bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1663: CD40 agonists drive the anti-tumor functions of macrophages and induce systemic immune activation survival the Pan02 orthotopic pancreatic model
Authors: Luheshi Nadia , Harper James , Coates-Ulrichsen Jane , Sainson Richard , Wilkinson Robert W. , Davies Gareth , Legg James William 
Published: May 2015

Abstract
Pancreatic cancer represents an area of high unmet medical need. Antibodies agonising CD40 (αCD40) inhibit tumor growth in preclinical models, and are showing activity in early clinical trials in pancreatic cancer. αCD40 antibodies can directly drive apoptosis and promote antibody-dependent cell cytotoxicity of CD40 positive tumor cells, and may also drive antitumor effects through endothelial cells and B cells. However, data from preclinical models indicate that a major mechanism of action for αCD40 antibodies is through targeting of macrophages and dendritic cells, in some cases promoting long term CD8 T cell-dependent anti-tumor immunity. Pancreatic tumors often become highly infiltrated with immunosuppressive tumor macrophages. Our aim was therefore to test the hypothesis that αCD40 inhibits pancreatic tumor growth and spread by re-educating tumor macrophages to have anti-tumor functions, promoting a Th1 anti-tumor immune response, and gaining direct tumoricidal activity. We found that CD40 activation licenses human macrophage anti-tumor functions in vitro, and that this was dependent on the presence of T cell derived cytokines. In a syngeneic orthotopic model of pancreatic cancer (Pan02), we found that αCD40 significantly improved survival. This correlated with a significant enhancement in macrophage activation and in systemic immune activation (reduction in myeloid derived suppressor cells and increase in CD8 T cells) as determined by flow cytometry analysis. These data add support to the hypothesis that αCD40 inhibits pancreatic tumor growth through promoting anti-tumor functions of tumor macrophages.
Citation Format: Nadia Luheshi, James Harper, Jane Coates-Ulrichsen, Richard Sainson, Robert W. Wilkinson, Gareth Davies, James William Legg. CD40 agonists drive the anti-tumor functions of macrophages and induce systemic immune activation survival the Pan02 orthotopic pancreatic model. [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 1663. doi:10.1158/1538-7445.AM2014-1663
Abstract 1666: Suppression of cyclooxygenase-2 by dual-specificity phosphatase-2 ameilorates cancer malignancy
Authors: Li Yo-Hua , Lin Shih-Chieh , Tsai Shaw-Jenq 
Published: May 2015

Abstract
Aberrant production of cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandin E2 (PGE2) have been demonstrated to contribute to tumor development and malignancy in many human cancers. However, the initiating factor responsible for maintaining high levels of COX-2 expression during cancer development remains enigmatic. We hypothesize that aberrant expression of COX-2 in cancer cells is initiated by hypoxia, a common phenomenon occurs in very early stage during cancer development. Herein, we present data demonstrating that levels of COX-2 in cancer cells are induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. Intriguingly, HIF-1α does not directly induce COX-2 promoter activity. In contrast, induction of COX-2 expression is mediated by HIF-1α-induced downregulation of dual specificity phosphatase-2 (DUSP-2), a MAPK-specific phosphatase. Forced expression of DUSP2 reduces the levels of COX-2, while knockdown of DUSP2 induces COX-2 expression in cancer cells. Moreover, depletion of DUSP2 also induces the expression of microsomal prostaglandin E synthase (mPGES) and consequently increases the production of PGE2. Further study reveals that re-induction of DUSP2 abolishes hypoxia-induced COX-2 expression and PGE2 production. To test the hypothesis that COX-2 mediates loss-of-DUSP2-induced tumorigenesis, a selective COX-2 inhibitor, NS-398, was used to block the function of COX-2 in the DUSP2-knockdown xenograft mouse model. Knockdown of DUSP2 markedly enhances tumor growth while treatment with NS-398 reverses loss-of-DUSP2-induced tumor development in vivo. Taken together, our data indicate that DUSP2, a negative regulator of COX-2, plays a critical tumor suppressive role and hypoxia, a common stress during cancer development, suppresses DUSP2 to initiate COX-2 overexpression and promote cancer progression. Our findings suggest that preventing DUSP2 from hypoxia-mediated downregulation or re-induction of DUSP2 during cancer development may represent a potential approach for cancer therapy.
Citation Format: Yo-Hua Li, Shih-Chieh Lin, Shaw-Jenq Tsai. Suppression of cyclooxygenase-2 by dual-specificity phosphatase-2 ameilorates cancer malignancy. [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 1666. doi:10.1158/1538-7445.AM2014-1666
Abstract 1672: Tumor educated B cells acquire immune suppressive function and promote tumor growth
Authors: Zhang Yu , Morgan Richard , Shin Seung-uon , Cho Hyun-Mi , Albayati Ahmed , Pimentel Augustin , Rosenblatt Joseph D. 
Published: May 2015

