bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4910: Eribulin rapidly impairs TGF-β signaling
Authors: Kaul Roma , Risinger April L. , Mooberry Susan L. 
Published: July 2017

Abstract
Microtubule targeting agents (MTAs) continue to be valuable in treating breast cancer. While decades of research have shown that these drugs cause mitotic arrest in cells by suppressing the dynamic instability of microtubules, recent evidence demonstrates that the ability of MTAs to disrupt the microtubule-dependent transport of key signaling components in interphase cells likely contributes to their anticancer actions. Cell signaling messages are relayed by proteins that organize or scaffold signaling hubs. These signaling nodes facilitate the complex organization and coordination of multiple signaling partners. NEDD9 is a member of the CAS scaffold family and it has been shown to coordinate TGF-β signaling, a driver of oncogenesis and epithelial-to-mesenchymal transition (EMT). Ligand-mediated stimulation of TGF-β receptors leads to the activation of downstream canonical and non-canonical signaling pathways. These pathways collectively induce the expression of Snail and Slug, key transcriptional-repressors that promote EMT. We tested the hypothesis that a short-term treatment of breast cancer cells with eribulin or 3 other clinically relevant MTAs would differentially disrupt interphase microtubules and alter TGF-β-dependent signaling. BT-549 cells were treated for 2 h with concentrations of MTAs that are clinically relevant and cause maximum disruption of the interphase microtubule network; 100 nM was used for the destabilizers, eribulin and vinorelbine and 1 µM was used for the stabilizers, paclitaxel and ixabepilone. The results showed that eribulin and vinorelbine significantly inhibited TGF-β- induced expression of Snail and Slug. The microtubule stabilizers had no effect on Snail and Slug expression following TGF-β stimulation. Further studies evaluated whether NEDD9 contributes to the downregulation of Snail and Slug. Co-immunoprecipitation and knockdown studies suggest that eribulin impairs the ability of NEDD9 to scaffold TGF-β signaling partners, thus inhibiting downstream transcriptional signaling. Consistent with the ability of eribulin to reverse EMT in experimental models within 7 days, this study begins to shed light on the mechanisms underlying its action. Funding for this work was provided by Eisai Inc.
Citation Format: Roma Kaul, April L. Risinger, Susan L. Mooberry. Eribulin rapidly impairs TGF-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4910. doi:10.1158/1538-7445.AM2017-4910
Abstract 4912: Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases
Authors: Rubin Ayelen , Fuente Veronica de la , Salvatierra Edgardo , Vanzulli Silvia , Podhajcer Osvaldo , Lanari Claudia , Rojas Paola 
Published: July 2017

Abstract
The treatment of brain metastasis is limited due to the drug’s inability to cross the blood brain barrier, because of the presence of endothelial cells’ multidrug resistance efflux transporters, such as the P-glycoprotein (P-gp). The antiprogestin Mifepristone (MFP) is known to inhibit the P-gp activity. We hypothesize that a combination of MFP and Pegylated doxorubicin liposomes (doxo) improves the drug efficacy on breast tumors that do not express progesterone receptors. Using the metastatic triple negative MDA-231-BrM2 breast cancer cell line, transfected with GFP and luciferase, we explored different protocols to generate tumors growing in the brain of NSG mice. Spontaneous metastases were obtained by subcutaneous injection (sc) of 2 x 106 cells, and experimental metastases by intracardiac injection (ic) of 1 x 106 cells or by intracranial injection of 2 x 105 cells. In the ic and sc models small and scattered brain metastases as well as liver, lung and kidney metastases were observed. The intracranial model enabled us to obtain measurable brain tumors in a short time. Thus we selected this method to evaluate the effect of MFP (6 mg pellets, sc) and /or doxo (4,5 mg/kg, iv) on tumors growing in the brain. Treatment was initiated 10 days after cell inoculation. The amount of tumor cells after brain excision was measured by flow cytometry (GFP) and by luminometry (luciferase activity). A decreased luminescence signal was observed in brains from mice treated with both agents as compared with the control mice (p&lt;0.05), whereas no effects were observed between the single treatment groups and the controls. Moreover, the flow cytometry analysis showed that the combined treatment, MFP+doxo, reduced the number of tumor cells further than the single chemotherapeutic agent (p&lt;0.05). Our data suggest that MFP may be a promising agent to treat brain metastasis of breast cancers, which do not necessarily express progesterone receptors, to increase the effectiveness of chemotherapeutic agents. The participation of the P-gp mediating this effect needs to be confirmed.
Citation Format: Ayelen Rubin, Veronica de la Fuente, Edgardo Salvatierra, Silvia Vanzulli, Osvaldo Podhajcer, Claudia Lanari, Paola Rojas. Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4912. doi:10.1158/1538-7445.AM2017-4912
Abstract 4917: Therapeutic inhibition of Notch1 in metastatic prostate cancer
Authors: Rice Meghan A. , Hsu En-Chi , Stoyanova Tanya 
Published: July 2017

