tbuckley/cabot-search huggingface dataset:
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: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann
Journal: Cancer Research (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&amp;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&amp;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 5140: Encapsulation of the atypical retinoid ST1926 in nanoparticles prolongs the survival of acute myeloid leukemia xenografted mice at multiple folds lower concentrations than the naked drug
Authors: Leeanna El-Houjeiri, Walid Saad, Berthe Hayar, Patrick Aouad, Nadim Tawil, Rana Abdel-Samad, Claudio Pisano, Ali Bazarbachi, Hiba El Hajj, Nadine Darwiche
Journal: Cancer Research (2017)

Abstract Acute myeloid leukemia (AML) represents one of the most complex types of leukemia. It is a clinically and genetically heterogeneous disorder of hematopoietic progenitor cells, which have lost their ability to differentiate normally. Retinoids regulate vital biological processes including development, differentiation, proliferation, and cell death of hematopoietic progenitor cells. The natural retinoid all-trans retinoic acid (ATRA) became the paradigm for the treatment of acute promyelocytic leukemia (APL), an AML subtype. However, in non-APL AML patients, ATRA is possibly only effective in patients with Nucleophosmin-1 mutations without FMS-like tyrosine kinase 3 internal tandem duplication (FLT-3 ITD). Therefore, synthetic retinoids, specifically the adamantyl ST1926, emerged as potential alternatives. However, despite its lack of toxicity, ST1926 development in clinic was limited due to its rapid glucuroconjugation resulting in low plasma concentrations. Nanomedicine enables more efficient drug delivery and bioavailability. Here, we investigate the pre-clinical efficacy of ST1926 and polymer stabilized ST1926 nanoparticles in AML in vitro and in vivo models. We show that ST1926, at low sub-µM concentrations, potently inhibited the growth of human non-APL ATRA-resistant AML cell lines and AML patient cells while sparing resting and activated normal leukocytes at ten- to hundred-fold higher concentrations. ST1926 induced early DNA damage and massive apoptosis in all tested AML cell lines. To optimize the drug’s bioavailability burden, polymer stabilized ST1926 nanoparticles were developed using Flash NanoPrecipitation, and were shown to display comparable anti-growth activities to the naked drug in vitro. In murine AML xenograft model, ST1926 and ST1926 nanoparticles significantly prolonged survival. Strikingly, ST1926 encapsulated in nanoparticles extended survival in AML xenografted mice at four-fold lower concentrations than the naked drug. These results highlight the promise of ST1926 in AML therapy and warrant further clinical development of this adamantly retinoid. Citation Format: Leeanna El-Houjeiri, Walid Saad, Berthe Hayar, Patrick Aouad, Nadim Tawil, Rana Abdel-Samad, Claudio Pisano, Ali Bazarbachi, Hiba El Hajj, Nadine Darwiche. Encapsulation of the atypical retinoid ST1926 in nanoparticles prolongs the survival of acute myeloid leukemia xenografted mice at multiple folds lower concentrations than the naked drug [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 5140. doi:10.1158/1538-7445.AM2017-5140
Social Control of Hypothalamus-Mediated Male Aggression
Authors: Taehong Yang, Cindy F. Yang, M. Delara Chizari, Niru Maheswaranathan, Kenneth J. Burke, Maxim Borius, Sayaka Inoue, Michael C. Chiang, Kevin J. Bender, Surya Ganguli, Nirao M. Shah
Journal: Neuron (2017)
Abstract 144: Src leads to a novel mechanism of resistance to PI3K inhibitors through regulation of PI3K/p85 activation
Authors: Gui Chul Kim, Hae Yun Nam, Hyang Ju Lee, Min Kyung Kim, Geun Hee Lee, Myung Woul Han, Seong Who KIM, Sang Yoon Kim
Journal: Cancer Research (2017)

