tbuckley/cabot-search huggingface dataset:
Abstract 4074: Macrophages promote the progression of premalignant mammary gland lesions through activation of the Axl signaling cascade
Authors: Emily C. Carron, Heather L. Machado, Samuel Homra
Journal: Cancer Research (2016)

Abstract Infiltrating inflammatory cells, including tumor-associated macrophages (TAMs), have been shown to promote breast cancer cell invasion and have been correlated with metastasis and poor prognosis. While it is well-established that macrophages are recruited to the invasive fronts of established tumors to exert pro-tumor signals, their role in premalignancy remains poorly understood. Using a novel p53−/− syngeneic transplantable model of premalignancy, we show that inflammatory cells, including macrophages, are indeed recruited to early lesions prior to invasion. Microarray analysis was performed on two different pre-invasive lines, termed PN1a, (high tumor-forming potential) and PN1b (low tumor-forming potential). Interestingly, several pro-inflammatory chemokines, macrophages markers, and the pro-inflammatory cytokine growth arrest specific 6 (Gas6) were increased in PN1a lesions as compared to PN1bs. In a 3-D co-culture system, macrophages were recruited to PN1a acini and induced invasion, while PN1b cells remained non-invasive, supporting our in vivo data. Depletion of macrophages in vivo with clodronate containing liposomes significantly delayed progression of PN1a lesions to invasive cancer, indicating a critical role for macrophages in early progression. Gas6 and its receptor tyrosine kinase, Axl, were highly expressed in PN1a preinvasive lesions, but decline in invasive tumors, suggesting that this pathway is a key driver of the transition from pre-invasive to invasive cancer. Further studies using our 3-D co-culture system with Gas6−/− macrophages demonstrated that macrophages promote the formation of non-polar disorganized structures by activating Axl. Finally, transplantation of PN1a cells into Gas6 +/− mice resulted in a delay in tumor formation, indicating that stromal-derived Gas6 (and potentially macrophage derived) may promote the progression of early stage lesions through the paracrine activation of Axl. As a plethora of Axl inhibitors have been developed and are currently in clinical trial, these studies have critical implications for the prevention and treatment of invasive breast cancer. Citation Format: Emily C. Carron, Heather L. Machado, Samuel Homra. Macrophages promote the progression of premalignant mammary gland lesions through activation of the Axl signaling cascade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4074.
Abstract 1508: Integration of transcriptomic and metabolomic data reveals a central role for EGR1 in regulating survival and cellular metabolism in endocrine-resistant breast cancer
Authors: Ayesha N. Shajahan-Haq, Amrita Cheema, Lu Jin, Simina Boca, Yuriy Gusev, Krithika Bhuvaneshwar, Diane Demas, Kristopher Raghavan, Subha Madhavan, Robert Clarke
Journal: Cancer Research (2016)

Abstract Breast cancer is the most commonly diagnosed cancer in women. About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and are treated with antiestrogens. However, endocrine resistance is prevalent in the clinic and the underlying mechanisms remain unclear. MYC is overexpressed in endocrine resistant ER+ breast cancers, which suggests that the metabolomic profile of endocrine resistant breast cancers may contain features that are distinct from sensitive cells. We integrated data from transcriptomics and metabolomics analysis of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or resistant (LCC9; resistant to ICI182,780). To validate our model, we tested a gene-metabolite network associated with EGR1 (early growth response 1), which was significantly higher in LCC1 cells compared with LCC9 cells. In ER+ human breast tumors treated with endocrine therapy, higher EGR1 expression was associated with a more favorable prognosis. In both LCC1 and LCC9 cell lines, compared to respective controls, knockdown of EGR1 decreased cell proliferation, ERα and MYC protein levels while overexpression of EGR1 did not change these. Comparison of metabolite profiles in LCC9 cells following knockdown or overexpression of EGR1 showed interruption of several biochemical pathways such as glycolysis, lipid metabolism, glutathione, and polyamine metabolism. Treatment with tolfenamic acid (TOL), a nonsteroidal anti-inflammatory drug (NSAID) known to target EGR1, decreased EGR1 protein levels and had an additive effect with ICI182,780 in inhibiting cell proliferation in LCC9 cells. Collectively, these findings indicate that down-regulated EGR1 is an important regulator of the aberrant cellular metabolic pathways specific to endocrine resistance, and targeting EGR1 may be an effective therapeutic approach in inhibiting growth of these tumors. Furthermore, high levels of EGR1 may serve as a favorable prognostic marker in some endocrine resistant tumors. Citation Format: Ayesha N. Shajahan-Haq, Amrita Cheema, Lu Jin, Simina Boca, Yuriy Gusev, Krithika Bhuvaneshwar, Diane Demas, Kristopher Raghavan, Subha Madhavan, Robert Clarke. Integration of transcriptomic and metabolomic data reveals a central role for EGR1 in regulating survival and cellular metabolism in endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1508.
Immune Characteristics Associated with Lymphomatoid Granulomatosis and Outcome Following Treatment with Interferon-Alpha
Authors: Kieron Dunleavy, Pratip Chattopadhyay, Junichi Kawada, Sara Calattini, Emma Gostick, David Price, Mario Roderer, Jeffrey Cohen, Nicole Grant, Stefania Pittaluga, John E Janik, Elaine S Jaffe, Wyndham H. Wilson
Journal: Blood (2010)
Abstract 060: CCN1/a <sub>6</sub> β <sub>1</sub> Mediates Myocardial Injuries Induced by Work Overload or by Doxorubicin in Mice
Authors: Pei-Ling I Hsu, Fan-E Mo
Journal: Circulation Research (2013)