Abstract
Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer specific mortality, and is currently incurable. Defining new mechanisms that can predict progression and drive lethal CRPC is critical. Notch1 receptor, a cell surface-signaling molecule dysregulated in many cancers, is highly expressed in CRPC. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of poorly differentiated prostate carcinoma. Consistent with its activation in clinical CRPC, tumors driven by NICD1 in combination with alternative pathways altered in prostate cancer are metastatic and resistant to androgen deprivation.
Genetic and pharmacological inhibition of Notch1 activity decreases cell proliferation and colony formation of 22RV1 prostate cancer cells in vitro. 22RV1 subcutaneous xenograft growth was significantly impaired by treatment with pharmacological inhibitors of Notch1 activation over the course of 20-day treatment. Further, Notch1 inhibition in combination with other standard prostate cancer treatments compounded efficacy of individual treatments to attenuate colony formation potential of prostate cancer cells in vitro.
The Notch1 signaling axis, confirmed to synergize with multiple pathways to promote metastatic CRPC already provides a novel pathway for diagnostic stratification of prostate cancer patients. Our studies additionally implicate Notch1 as a therapeutically relevant target for aggressive prostate cancer.
Citation Format: Meghan A. Rice, En-Chi Hsu, Tanya Stoyanova. Therapeutic inhibition of Notch1 in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2017-4917
Abstract 4929: Cooperation between the microbiota and oncogenic mutations leading to the development of colon cancer
Authors: Hey Dana Van De , Payne Susan , Pasch Cheri , Clipson Linda , Matkowskyj Kristina , Deming Dustin 
Published: July 2017

Abstract
Background: The microbiome of the colon has been shown to play a role in colon cancer tumorigenesis. Inflammation is a key step in the formation of tumors, and it is possible that microbiota induce this inflammation, further stimulating tumor growth. The interaction between mutant cells in the colon and the microbiota has been understudied. We hypothesized that eradication of the intestinal microbiota could prevent tumorigenesis in the colon despite the presence of oncogeneic mutations.
Methods: We have previously generated a transgenic murine model in which a constitutively active PI3K is expressed in the distal small intestine and colon (FC3K). These mice develop aggressive cancers in the proximal colon via a non-canonical mechanism without loss of APC. In addition, we developed a murine model possessing both PIK3CA mutations and loss of APC (FCAK3K). These mice were treated with vancomycin in their drinking water. Necropsy was performed at specific time-points or at moribund to determine tumor counts and size. Spheroid cultures were also utilized to determine the potential for cytotoxic effects of vancomycin treatment.
Results: Treatment with vancomycin in FC3K mice at weaning resulted in a reduction in tumor incidence and growth and prolonged survival, indicated by a 42% tumor frequency and median lifespan of 101 days, compared to 100% frequency and 86.5-day lifespan of control mice (p&lt;0.001). In the tumors that formed there was no difference in the epithelial mesenchymal transition (EMT), Ki67 index, nuclear localization of CTNNB1, or activation of the PI3K/AKT/mTOR signaling pathway. FCAK3K spheroid and mouse models portrayed ineffectiveness of vancomycin through an absent change in spheroid diameter and also 100% frequency of both treated and control mice.
Conclusion: The above results indicate that colon cancers induced by PIK3CA mutations are at least partially dependent on the microbiota for tumorigenesis. This dependence appears to be overcome in the setting of both APC and PIK3CA mutations.
Citation Format: Dana Van De Hey, Susan Payne, Cheri Pasch, Linda Clipson, Kristina Matkowskyj, Dustin Deming. Cooperation between the microbiota and oncogenic mutations leading to the development of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4929. doi:10.1158/1538-7445.AM2017-4929
Abstract 4934: Brain metastatic microenvironment reshapes cancer cell metabolism through epigenetic up-regulation of glutamate decarboxylase 1
Authors: Schnepp Patricia M. , Lee Dennis D. , Guldner Ian H. , O'Tighearnaigh Treasa , Palakurthi Bhavana , Eckert Kaitlyn E. , Toni Tiffany A. , Ashfeld Brandon L. , Zhang Siyuan 
Published: July 2017

