bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2603: Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models
Authors: Ma Jianguo , Syed Sakeena , Crowley Lindsey , Shaw Jamie , Ogden Janet , Elenbaas Brian , Goodstal Samantha 
Published: August 2015

Abstract
The efficacy and tolerability of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 combination were explored in pancreatic and biliary tract preclinical tumor xenograft models. These studies were based on the hypotheses that combination efficacy may occur by several possible mechanisms including inhibition of DNA repair or increase of hypoxia by Pimasertib, or by differential targeting of the oxic and hypoxic tumor compartments by Pimasertib and TH-302 respectively. Since Pimasertib and TH-302 had each been tested in separate clinical trials in pancreatic cancer with gemcitabine (NCT01016483 and NCT01144455 respectively), these data could provide the rationale for clinical testing of this novel combination in pancreatic cancer. The combination was also tested in biliary tract cancer models (cholangiocarcinoma and gall bladder) based on the reported sensitivity of these tumor types to MEK inhibitors, their hypoxic nature, and the prevalence and high unmet need of these indications, particularly in Asia. The results showed that in the MIA PaCa-2 human pancreatic xenograft model, combination efficacy was observed and found to be schedule dependent. The greatest combination efficacy occurred when Pimasertib was administered first, 2 hours prior to TH-302, suggesting a unique combination mechanism in cells when the MAPK signaling pathway is suppressed first. The combination was subsequently explored in 2 additional pancreatic models and a panel of biliary tract patient-derived xenograft (PDX) models. In 10 cholangiocarcinoma PDX models tested, 3 models were responders to Pimasertib monotherapy and 4 models converted from being a non-responder with either monotherapy to a responder with the Pimasertib TH-302 combination using the%TV (tumor volume) criteria, which is related to a clinical PR RECIST response. Combination effects were not observed in 2 additional pancreatic or 6 gall bladder models tested. Some models were highly sensitive to Pimasertib or TH-302 monotherapy, making combination effects difficult to observe. Biomarker analyses are ongoing to identify markers that could predict which tumors are the most sensitive to this combination therapy.
Citation Format: Jianguo Ma, Sakeena Syed, Lindsey Crowley, Jamie Shaw, Janet Ogden, Brian Elenbaas, Samantha Goodstal. Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2603. doi:10.1158/1538-7445.AM2015-2603
Abstract 2613: STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia via the MEK/ERK and PKC pathway
Authors: Doshi Ushma Atul , Loughran Thomas P. , Kester Mark 
Published: August 2015

Abstract
Chronic lymphocytic leukemia (CLL) constitutes 70% of adult leukemic cases in the Western world. Despite high incidence, its pathogenesis is still poorly understood and it remains incurable with current therapies. We have previously shown that nanoliposomal C6-ceramide, a liposomal formulation of a ‘tumor suppressor’ lipid, is an effective therapy in several solid and non-solid tumor models. Specifically in CLL, nanoliposomal C6-ceramide selectively induces cell death in leukemic cells by targeting the Warburg effect with no detrimental effects on normal peripheral blood mononuclear cells. Additionally, treatment with nanoliposomal C6-ceramide results in tumor regression in an in vivo murine model of CLL. However, the mechanism and key molecular players mediating C6-ceramide-induced cell death in CLL remains unknown. We hypothesize that STAT3 is a target of C6-ceramide in CLL cells. After validating STAT3 as a as a therapeutic target in CLL, we show that C6-ceramide treatment suppresses the levels of p-STAT3-Y705 and p-STAT3-S727 in both cell lines and patient cells, while having no effect on total STAT3 levels. C6-ceramide treatment also reduces STAT3-dependent expression of survival factors like Mcl-1, XIAP and survivin. Our results suggest that suppression in STAT3 phosphorylation might be critical for cell death induction since it precedes induction of C6-ceramide-mediated cell death in CLL cells. Analysis of the upstream kinases revealed that C6-ceramide-induced suppression of p-STAT3 might be, in part, a consequence of suppression of MEK1/2 kinase and protein kinase C (PKC). Preliminary results also demonstrate that C6-ceramide treatment reduces p-STAT3-S727 in the mitochondrial fraction, which might be critical to the cell death induction since overactivation of mitochondrial p-STAT3-S727 confers viability and stress protection to CLL cells. Ongoing studies will focus on identifying the specific phosphorylation site(s) that mediates cell death in an effort to delineate the molecular mechanism of C6-ceramide-induced cell death in CLL. We would also like to define the molecular link between CNL-induced dephosphorylation of mitochondrial STAT3 and suppression of the Warburg effect in CLL. In conclusion, our data suggests that targeting STAT3 with nanoliposomal C6-ceramide is a potential therapy for CLL. This work is the first body of evidence demonstrating an effect of C6-ceramide on STAT3 phosphorylation.
Citation Format: Ushma Atul Doshi, Thomas P. Loughran, Mark Kester. STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia via the MEK/ERK and PKC pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2613. doi:10.1158/1538-7445.AM2015-2613
Abstract 2615: Dual ErbB blockade with KTN3379 and cetuximab yields enhanced antitumor activity by inhibiting parallel signaling pathways in SCCHN
Authors: Alvarado Diego , Seibel Scott B. , Ligon Gwenda F. , Lillquist Jay S. , Pierce Andrew , Gedrich Richard , LaVallee Theresa M. 
Published: August 2015