Introduction: Matricellular protein CCN1 is expressed in myocardial infarction, pressure overload, and ischemia in mice, and in patients with a failing heart. Despite its well-documented angiogenic activities, CCN1 promotes fibroblast apoptosis in some contexts. The role of CCN1 in an injured heart was not clear. We assessed the hypothesis that CCN1 plays a detrimental role and mediates cardiac injury through its proapoptotic activities. Methods and Results: To test the role of CCN1 in cardiac injury, we employed two different myocardial injury models in mice, including a work-overload-induced injury created by isoproterenol treatment (ISO; 100 mg/kg/day; s.c. for 5 days; n= 6 for each group) and an injury induced by the cardiotoxicity of doxorubicin (DOX, single dose of 15 mg/kg; i.p. sacrificed after 14 days). Ccn1 expression was induced in the damaged myocardium in both injury models. A line of knock-in mice carrying an apoptosis-defective Ccn1 mutant allele, Ccn1-dm , which has disrupted integrin α 6 β 1 binding sites, were tested in the ISO- or DOX -induced cardiac injury. Myocardial damage was seen in tissues from wile-type (WT) hearts after receiving ISO. Ccn1 dm/dm (DM) mice possessed remarkable resistance against ISO or DOX treatments and exhibited no tissue damage or fibrosis compared to WT mice after H&amp;E or Masson’s trichrome stainings. DM mice were resistant to both ISO- and DOX-induced cardiac cell apoptosis, indicating that CCN1 is critically mediating cardiomyocyte apoptotic death in cardiac injury. Moreover, we found that death factor Fas ligand (FasL) and its receptor Fas were upregulated in WT mice receiving ISO or DOX treatments by immunohistochemical staining, compared with the PBS-control. 8-OHdG-positive, a marker for oxidative stress, cardiomyocytes were increased by ISO or DOX treatments as well. In contrast, the expression of Fas/FasL, and the 8-OHdG-positive cardiomyocytes in the myocardium of DM mice were not changed by ISO or DOX. Conclusions: We identify CCN1 as a novel pathophysiological regulator of cardiomyocyte apoptosis in cardiac injury. Blocking apoptotic function of CCN1 effectively prevents myocardial injury in mice. CCN1 and its receptor α 6 β 1 represent promising future therapeutic targets in cardiac injury.
Abstract 2089: Therapeutic index prediction of the agonistic aglycosylated TWEAK receptor binding antibody BAY-356
Authors: Anders Viberg, Eva Hanze, Lisa Dietz, Ruprecht Zierz, Sandra Berndt, Sabine Wittemer-Rump
Journal: Cancer Research (2016)