Abstract
Cancer metabolism has been well documented to influence primary tumor development. Yet, the role of deregulated metabolism in metastasis progression is not well understood. Based on a distinct metabolic transcriptome profile in brain metastases compared to their primary tumor counterparts, we hypothesized that metabolic transcriptome shifting during metastatic evolution is crucial for metastatic success to the brain. Here we show that, despite a global down-regulation of multiple metabolic pathways in the brain metastatic tumors, the expression of the GABA metabolic pathway mediator glutamate decarboxylase 1 (GAD1) is significantly up-regulated. Using cell based co-culture models for different primary and brain metastatic microenvironments and in vivo brain metastasis models, we demonstrate that down-regulation of DNA methyltransferase 1 (DNMT1) induced by the brain microenvironment results in decreased GAD1 promoter methylation and subsequent up-regulation of GAD1 expression in tumor cells. To dynamically visualize the cellular metabolic responses mediated by GAD1, we utilized the Peredox biosensor to monitor the cytosolic NADH:NAD+ equilibrium in tumor cells using time-lapse imaging. By knocking down of GAD1 induced by primary glia cell co-culture, we abolished the capability of tumor cells to utilize extracellular glutamine, leading to an NADH accumulation in the cytosol and a more oxidative cellular status. Lastly, either loss of GAD1 genetically or targeting GABA metabolic pathway by the repurposing of a neurological drug, vigabatrin, results in a significant decrease in brain metastasis incidence. Taken together, our results demonstrated that brain microenvironment-specific metabolic shifting through GAD1 promoter de-methylation drives brain metastasis outgrowth.
Citation Format: Patricia M. Schnepp, Dennis D. Lee, Ian H. Guldner, Treasa O'Tighearnaigh, Bhavana Palakurthi, Kaitlyn E. Eckert, Tiffany A. Toni, Brandon L. Ashfeld, Siyuan Zhang. Brain metastatic microenvironment reshapes cancer cell metabolism through epigenetic up-regulation of glutamate decarboxylase 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4934. doi:10.1158/1538-7445.AM2017-4934
Abstract 4946: Host tissue stiffness regulates chemotherapy-induced cancer cell dormancy
Authors: Anlas Alisya , Nelson Celeste M. 
Published: July 2017