Abstract
The receptor tyrosine kinase ErbB3/HER3 has been implicated as an oncogenic driver in pre-clinical models of solid tumors, and is the target of several monoclonal antibodies currently in clinical development. In squamous cell carcinoma of the head and neck (SCCHN), ErbB3 activation is regulated by its ligand neuregulin (NRG). Studies, including our own, have reported high NRG expression in a significant subset of SCCHN, providing a scientific rationale for the use of ErbB3 targeted therapies in this disease setting. Here we show that KTN3379, a potent human ErbB3 monoclonal antibody with a dual mechanism of action, demonstrates significant monotherapy activity in NRG expressing xenograft models of SCCHN and enhances cetuximab anti-tumor activity. Using a panel of SCCHN cell lines, we demonstrate that KTN3379 inhibits PI3K/AKT signaling whereas cetuximab chiefly suppresses the ERK pathway, providing an explanation for the increased anti-tumor activity of combining both drugs. Our data also suggest that ErbB3 and EGFR act independently of one another at the receptor level. Interestingly, mRNA analysis of 303 SCCHN human tumor samples shows a strong correlation between NRG expression and the EGFR ligands Amphiregulin (AREG) and TGFα. Moreover, KTN3379 activity correlates with expression of ErbB3, its ligand NRG, and both of these EGFR ligands. Overall, our data support evaluation of the combination of KTN3379 and cetuximab in SCCHN.
Citation Format: Diego Alvarado, Scott B. Seibel, Gwenda F. Ligon, Jay S. Lillquist, Andrew Pierce, Richard Gedrich, Theresa M. LaVallee. Dual ErbB blockade with KTN3379 and cetuximab yields enhanced antitumor activity by inhibiting parallel signaling pathways in SCCHN. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2615. doi:10.1158/1538-7445.AM2015-2615
Abstract 2618: Gemcitabine based peptide conjugates: Overcoming the pitfalls of conventional therapies by targeted approaches
Authors: Tamvakopoulos Constantin , Karampelas Theodoros , Argyros Orestis 
Published: August 2015

Abstract
Although gemcitabine has been proved to be a valuable ally against several types of cancer, it is characterized by some weaknesses that limit its anticancer potential. These limitations are mainly associated with gemcitabine rapid inactivation as well as the different types of resistance that are related with its use. We have previously shown that conjugation of gemcitabine to a ligand peptide (molecule GSG) enhanced its metabolic stability systemically and locally (within the cancer cell), and lead to improved efficacy in a castration resistant prostate cancer (CRPC) animal model.
In order to refine our previous findings, a bioanalytical methodology based on mass spectrometry that allows the simultaneous monitoring of gemcitabine as well as its active (dFdCDP, dFdCTP) and inactive (dFdU) metabolites was developed in the context of this study. The balance of gemcitabine and its active/inactive metabolites was evaluated in in vitro and in vivo systems after treatment with gemcitabine or selected gemcitabine based peptide conjugates (GSG). Furthermore, since GSG's structure contains a potent agonist peptide of the GnRH-R we investigated whether it could have a central effect through the pituitary by performing testosterone measurements in animals dosed with GSG.
Interestingly, GSG appears to offer metabolic advantages in comparison to gemcitabine, an important attribute if we had to overcome gemcitabine acquired resistance. In addition, GSG is a potent GnRH-R agonist based on our in vivo biomarker model, suggesting that testosterone ablation might also represent a key attribute of the mechanism of action for our conjugate of interest.
These findings along with the targeted delivery nature of this approach could ameliorate the therapeutic status of gemcitabine and expand the use of gemcitabine based conjugates in other types of cancers.
Citation Format: Constantin Tamvakopoulos, Theodoros Karampelas, Orestis Argyros. Gemcitabine based peptide conjugates: Overcoming the pitfalls of conventional therapies by targeted approaches. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2618. doi:10.1158/1538-7445.AM2015-2618
Abstract 262: Inhibition of the novel immune checkpoint CEACAM1 enhances antitumor immunological activity
Authors: Markel Gal , Mandel Ilana , Sapir Yair , Hakim Motti , Hashmueli Sharon , Ben-Moshe Tehila 
Published: August 2015