Abstract BAY-356 is a novel aglycosylated anti-TWEAK receptor antibody with potent agonistic activity evaluated for cancer therapy. In order to predict an efficacious therapeutic dose of BAY-356 in man, we sought to determine a therapeutic index where the exposure related to therapeutic efficacy was compared with the exposure obtained following doses tested in toxicology studies. BAY-356 (1 mg/kg) was administered intravenously to healthy Cynomolgus monkeys and plasma concentrations measured in order to determine pharmacokinetic (PK) parameters. Using allometric scaling, the PK in humans was predicted. Efficacy data of BAY-356 in WiDr, HN10321, A253 and SCaBER xenograft models representing colorectal, head and neck squamous cell carcinoma and bladder cancer, were used to derive exposure-response models for each tumor model where the plasma exposure of BAY-356 is assumed to have an effect on the tumor size in a tumor growth model. NONMEM 7.3 was used in the estimations. The tolerability of BAY-356 was tested in monkeys at doses of 10, 20 and 40 mg/kg by weekly intravenous injections over 4 weeks. Treatment resulted in slight to moderate toxicity in liver, kidneys and pancreas and 10 mg/kg was set to be an exposure dose well tolerated and not to be exceeded by therapeutic exposure. A dosing strategy in humans predicted to result in the same exposure as 10 mg/kg weekly in monkey is 18 mg/kg every third weeks (Q3W). Using the estimated exposure-response in xenograft models, human tumor doubling times of 8 weeks (A253 and HN10321), 24 weeks (WiDr) and 12 and 24 weeks (SCaBER) in combination with human predicted PK parameters, tumor reduction over time in humans was predicted based on a human dosing strategy of 18 mg/kg BAY-356 Q3W. For the A253 tumor model, stable disease in humans was predicted while the results from HN10321 and SCaBER models predicted a 13-60% decrease in tumor size in humans following 12 weeks treatment. For WiDr, this dosing strategy was predicted to not be efficacious in humans. The results based on modelling of xenograft data indicate that 18 mg/kg BAY-356 dosed Q3W is predicted to be efficacious in humans for certain tumor cells. Citation Format: Anders Viberg, Eva Hanze, Lisa Dietz, Ruprecht Zierz, Sandra Berndt, Sabine Wittemer-Rump. Therapeutic index prediction of the agonistic aglycosylated TWEAK receptor binding antibody BAY-356. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2089.
Abstract 2359: A-337, a potent bispecific antibody targeting EpCAM×CD3, as a potential immunotherapeutic agent for human solid tumors
Authors: Yumin Cui, Zhihua Huang, Hanyang Chen, Xinfeng Zhang, Bo Qi, Heng Liu, Xiaoqiang Yan
Journal: Cancer Research (2016)

Abstract T cell bi-specific antibodies are potent molecules by binding and re-directing T cells to tumor cells through tumor associate antigens (TAAs), and triggering strong T cell activation and resulting in the killing of tumor cells. Bi-specific T cell engager antibody (BITE®) has demonstrated a remarkable clinical efficacy in liquid tumor. It remains to be a tremendous challenge for the development these types of bi-specific antibodies due to the induction of cytokine storm, thus limiting the dose-escalation in patients. A new immunotherapy antibody platform, (ITab TM), was developed to generate bi-specific antibody-like molecules. The molecules target TAA and activate human CD3 T cells simultaneously. A-337 is a bi-specific antibody targeting on EpCAM (Epithelial cell adhesion molecule) on tumor cells and CD3 in human T cells. In vitro, A-337 demonstrated high potency on activating human T cell measured by CD69 expression, and killing of EpCAM highly expressing tumor cell lines with EC50 values at &amp;lt; 100 pM in the presence of human peripheral blood mononuclear cells (PBMC). The human PBMC dependent cell killing activity of A-337 was correlated to the expression levels of EpCAM on the surface of tumor cell lines. In the mouse model, A-337 showed dose-dependent growth inhibition of SW480 xenograft. In cynomolgus monkey studies, A-337 by single IV infusion induced peripheral T cell re-distribution or activation and cytokine release and showed favorable pharmacokinetics features. The current studies reveal that A-337 has potent anti-tumor activities in vitro and in vivo. These results demonstrate that A-337 is a promising and potent immunotherapeutic agent to treat EpCAM-expressing solid tumors and warrants further development. Citation Format: Yumin Cui, Zhihua Huang, Hanyang Chen, Xinfeng Zhang, Bo Qi, Heng Liu, Xiaoqiang Yan. A-337, a potent bispecific antibody targeting EpCAM×CD3, as a potential immunotherapeutic agent for human solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2359.
Abstract 4565: Antizyme inhibitor regulates the expression of proteins involved in mitosis and affects prostate cancer cell growth
Authors: James M. Rice, Amanda Kusztos, Bruce R. Zetter
Journal: Cancer Research (2016)