Abstract
This study investigates how the tumor microenvironment, namely host tissue stiffness, affects the propensity of disseminated tumor cells to become dormant at secondary sites.
Approximately 90% of cancer-related deaths result from metastasis. In breast cancer, disseminated cancer cells cannot be detected at the time of diagnosis of the primary tumor because they form “dormant” micrometastases that are not clinically detectable. Thus, metastases in secondary sites such as the lungs, bone marrow, liver and brain are
usually discovered months or years after the initial diagnosis and/or treatment of the primary tumor.
A 2D polyacrylamide gel-based tissue culture model was used to investigate the effects of host tissue stiffness on the proliferative behavior of breast cancer cells. To assess the dormant phenotype, Ki67 and RNA staining were used to quantify proliferation and RNA
content, respectively. Additionally, changes in levels of cell-cycle regulators were determined by quantitative RT-PCR. Dormant cells have decreased levels of transcription and proliferation.
We found that both tamoxifen and 5-fluorouracil induce dormancy in estrogen receptor-positive breast cancer cells cultured on soft and stiff substrata. After repeated rounds of 5-fluorouracil treatment and recovery, cells cultured on soft substratum, mechanical properties of which represent common metastatic sites, had a higher tendency to recover.
This suggests that cell growth at secondary sites favors a soft microenvironment, characteristic of organs where breast cancer metastases often become clinically overt. Dormant cancer cells, or minimal residual disease, cannot be detected with current
diagnostic tools and cannot be targeted by conventional therapies. Therefore, current clinical practices rely on estimating the probability of recurrence from various prognostic factors including the grade and the stage of the disease. Elucidating the mechanisms that regulate the switch from dormancy to proliferation at metastatic sites will pave the way for new treatments to control this incurable disease.
Citation Format: Alisya Anlas, Celeste M. Nelson. Host tissue stiffness regulates chemotherapy-induced cancer cell dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4946. doi:10.1158/1538-7445.AM2017-4946
Abstract 4948: Characterization of hTERT-immortalized prostate-derived stromal and epithelial cells: An authentic in vitro model for tumor microenvironment studies
Authors: Rodriguez Luis G. , McDaniel Russell E. , Zhao Xiangshan , Turner Elizabeth , Annesi Christopher , Zou Chaozhong 
Published: July 2017

Abstract
Tumor development begins with mutational changes to the genetic makeup of a cell, but its progression is not solely determined by the mutated cell, but also by the tumor’s microenvironment. Prostate cancer, a leading cancer diagnosed in men, has been shown to be highly influenced by its surrounding stroma, particularly fibroblasts. It has been demonstrated that cancer-associated prostate fibroblast (CAFs) differ from normal-associated prostate fibroblast (NAFs). However, human prostate cancer model systems have focused largely on prostate cancer epithelial cells. Currently, a need exists for a more physiologically relevant human cell model system to study prostate cancer progression within the context of its tumor microenvironment. In this study, we characterized three prostate-derived cells: prostate cancer-associated fibroblast (CAFs), prostate normal-associated fibroblast (NAFs) and prostate cancer epithelial (PrE) cells; all three lines were immortalized by hTERT (human telomerase reverse transcriptase) alone, and have been continuously passaged for more than 40 PDL in our hands. Our data shows that the hTERT immortalized CAFs proliferate faster than the NAFs; in addition, both CAFs and NAFs express fibroblast markers such as TE7 and alpha smooth muscle actin (α-SMA), while neither cell line expresses epithelial marker such as CK14. Both CAFs and NAFs also express elevated levels of α-SMA upon TGF-β stimulation. All three prostate-derived cells express the prostate specific marker AR, and show similar markers staining after long time passaging. Importantly, conditioned media collected from CAFs promotes tumor cell growth better than NAF conditioned media. In conclusion, CAFs, NAFs, and immortalized prostate cancer epithelium may provide a very valuable model system for the study of prostate cancer cell progression and tumor microenvironment studies.
Citation Format: Luis G. Rodriguez, Russell E. McDaniel, Xiangshan Zhao, Elizabeth Turner, Christopher Annesi, Chaozhong Zou. Characterization of hTERT-immortalized prostate-derived stromal and epithelial cells: An authentic in vitro model for tumor microenvironment studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4948. doi:10.1158/1538-7445.AM2017-4948
Abstract 4955: PD-L1 expression on circulating epithelial tumor cells (CETCs) correlates with the presence of metastasis in breast cancer patients and differs from PD-L2 expression
Authors: Pizon Monika , Schott Dorothea , Pachmann Ulrich , Pachmann Katharina 
Published: July 2017