Abstract
B lymphocytes may play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are poorly understood.
Murine EMT-6 mammary tumors grow readily in wild type mice (WT) but are rejected or grow very poorly in B-cell deficient μ-/- BALB/c mice (BCDM). Relative to BCDM, B cell reconstituted BCDM demonstrate enhanced tumor growth, marked expansion of Tregs in response to EMT-6 implantation, increased infiltration of both B cells and Tregs into tumor, and a markedly reduced cytolytic T cell response. Markedly decreased levels of CD49b+ NK cell and CD8+ T cell infiltration into the tumor bed were seen in WT or in B cell reconstituted BCDM, compared to levels of infiltration seen in BCDM. Adoptive transfer of either IL-10-/- B cells or MHC-II-/- B cells into BCDM also promoted tumor growth and expansion of Treg and suppressed cytotoxic CD8+ T cell anti-tumor activity and IFN-γ production in vivo. We hypothesized that tumor infiltrating B cells promote Treg expansion but also may directly suppress T cell activation and proliferation due to acquired regulatory function.
In vitro co-culture of EMT-6 tumor cells with naïve B cells generated B cells of a distinct phenotype (PD-L1hiCD86hiIAdhiCD62LhiLAP+CD44lo but CD25-CD69-CD80-). EMT-6 co-cultured B cells markedly suppressed naïve CD4 T cell proliferation. Flow cytometric analysis of tumor infiltrating B cells (TIL-B) revealed that at day 21 post tumor implantation, TIL-B cells are LAPhiCD62LhiCD86hiIAdhiPD-L1hiCD44+CD25-. LAP/TGF-β expression on TIL-B cells was gradually upregulated as tumor burden increased, from 2∼3% on day 8 to ∼50% of infiltrating B cells by day 21. In contrast, splenic B cells at day 21 did not express LAP/TGF-β. TIL-B cells also markedly suppressed CD4+ T cell proliferation in-vitro when compared to splenic B cells.
Our studies indicate that the T cell anti-tumor response is enhanced in the absence of B cells, due to acquisition of a suppressive immmunoregulatory phenotype by migrating B cells following tumor infiltration. We are currently looking for evidence of human correlates of B regulatory activity observed in murine models.
Citation Format: Yu Zhang, Richard Morgan, Seung-uon Shin, Hyun-Mi Cho, Ahmed Albayati, Augustin Pimentel, Joseph D. Rosenblatt. Tumor educated B cells acquire immune suppressive function and promote tumor growth. [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 1672. doi:10.1158/1538-7445.AM2014-1672
Abstract 1674: Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints
Authors: Baia Gilson S. , Vasquez David , Ciznadija Daniel , Wilkinson Brandy , Sidransky David , Katz Amanda , Paz Keren 
Published: May 2015