Abstract Upregulation of polyamine biosynthesis is a requirement for cell growth and proliferation. Increases in polyamine levels are mediated by the enzyme ornithine decarboxylase (ODC), which is inhibited by antizyme (AZ). Rescue of ODC activity is accomplished by expression of antizyme inhibitor (AZI), which prevents binding of AZ to ODC. Increases in AZI gene copy number, mRNA transcripts, protein expression and AZI nuclear localization are all associated with prostate cancer. Furthermore, knockdown of AZI expression prevents prostate cancer cell growth in vitro and in vivo. To determine if AZI regulation affects prostate cancer cell growth via mechanisms that are independent of polyamide levels, we conducted a proteomic analysis of the AZI interactome by co-IP and MS/MS. This resulted in the identification of 29 high-confidence interacting proteins (HCIPs), 10 of which are associated with microtubules or with the mitotic spindle including TPX2 and KIFC1. Constitutive overexpression of AZI in PC3M-LN4 prostate cancer cells leads to a decrease in expression of the microtubule associated protein KIFC1, further supporting an interaction between AZI and KIFC1. Silencing of AZI gene expression using siRNA nanoparticles results in a decrease in prostate cancer cell proliferation and altered expression of proteins involved in mitosis. Taken together, this data suggests that AZI may influence prostate cancer cell proliferation via mechanisms that are independent of polyamine regulation. Citation Format: James M. Rice, Amanda Kusztos, Bruce R. Zetter. Antizyme inhibitor regulates the expression of proteins involved in mitosis and affects prostate cancer cell growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4565.
Reprogramming Müller glia via in vivo cell fusion regenerates murine photoreceptors
Authors: Daniela Sanges, Giacoma Simonte, Umberto Di Vicino, Neus Romo, Isabel Pinilla, Marta Nicolás, Maria Pia Cosma
Journal: Journal of Clinical Investigation (2016)

Vision impairments and blindness caused by retinitis pigmentosa result from severe neurodegeneration that leads to a loss of photoreceptors, the specialized light-sensitive neurons that enable vision. Although the mammalian nervous system is unable to replace neurons lost due to degeneration, therapeutic approaches to reprogram resident glial cells to replace retinal neurons have been proposed. Here, we demonstrate that retinal Müller glia can be reprogrammed in vivo into retinal precursors that then differentiate into photoreceptors. We transplanted hematopoietic stem and progenitor cells (HSPCs) into retinas affected by photoreceptor degeneration and observed spontaneous cell fusion events between Müller glia and the transplanted cells. Activation of Wnt signaling in the transplanted HSPCs enhanced survival and proliferation of Müller-HSPC hybrids as well as their reprogramming into intermediate photoreceptor precursors. This suggests that Wnt signaling drives the reprogrammed cells toward a photoreceptor progenitor fate. Finally, Müller-HSPC hybrids differentiated into photoreceptors. Transplantation of HSPCs with activated Wnt functionally rescued the retinal degeneration phenotype in rd10 mice, a model for inherited retinitis pigmentosa. Together, these results suggest that photoreceptors can be generated by reprogramming Müller glia and that this approach may have potential as a strategy for reversing retinal degeneration.
Abstract 255: Docetaxel inhibits testosterone mediated activation of the AR pathway by SLCO1B3
Authors: Ellen S. de Morree, Ashraf Aghai, Alice A. Gibson, Ron H.J. Mathijssen, Eric A.C. Wiemer, Alex Sparreboom, Wytske M. van Weerden, Ronald de Wit
Journal: Cancer Research (2016)

