 and cleavage of PARP as well as M phase arrest. Furthermore, PAB significantly increased 2',7'-dichlorofluorescin diacetate (DCF)-reactive oxygen species (DCF-ROS) in LNCaP cells and addition of antioxidant N-acetyl-L-cysteine (NAC) attenuated P53/P21Cip1 cascade and cPARP/apoptosis, but did not affect M phase arrest. Knocking-down of P53 or P21Cip1 by siRNA attenuated cPARP and apoptosis without affecting p-H2A.X. Taken together, these results suggest a rapid induction of M phase arrest by PAB that was primarily mediated by JNK stress signaling, either parallel to or upstream of ROS-DNA damage-driven P53-P21Cip1 apoptosis cascade in LNCaP cells.
Citation Format: Kartick C. Pramanik, Nehal Gupta, Min Ye, Junxuan Lu, Cheng Jiang. Diterpenoid pseudolaric acid B induces M-phase arrest and apoptosis primarily through JNK stress signaling in LNCaP prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 271.
Abstract 2721: Selective FcγR engagement by CTLA-4 antibodies results in increased functional activity
Authors: Waight Jeremy D. , Chand Dhan , Dietrich Sylvia , Gombos Randi , Horn Thomas , Gonzalez Ana M. , Manrique Mariana , Tanne Antoine , Dupont Christopher , Swiech Lukasz , Croker Ben A. , Buell Jennifer S. , Stein Robert , Duncan Alex , Savitsky David A. , Wilson Nicholas S. 
Published: August 2018

Abstract
Therapeutic antibodies targeting T cell co-inhibitory pathways, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1), have emerged as an important class of cancer therapies. Insights into how different IgG isotypes modulate biological activities of antibodies have opened new avenues to enhance their therapeutic effects. For example, Fc-FcγR interactions have been shown to enhance antibody-directed effector cell activities, as well as antibody-dependent forward signaling into target cells via receptor clustering. Here, we describe a novel FcγR-dependent mechanism for antibodies targeting CTLA-4. Our findings suggest that selective Fc-FcγR binding dramatically improves the quality of the immune synapse, which in turn modifies apical T cell receptor signaling events to increase effector T cell activity. Our data also suggest that subsets of antigen-presenting cells (APCs), expressing FcγRIV in mice and FcγRIIIA in humans are important mediators of this effect. Importantly, we find this mechanism to be independent of regulatory T cell (Treg) depletion. Altogether, we describe a novel mechanism of action that provides a foundation for a new class of Fc-engineered antibodies to enhance antitumor immune responses.
Citation Format: Jeremy D. Waight, Dhan Chand, Sylvia Dietrich, Randi Gombos, Thomas Horn, Ana M. Gonzalez, Mariana Manrique, Antoine Tanne, Christopher Dupont, Lukasz Swiech, Ben A. Croker, Jennifer S. Buell, Robert Stein, Alex Duncan, David A. Savitsky, Nicholas S. Wilson. Selective FcγR engagement by CTLA-4 antibodies results in increased functional activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2721.
Abstract 2726: In vitro functional activity of OMP-336B11, a GITRL-Fc fusion protein, on primary human immune cells
Authors: Chan Ivan H. , Xie Ming-Hong , Lam Andrew , Axelrod Fumiko T. , Elechko Jennifer , Park Angie I. , Gurney Austin 
Published: August 2018