Abstract
Blockade of co-inhibitory immune receptors has become a promising approach for the activation of anti-tumor immunity. CEACAM1, a recently characterized immune checkpoint, is a member of the Ig superfamily expressed by activated effector lymphocytes and cancer cells. Expression of CEACAM1 on cancer cells induces a co-inhibitory signal to T and NK cells through homophilic CEACAM1 interactions. CEACAM1 is expressed across multiple tumor types and its presence is independent of PD-L1 expression.
CM-24 is a humanized anti-CEACAM1 IgG4 antibody with high affinity and selectivity for CEACAM1. We investigated the activity of CM-24 and its ability to reverse CEACAM1-induced immune evasion alone and in combination with other checkpoint inhibitors. CM-24 was demonstrated to be a potent blocker of intercellular CEACAM1-CEACAM1 interactions and reversed inhibition of activated lymphocytes by restoring the phosphorylation signal of ZAP70. CM-24 enhanced the cytotoxic activity of cytotoxic T cell and NK cells against various cancer types, which was accompanied by higher secretion of Granzyme B and IFNγ. In addition, a synergistic activity with various immune checkpoint blockers was observed, including ones that target the PD-1 pathway. Various in vivo tumor xenograft models demonstrated that CM-24 has clear anti-tumor activity accompanied by an increase in immunological activity of T cells within the tumor. Collectively, preclinical data show that CM-24 has effective anti-tumor activity in various in vitro and in vivo models and demonstrate that CM-24 has the potential to enhance the cytotoxic activity of lymphocytes against malignant cells. CM-24 is now moving towards phase 1 clinical study.
Citation Format: Gal Markel, Ilana Mandel, Yair Sapir, Motti Hakim, Sharon Hashmueli, Tehila Ben-Moshe. Inhibition of the novel immune checkpoint CEACAM1 enhances antitumor immunological activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 262. doi:10.1158/1538-7445.AM2015-262
Abstract 2620: Plumbagin induces growth inhibition of human glioma cells by downregulating the expression and activity of FOXM1
Authors: Liu Xuejiao , Cai Wei , Niu Mingshan , Yu Rutong 
Published: August 2015

Abstract
Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that plumbagin induced G2/M arrest. Interestingly, we found that plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21CIP1 and p27KIP1. Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced plumbagin-induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced plumbagin-induced glioma cell growth inhibition. Further investigation revealed that plumbagin inhibition of glioma cell growth was also evident in a nude mouse model. Taken together, these results suggest that plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas.
Citation Format: Xuejiao Liu, Wei Cai, Mingshan Niu, Rutong Yu. Plumbagin induces growth inhibition of human glioma cells by downregulating the expression and activity of FOXM1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2620. doi:10.1158/1538-7445.AM2015-2620
Abstract 2630: Inhibition of angiogenesis contributes to enhanced radiation response in tumors following MDM2 inhibition by AMG 232
Authors: Werner Lauryn R. , Huang Shyhmin , Armstrong Eric A. , Ma Fang , Canon Jude , Harari Paul M. 
Published: August 2015

Abstract
MDM2-p53 interaction and downstream signaling impacts cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We previously elucidated the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. In the current study, we examine the capacity of AMG 232 to inhibit angiogenesis and assess the resultant impact on AMG 232-induced radiosensitivity.
We first examined the impact of AMG 232 on the growth and radiosensitivity of human umbilical vein endothelial (HUVEC) and dermal lymphatic endothelial cells (HDLEC). We found that AMG 232 inhibited the proliferation of both endothelial cell types in a dose dependent manner. Importantly, treatment with AMG 232 significantly reduced angiogenesis-related tube formation in both endothelial cell types. Using clonogenic survival analysis, we identified that treatment with AMG 232 significantly enhanced radiosensitivity. Immunoblot analysis showed that combined treatment with AMG 232 and radiation resulted in a profound impact on molecules involved in cell cycle progression, DNA damage repair, and apoptosis signaling, including FoxM1, ATM/ATR, CHK2, Rad51, and Bax. Flow cytometric analysis also showed a significant cell cycle arrest in G2/M phase with an increase of DNA damage related γH2AX level at 48 hrs following radiation and AMG 232 treatment. In H460 and SJSA-1 tumor xenografts, we found a markedly increased antitumor capacity of AMG 232 when combined with radiation. Immunohistochemical analysis revealed a significant reduction of cellular proliferation and vascular density in both tumor types following combined treatment of AMG 232 and radiation. Taken together, these findings reveal the potential anti-angiogenic capacity of AMG 232 that may contribute to augmentation of radiation response previously observed in tumor xenograft studies. A detailed investigation is in progress to examine changes in the tumor microenvironment following AMG 232 and radiation treatment, including hypoxia and vascular normalization, to assess their respective impact on tumor response to radiation.
Citation Format: Lauryn R. Werner, Shyhmin Huang, Eric A. Armstrong, Fang Ma, Jude Canon, Paul M. Harari. Inhibition of angiogenesis contributes to enhanced radiation response in tumors following MDM2 inhibition by AMG 232. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2630. doi:10.1158/1538-7445.AM2015-2630
Abstract 2632: The COX inhibitor, diclofenac induces mantle cell lymphoma apoptosis independent of p53 status
Authors: Hassan Hesham M. , Varney Michelle L. , Aly Aalia M. , Joshi Shantaram S. , Singh Rakesh K. , Dave Bhavana J. 
Published: August 2015