Abstract Background Docetaxel is the first line of chemotherapy in metastatic castration resistant prostate cancer (mCRPC) patients. More than 50% of prostate cancer tumors express the solute carrier organic anion transporter family member 1B3 (SLCO1B3/OATP1B3), an uptake transporter that actively transports docetaxel into the cell. Interestingly, SLCO1B3 is also a transporter of endogenous substrates, such as testosterone. As the androgen receptor (AR) pathway is still active in mCRPC patients, we hypothesize that docetaxel can interact with the uptake of testosterone through SLCO1B3, which would result in decreased AR-pathway activation and subsequent tumor growth inhibition. Materials and Methods SLCO1B3 overexpressing cells (CHO-1B3) were used for uptake experiments with radioactively labeled hormones, such as estradiol-β-glucuronide (E2G). We stably transfected prostate cancers cells (PC346C-DCC and PC346C-DCC-G) with SLCO1B3 or with a green fluorescent protein (GFP) tag only. An androgen responsive element (ARE)-luciferase assay was created as a sensitive measure of AR pathway activation. ARE-activity and prostate specific antigen (PSA) production were analyzed with an ELISA assay after exposure to 1nM testosterone for 30 minutes with or without preincubation with docetaxel 10 μM in SLCO1B3 overexpressing and GFP- tagged control cells. Results SLCO1B3 overexpressing cells showed testosterone-mediated activation of the AR pathway: ARE-activity increased 6.4-fold and PSA production 7-fold in SLCO1B3-overexpressing cells as compared to control cells. Pre-incubation of CHO-1B3 cells with docetaxel resulted in reduced uptake of E2G to the level observed in control cells. Similarly, after exposure to testosterone and docetaxel ARE-activity was significantly decreased in SLCO1B3-overexpressing cells compared to that of controls. Conclusion: Docetaxel inhibits the activation of the AR pathway via SLCO1B3. This is a novel anti-androgenic effect exerted by docetaxel in addition to inhibition of the AR translocation that we demonstrated previously. Experiments are ongoing to investigate if testosterone uptake via SLCO1B3 is inhibited by docetaxel. Citation Format: Ellen S. de Morree, Ashraf Aghai, Alice A. Gibson, Ron H.J. Mathijssen, Eric A.C. Wiemer, Alex Sparreboom, Wytske M. van Weerden, Ronald de Wit. Docetaxel inhibits testosterone mediated activation of the AR pathway by SLCO1B3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 255.
Abstract LB-245: Preclinical study of epigenetic drug-based differentiation therapy for neuroblastoma
Authors: Naoko Hattori, Akiko Mori, Kana Kimura, Emi Kubo, Kiyoshi Asada, Hiroshi Kawamoto, Toshikazu Ushijima
Journal: Cancer Research (2016)

Abstract Neuroblastoma (NBL) is the most common extracranial solid tumor in children. We previously reported that the CpG island methylator phenotype (CIMP) of NBL was strongly associated with poor prognosis, and also suggested that CIMP may be a possible target for DNA demethylation therapy. Differentiation therapy with 13-cis-retinoic acid has already been established as the standard for high-risk NBLs in the USA. In this study, we aimed to establish an “epigenetic drug-based differentiation therapy” using a combination of a DNA demethylating agent (5-aza-2’-deoxycytidine: 5-Aza-CdR) and a differentiation agent (tamibarotene: TBT), a new synthetic retinoid. Treatment with 5-Aza-CdR suppressed the growth of 12 NBL cell lines by increasing the number of cells in the S-phase. Genome-wide DNA methylation analysis revealed that 5-Aza-CdR treatment induced global DNA hypomethylation, and that genes related to cell death and neurological processes were enriched as hypomethylated genes, suggesting that DNA demethylation therapy might assist the differentiation agent in inducing neuron differentiation. TBT induced differentiation of five NBL cell lines along with induction of neural extension and upregulation of differentiation markers, such as HOXD4, NGFR, and NTRK1. Pretreatment with 5-Aza-CdR increased the expression levels of differentiation markers, indicating that 5-Aza-CdR enhanced TBT-induced differentiation in vitro. Finally, the tumor suppression effect of 5-Aza-CdR and TBT in vivo was investigated using a mouse xenograft model of KELLY and NB-1 cell lines. Although a synergistic effect of 5-Aza-CdR and TBT was not apparent, they could induce significant tumor regression without severe side-effects. From these data, we concluded that 5-Aza-CdR and TBT had antitumor activity in vitro and in vivo, and that epigenetic drug-based differentiation therapy is a promising therapeutic strategy for NBL. Citation Format: Naoko Hattori, Akiko Mori, Kana Kimura, Emi Kubo, Kiyoshi Asada, Hiroshi Kawamoto, Toshikazu Ushijima. Preclinical study of epigenetic drug-based differentiation therapy for neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-245.
Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction
Authors: Qingjie Wang, Hui Yang, Aobing Bai, Wei Jiang, Xiuya Li, Xinhong Wang, Yishen Mao, Chao Lu, Ruizhe Qian, Feng Guo, Tianling Ding, Haiyan Chen, Sifeng Chen, Jianyi Zhang, Chen Liu, Ning Sun
Journal: Biomaterials (2016)