Abstract
The blockade of immune checkpoints with monoclonal antibodies (mAbs) is a promising therapeutic avenue, with durable objective responses observed in patients with solid tumors, particularly melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma. Preclinical models that recapitulate a functional human immune system will therefore be essential tools for the continued investigation of immunotherapy approaches. Champions Oncology is engaged in advanced personalized solutions and our TumorGraft models have been developed and extensively characterized as a platform for use in personalizing cancer patient care, as well as pharmaceutical development. However, because TumorGrafts are established by engrafting patient tumors into immune-deficient mice, the therapeutic efficacy of immune-modulatory drugs cannot be directly examined. To circumvent this limitation, we reconstituted the human immune system by engrafting human hematopoietic cells (HLA-A2; CD34+) into immune-compromised mice (PrkdcscidIl2rgtm1Sug) carrying the scid mutation and a targeted mutation of the Il2r-gamma gene. Ten to twelve weeks later, mature CD45+ human T cells could be detected in these mice, at which time TumorGrafts were established, followed by drug-sensitivity testing with various mAbs targeting the immune system. Fifty six well-established melanoma, colorectal, breast and lung TumorGraft models were characterized and selected with regard to their HLA type and other molecular characteristics such as BRAF mutation status (in melanoma) and KRAS mutation status (in colorectal and lung cancer) as well as expression of PD-L1. With the present study, we demonstrated the potential of combining the humanized mouse with Champions TumorGraft to generate a preclinical platform for assessing the therapeutic value of mAbs targeting immune checkpoints in various solid tumors.
Citation Format: Gilson S. Baia, David Vasquez, Daniel Ciznadija, Brandy Wilkinson, David Sidransky, Amanda Katz, Keren Paz. Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints. [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 1674. doi:10.1158/1538-7445.AM2014-1674
Abstract 1675: Variations in the composition of inflammatory infiltrates are associated with persistence or regression of bronchial dysplasia
Authors: O'Keefe Mary C. , Dwyer-Nield Lori , Edwards Michael , Keith Robert L. , Franklin Wilbur A. , Sugita Michio , Miller York E. , Friedman Micah , Tennis Meredith , Choo Kevin S. , Hickey Gregory , Porter Jeannine , Wilson Storey , Osypuk Andrea , Weiser Mary , Bokhoven Adrie van , Geraci Mark , Nemenoff Raphael , Merrick Daniel T. 
Published: May 2015

Abstract
INTRODUCTION: The clinical course of dysplastic bronchial lesions is variable. While some regress, others progress to invasive carcinoma. We sought to identify how variations in inflammatory infiltrates might influence the clinical outcome of dysplastic bronchial lesions.
METHODS AND RESULTS: Gene expression microarray analyses identified 318 genes that distinguish persistent from regressive bronchial dysplastic lesions. Pathway analysis utilizing this genelist was performed using Ingenuity© software. Gene expression data showed several inflammation related pathways with statistically different levels of activity in persistent versus regressive lesions. Expression of genes associated with CD4 positive T-cells and HLA-DRA positive macrophages were both increased in regressive lesions. To further investigate these findings, a similar set of progressive and regressive lesions were selected for immunohistochemical (IHC) analysis. For each biopsy, IHC for T-cell markers CD3, CD4 and CD8 and macrophage marker CD68 was performed. Immunohistochemically positive inflammatory cell subsets were counted in a single high power field corresponding to the focus of maximum inflammation. For each marker, separate counts for epithelium and stroma-associated inflammation were performed. Preliminary IHC data (n=6) shows a strong trend towards increased numbers of macrophages in the dysplastic epithelium of regressive lesions (4.6 fold increase, p=0.082).
CONCLUSION: Our findings suggest that differences in inflammatory cell subsets may distinguish persistent and regressive bronchial dysplasia. Preliminary data points to CD4 positive T-cells and intraepithelial macrophages as differentiating factors that correlate with regression.
Citation Format: Mary C. O'Keefe, Lori Dwyer-Nield, Michael Edwards, Robert L. Keith, Wilbur A. Franklin, Michio Sugita, York E. Miller, Micah Friedman, Meredith Tennis, Kevin S. Choo, Gregory Hickey, Jeannine Porter, Storey Wilson, Andrea Osypuk, Mary Weiser, Adrie van Bokhoven, Mark Geraci, Raphael Nemenoff, Daniel T. Merrick. Variations in the composition of inflammatory infiltrates are associated with persistence or regression of bronchial dysplasia. [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 1675. doi:10.1158/1538-7445.AM2014-1675
Abstract 1676: The HSP90 inhibitor 17-AAG improves chemoresistance of cisplatin-resistant esophageal squamous cell carcinoma cell lines
Authors: Ui Takashi , Morishima Kazue , Saito Shin , Sakuma Yuji , Fujii Hirofumi , Hosoya Yoshinori , Yasuda Yoshikazu , Niki Toshiro 
Published: May 2015