Abstract
Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapses and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome in MCL. Diclofenac has been reported to increase p53 pathway activity, upregulates p73 expression and inhibit cell growth; hence we investigated the ability of diclofenac to induce apoptosis and/or cell cycle arrest in MCL, and its dependence on p53 status. To investigate the response of MCL to diclofenac, wild-type p53 [Granta-519 and JVM-2] and mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines and primary human cells isolated from MCL patients were used. Cell proliferation, apopotosis, and expression of down-stream signaling p53 targets were analyzed. Nontoxic concentrations of diclofenac induced concentration- and duration-dependent inhibition of MCL cell growth independent of p53 status. Diclofenac treatment also resulted in cell cycle arrest and cell death. Molecularly, diclofenac treatment was associated with increased activity of caspases 3, 7, and 8. Increased p53 pathway activity was demonstrated by duration-dependent induction of p53 transcriptional target genes, including the cell cycle regulatory molecule p21 and pro-apoptotic molecules including, PUMA, NOXA, BIM, and CD95. Most importantly, diclofenac treatment was associated with enhanced expression of the pro-apoptotic isoforms of the p53 homologue TAp73. Our data demonstrates that diclofenac treatment results in decreased cell cycle progression, and increased apoptosis that is associated with increased p53 pathway activity, independent of p53 status, and increased activity of its family member p73.
Citation Format: Hesham M. Hassan, Michelle L. Varney, Aalia M. Aly, Shantaram S. Joshi, Rakesh K. Singh, Bhavana J. Dave. The COX inhibitor, diclofenac induces mantle cell lymphoma apoptosis independent of p53 status. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2632. doi:10.1158/1538-7445.AM2015-2632
Abstract 2636: Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer
Authors: Stahlhut Carlos E. , Watrud Kaitlin E. , Ambrico Alexandra J. , Cho Hyejin , Wang Lily , Qi Jun , Cantley Lewis C. , Bradner James , Trotman Lloyd C. 
Published: August 2015

Abstract
Metastasis is a major driver of mortality and morbidity in prostate cancer, the most common cancer type in men and the second leading cause of cancer-related deaths in the western world. To recapitulate the process in genetically engineered mice, we have developed the RapidCaP system, which uses prostate-directed viral infection to trigger focal loss of Pten and Trp53. The system provides a powerful platform for identification and validation of candidate driver genes and for efficient testing of novel therapeutics. Using this approach, we have recently identified Myc as a critical, spontaneously activated driver in Pten-negative metastatic prostate cancer. In agreement, our previous trials indicated that the Myc-suppressing Brd4 inhibitor JQ1 is ineffective towards primary disease, but causes metastatic regression. Mechanistically, this specificity correlates with the switch from Akt-driven primary to Myc-driven metastatic disease.
Intriguingly, however, advanced metastases in RapidCaP do not express the androgen receptor, in spite of being of epithelial origin as shown by the Nkx3.1 prostate marker. As a consequence, metastatic disease often shows little to no response to castration therapy and invariably results in lethal disease. Therefore, we will discuss how, when and why targeting of Myc using JQ1 and the PI 3-Kinase pathway using NVP-BKM120 are best used to treat naïve or castration-resistant metastatic disease.
Citation Format: Carlos E. Stahlhut, Kaitlin E. Watrud, Alexandra J. Ambrico, Hyejin Cho, Lily Wang, Jun Qi, Lewis C. Cantley, James Bradner, Lloyd C. Trotman. Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2636. doi:10.1158/1538-7445.AM2015-2636