Abstract
Background: Strategies to improve the efficacy of the immune system against malignant tumors represent a major innovation focusing on the programmed cell death-1 receptor (PD-1), with its two ligands PD-L1 and PD-L2. The expression of PD-L1 has been evaluated in a number of different tumor types and can be used as a predictive biomarker for PD-1/PD-L1 checkpoint inhibitor treatment response. PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. We used a non-invasive, real-time liquid biopsy to better characterize PD-L1/-L2 expression on circulating epithelial tumor cells (CETCs) in breast cancer patients.
Methods: CETCs were determined from blood of 72 patients suffering from breast cancer. The number of vital CETCs and their expression of PD-L1 and PD-L2 were investigated using the maintrac® method.
Results: PD-L1 expressing CETCs were detected in 94.5 % of breast cancer patients whereas only 82% patients had PD-L2 positive CETCs. Breast cancer patients with metastatic disease had significantly more PD-L1 positive CETCs as compared to patients without metastasis (median 75% vs. 61.1%; p&lt;0.05). The fraction of PD-L1 positive CETCs was significantly higher than the fraction of PD-L2 positive CETCs (54.6% vs. 28.7%; p&lt;0.001). Moreover, we observed a significant heterogeneity in PD-L1 and PD-L2 immunostaining intensity across CETCs from the same patients.
Conclusion: Breast cancer patients have detectable CETCs with a high frequency of PD-L1 which correlates with progression of cancer disease. PD-L1 seems to be a major factor in immune evasion and may be a promising target of anticancer therapies. Monitoring the frequency of PD-L1 positive CETCs could reflect individual patient’s response to an anti-PD-1/PD-L1 therapy.
Citation Format: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann. PD-L1 expression on circulating epithelial tumor cells (CETCs) correlates with the presence of metastasis in breast cancer patients and differs from PD-L2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4955. doi:10.1158/1538-7445.AM2017-4955
Abstract 4964: Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor
Authors: Hunt John T. , Balog Aaron , Huang Christine , Lin Tai-An , Lin Tai-An , Maley Derrick , Gullo-Brown Johnni , Swanson Jesse , Brown Jennifer 
Published: July 2017

Abstract
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the degradation of tryptophan along the kynurenine pathway, and is frequently expressed in human malignancies. The activity of IDO1 induces an immunosuppressive microenvironment in tissues by inhibiting T-cell function through local depletion of tryptophan and through generation of kynurenine pathway metabolites. Inhibition of IDO1 is expected to diminish the immunosuppressive tumor microenvironment and improve cancer patient outcomes, particularly when used in combination with cancer immunotherapy agents such as nivolumab and ipilimumab. In this presentation, we will disclose the chemical structure, enzyme inhibitory mechanism, in vitro potency and in vivo pharmacodynamic (PD) activity of BMS’ IDO1 inhibitor currently in Phase I clinical trials. The compound is a potent and selective IDO1 inhibitor with no activity against another tryptophan degrading enzyme, tryptophan 2,3-dioxygenase (TDO). It exhibited potent cellular activity, suppressing kynurenine production in HEK293 cells overexpressing human IDO1 (IC50 = 1.1 nM) and in HeLa cells stimulated with IFNγ (IC50 = 1.7 nM). The compound also potently restored T-cell proliferation in a co-culture of T cells and human cancer cells and in a mixed lymphocyte reaction where T cells were co-cultured with allogeneic IDO1-expressing dendritic cells (EC50 = 1.2 nM). In vivo, when given once a day orally, the compound exhibited significant PD activity in mouse tumors grown subcutaneously in syngeneic hosts and in human tumors grown as xenografts in nude mice.
Citation Format: John T. Hunt, Aaron Balog, Christine Huang, Tai-An Lin, Tai-An Lin, Derrick Maley, Johnni Gullo-Brown, Jesse Swanson, Jennifer Brown. Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4964. doi:10.1158/1538-7445.AM2017-4964