Abstract
[Background] Although cisplatin is a platinum drug that is widely used to treat esophageal squamous cell carcinoma, acquired chemoresistance develops during the course of treatment and is often the reason for treatment failure. Overcoming chemoresistance is essential for improving the outcomes of patients. Heat shock protein 90 (HSP90) is known to be overexpressed in various cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effect of combining cisplatin with the HSP90 inhibitor, 17-N-allylamino-17-demethoxy geldanamycin (17-AAG), on two cisplatin-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150.
[Results] The results obtained demonstrated the synergistic inhibitory effects of cisplatin and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with cisplatin and 17-AAG than by the treatment with either cisplatin or 17-AAG alone. Western blotting revealed that the combined action of cisplatin and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase 3. Time lapse imaging revealed that the activations of caspase 3/7 preceded the cell death induced by the combined treatment of cisplatin and 17-AAG. These demonstrated that the reductions in both cell growth and cell number were mediated by apoptosis. Time-course experiments showed that reductions in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis.
[Discussion] The results of the present study demonstrated that 17-AAG synergized with cisplatin and induced apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect.
[Conclusion] Combination therapy with cisplatin and a HSP90 inhibitor may represent a promising strategy to overcome cisplatin resistance in esophageal squamous cell carcinoma.
Citation Format: Takashi Ui, Kazue Morishima, Shin Saito, Yuji Sakuma, Hirofumi Fujii, Yoshinori Hosoya, Yoshikazu Yasuda, Toshiro Niki. The HSP90 inhibitor 17-AAG improves chemoresistance of cisplatin-resistant esophageal squamous cell carcinoma 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 1676. doi:10.1158/1538-7445.AM2014-1676
Abstract 1679: Inhibiting KRAS-reprogrammed glutamine metabolism sensitizes pancreatic cancer to NQO1-bioactivatable drugs
Authors: Chakrabarti Gaurab , Boothman David A. 
Published: May 2015

Abstract
Patients with pancreatic cancers have one of the highest mortality rates of any cancer with 5-year survival rates of 6%. The therapeutic responses of pancreatic cancers are highly variable and there is a desperate need for agents to specifically and efficaciously treat pancreatic cancer patients. We recently discovered that not only were NAD(P)H:quinone oxidoreductase 1 (NQO1) levels elevated 5- to 40-fold in &gt;90% of pancreatic tumors vs associated normal tissue, but that catalase levels were inversely expressed comparatively, elevated in normal vs tumor tissue. NQO1 represents a unique target to exploit for the therapeutic elimination of pancreatic cancers. NQO1 bioactivatable drugs, such as β-lapachone (β-lap) or deoxynyboquinone (DNQ) and derivatives generate hydrogen peroxide as a mechanism to hyperactivate PARP1 and selectively kill tumors. In addition to catalase, reduced glutathione levels are essential for a cell's protection against hydrogen peroxide. Tumors with mutated KRAS, which constitutes &gt;90% of pancreatic cancers, are metabolically reprogrammed to rely on glutamine to maintain the cell's NADPH and glutathione levels, and therefore, anti-oxidant state (Son et.al., Nature, 2013). The present study evaluated the therapeutic potential of inhibiting this KRAS-reprogrammed metabolic pathway with the small molecule GLS1 inhibitor, BPTES, in combination with NQO1-bioactivatable drugs, β-lapachone or IB-DNQ. Synergistic cell lethality was noted using non-lethal doses of BPTES combined with sublethal doses of β-lapachone in KRAS-driven pancreatic or non-small cell lung cancer cells. ROS levels in BPTES and β-lap treated cell lines were dramatically higher than the ROS levels with either agent alone. This was further supported by a dramatic loss of glutathione and NADPH following combination treatment vs either agent alone. Lethality was completely rescued by the addition of the NQO1 inhibitor, dicoumarol, demonstrating that synergy is dependent on the NQO1 activation of β-lap. Partial rescue was seen with the addition of cell permeable glutathione further demonstrating the importance of ROS in synergy. The addition of cell permeable malate and oxaloacetate, downstream metabolites of the KRAS-driven glutamine pathway, also rescued synergy. Our findings indicate that NQO1-bioactivatable drugs may improve the sensitivities of clinical grade GLS1 inhibitors in pancreatic cancer patients.
Citation Format: Gaurab Chakrabarti, David A. Boothman. Inhibiting KRAS-reprogrammed glutamine metabolism sensitizes pancreatic cancer to NQO1-bioactivatable drugs. [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 1679. doi:10.1158/1538-7445.AM2014-1679
Abstract 1681: Iron chelation therapy increased the anticancer effect of sorafenib in hepatocarcinoma
Authors: Urano Shinichi , Ohara Toshiaki , Katsube Ryoichi , Watanabe Shinichiro , Noma Kazuhiro , Tomono Yasuko , Tazawa Hiroshi , Nouso Kazuhiro , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: May 2015