Abstract
Glucocorticoid-induced TNFR-related protein (GITR) is a member of the TNF receptor superfamily. GITR, a co-stimulatory surface receptor, is activated upon binding to GITR Ligand (GITRL) and mediates co-stimulation of T-cell and NK responses and inhibits the suppressive activity of regulatory T-cells (Tregs). As such, GITR is an attractive immuno-oncology target for activation via GITR agonists. OMP-336B11 is a single-gene recombinant fusion protein consisting of two trimeric human GITRLs and a human immunoglobulin (IgG1) Fc domain. Murine preclinical studies using a surrogate GITRL-Fc fusion protein demonstrated robust antitumor efficacy. Functional characterization of OMP-336B11 in various human immune cell assays is presented here. In human peripheral blood mononuclear cells (PBMC), OMP-336B11 stimulated IL-2 cytokine release in a dose-dependent manner. In activated human T-cells, OMP-336B11 enhanced cell proliferation in a dose-responsive fashion. OMP-336B11 also augmented IL-2 induced IFNγ from human NK cells. To elicit NK mediated cytotoxicity of high GITR expressing cells (i.e., Tregs), OMP-336B11 is designed with an IgG1 Fc domain. Co-incubation of primary human NK cells (effector) and GITR expressing cells (target) resulted in an OMP-336B11 dependent dose-titratable increase in target cytotoxicity. Furthermore, OMP-336B11 agonistic activity was compared to anti-GITR agonist antibodies. By measuring cell proliferation and IFNγ from activated T-cells, OMP-336B11 demonstrated superior activity compared to the other agonist anti-GITR antibodies. In conclusion, OMP-336B11 is designed to induce effective GITR activation and also to mediate depletion of GITR-high cells. OMP-336B11 is currently undergoing phase I clinical study.
Citation Format: Ivan H. Chan, Ming-Hong Xie, Andrew Lam, Fumiko T. Axelrod, Jennifer Elechko, Angie I. Park, Austin Gurney. In vitro functional activity of OMP-336B11, a GITRL-Fc fusion protein, on primary human immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2726.
Abstract 2728: Circulating levels of Resokine, a soluble modulator of the immune system, are upregulated in both experimental cancer models and in patients across multiple tumor types
Authors: Adams Ryan , Mertsching Elisabeth , Nangle Leslie , Ogilvie Kathy , Crampton Steven , Bruner John , Tyler Samantha , Rosengren Sanna , Cubitt Andrea , King David , Mendlein John 
Published: August 2018

Abstract
Resokine is a newly identified regulator of immune cell activity, and circulating levels of Resokine in normal individuals may represent a soluble set-point control to modulate T cell activity. Resokine activity is a non-canonical function arising from the tRNA synthetase gene family, and the activity is effected by a 60 amino acid N-terminal domain arising from the gene for histidyl-tRNA synthetase which is present in the full-length protein as well as multiple splice variants that have lost their original tRNA synthetase functionality. Resokine is secreted from cells, including tumor cell lines, and in vitro studies have demonstrated that Resokine can inhibit the activation of immune cells. In vitro, for example, Resokine addition during T cell activation induced by antibodies to CD3 and CD28, can result in reduced levels of inflammatory cytokines such as IL-2, interferon gamma, and TNF alpha; inhibition of the up-regulation of cell-surface activation markers, such as CD69, CD40L and 4-1BB; and inhibition of release of the cytotoxic mediator granzyme B.
We have tested levels of circulating Resokine in both mice with syngeneic tumors as well as &gt;300 cancer patients across multiple tumor types. In normal C57Bl6 mice serum levels of Resokine ranged from 70-250pM (n=10) whereas in mice bearing B16F10 tumors, levels were significantly higher (450-3000pM, p&lt;0.001) and correlated with tumor size. Resokine levels in normal human volunteers exhibit a more variable range, from 8pM to &gt;2333pM (n=148), with 18% of individuals having levels &lt;30pM, which was set as the active threshold level based on the concentration required to inhibit T cell activation in vitro. In contrast, samples across &gt;300 cancer patients with different tumor types, exhibited higher circulating levels with only 4% of individuals having levels below the activity threshold of 30pM. This data is consistent with the hypothesis that tumors secrete Resokine as an additional mechanism to down-regulate immune activity, and suggests further investigation of the utility of Resokine levels as a new biomarker of immune activity in patients.
Citation Format: Ryan Adams, Elisabeth Mertsching, Leslie Nangle, Kathy Ogilvie, Steven Crampton, John Bruner, Samantha Tyler, Sanna Rosengren, Andrea Cubitt, David King, John Mendlein. Circulating levels of Resokine, a soluble modulator of the immune system, are upregulated in both experimental cancer models and in patients across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2728.