Abstract
[Purpose]
Iron overload is known to associate with the progression of chronic hepatitis and the increase risk of hepatocellular carcinoma (HCC). We have reported that iron depletion inhibited the cancer cell proliferation and reciprocally induced angiogenesis. Anti-angiogenic drug synergistically enhanced the anti-tumor effect in iron depletion condition. Sorafenib is molecular-targeting drug with anti-angiogenic effect in HCC. We hypothesized that iron depletion also enhanced the effect of sorafenib and investigated it.
[Experimental Design]
HepG2 and HLE (Human HCC cell line) were used in this study. We used sorafenib (NexavarTM) and an oral iron chilator, deferasirox (EXJADETM). The anti-cancer effect and mechanism were determined using cell viability assay, VEGF ELISA, Flow Cytometry, Western blot analysis and in vivo subcutaneous tumor model. In clinical cases, we retrospectively analyzed the relationship between sorafenib response and serum iron-related makers(n=58).
[Results]
In HepG2 and HLE cells, deferasirox suppressed the cancer cell proliferation by itself and increased the suppression of sorafenib. Deferasirox increased VEGF secretion of supernatant on dose dependent manner. In the analysis of combination therapy, cell cycle arrest and apoptosis was enhanced in the combination therapy by down-regulation of cyclinD1 and cyclinE and up-regulation of cleaved PARP. The suppression of HepG2 subcutaneous tumor was enhanced in the combination therapy. In clinical cases, sorafenib prolonged overall survival in TIBC high and Ferritin low group.
[Conclusion]
Iron depletion by deferasirox increased the anti-cancer effect of sorafenib in vitro and in vivo experiments. In clinical cases, sorafenib was also effective in iron deficient patients. These results suggested that iron depletion therapy can be a novel combination chemotherapy with sorafenib for hepatocarcinoma patients.
Citation Format: Shinichi Urano, Toshiaki Ohara, Ryoichi Katsube, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Kazuhiro Nouso, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron chelation therapy increased the anticancer effect of sorafenib in hepatocarcinoma. [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 1681. doi:10.1158/1538-7445.AM2014-1681
Abstract 1682: Metformin synergistically enhances antitumor efficacy of sorafenib in vitro
Authors: KO YUNMI , Choi Bo Ra , Lee Jun Ah 
Published: May 2015

Abstract
Background: Previously, we observed anti-tumor effect of sorafenib in osteosarcoma cells. However, a number of studies suggested that cancer cells might escape from the therapeutic effects of sorafenib though activation of mTOR pathways. Metformin displays significant growth inhibitory effects in several cancer cells by modulating AMPK/Akt/mTOR signaling pathway. We evaluated the effect of metformin in osteosarcoma cells as a single agent, as well as in combination with sorafenib.
Methods: The effects of metformin on proliferation, migration and apoptosis of osteosarcoma cells were evaluated using MTT, wound-healing and FACS analysis. To elucidate the mechanisms of cell growth inhibition induced by metformin, we investigated expression of several key signaling proteins in OS cells. The synergistic interactions of metformin and sorafenib were determined by calcusyn analysis.
Results: We found that metformin significantly decreased the cell survival, wound-healing capacity of OS cells. Metformin also markedly activated AMPK and decreased the expression of Akt, ERK1/2, mTOR and its downstream target markers. And we observed that addition of sorafenib enhanced antiproliferative and proapoptotic effects of metformin by synergistic modulation of AMPK/Akt/mTOR signaling pathway.
Conclusion: We found that metformin exerts therapeutic potentials in OS cells. Currently, studies are underway to evaluate the possibilities of using metformin as an adjuvant therapeutic agent for osteosarcoma, in combination with chemotherapeutic agents or radiotherapy.
Citation Format: YUNMI KO, Bo Ra Choi, Jun Ah Lee. Metformin synergistically enhances antitumor efficacy of sorafenib in vitro. [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 1682. doi:10.1158/1538-7445.AM2014-1682