Abstract Activation of the PI3K pathway is commonly observed and is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies, such as radiotherapy, in most cancers. As a central node of this pathway, PI3K is an attractive target for PI3K-addicted cancer therapy and PI3K inhibitors may thus restore sensitivity to other treatments when administered as part of combination regimens. Here, we found that PI3K/p85 was expressed predominantly in the radioresistant head and neck cancer cell line (HN31 cell line). And then, we investigated whether PI3K modulation was crucial for the development of novel treatment strategies for radioresistant cancer cell line. Interestingly, we found that head and neck cancer cell lines with PI3K/p85 activation showed the resistance to PI3K inhibitors and the resistance mechanism was associated with Src activation which is a member of a superfamily of membrane-associated nonreceptor protein tyrosine kinases. Src inhibitor improves the efficacy of PI3K inhibitor treatment through suppression of Src and PI3K/p85 activation in HN31 cell line. Collectively, our study highlights the role of p85 and Src activation in the resistance for PI3K inhibition and the potential clinical application of combination regimens of Src and PI3K inhibitors in head and neck cancers. This is the first investigation to analyze the role of Src in resistance to the PI3K inhibitors of head and neck cancer. As a consequence, a greater understanding of resistance mechanisms through our results will enable the rational design of combination regimens and sequential treatment algorithms to improve clinical outcomes. Citation Format: Gui Chul Kim, Hae Yun Nam, Hyang Ju Lee, Min Kyung Kim, Geun Hee Lee, Myung Woul Han, Seong Who KIM, Sang Yoon Kim. Src leads to a novel mechanism of resistance to PI3K inhibitors through regulation of PI3K/p85 activation [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 144. doi:10.1158/1538-7445.AM2017-144
Abstract 3995: Identification of receptor tyrosine kinases (RTKs) expression in tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMC)
Authors: Dmitry Khochenkov, Maria Volkova, Ilya Tsimafeyeu
Journal: Cancer Research (2017)

Abstract Aim of this study is to discover expression levels of RTKs (VEGFR1, VEGFR2, PDGFRa, PDGFRb) in CD45+ population of PMBC and TILs isolated from patients with clear cell renal cell cancer (RCC). Here we present preliminary data. Species of tumors and blood were prospective collected from 9 patients with RCC after radical nephrectomy or tumor resection from July to October 2016. TILs isolation was performed under standard protocol with slight modification. Briefly, tumor was shredded with scissors on small pieces of 2-3 mm and twice washed in RPMI 1640 media by centrifugation for 10 min at 1500 rpm. After centrifugation, pellet was diluted RPMI 1640 with enzyme mix (Collagenase and Dispase II) on Petri dish and placed on shaker-thermostat andincubate sample for 12h at 37C with continuous shaking. After incubation, cell suspension was passed thought a cell strainer, mesh size 70 μm, placed on a 50 mL tube and washed twice washed in RPMI 1640 media by centrifugation. For TILs isolation cell suspension was placed on Ficoll-Paque Plus and isolated by centrifugation for 25 min at 1500 rpm. Cell pellet was resuspended in RPMI 1640 media. PMBC was isolated from whole blood using the Ficoll-Paque method. Isolated TIL and PMBC were prepared for flow cytometry at typical protocol with or without permeabilization. Cells were stained with anti-CD45 FITC-conjugated antibodies (Novus), primary anti-VEGFR1, anti-VEGFR2, anti-PDGFRa, anti-PDGFRb (Abcam) mouse antibodies and Alexa-568 conjuated secondary anti-mouse antibodies (Invitrogen) and analyzed on BD Canto II flow cytometer. Expression of RTKs on CD45+ cell population were evaluated. Among PMBC 86±9% of cells was CD45-positive and expressed RTKs (10±1% cells were positive for VEGFR1 and VEGFR2, and 6±2% cells were positive for PDGRFa and PDGFRb). TILs contained 65±18% of CD45-positive cells and did not express RTKs on the cell surface (less than 1% of cells), but intracellular staining showed presence of RTKs: 8±2% of cells were VEGFR1 or VEGFR2-positive, 20±8% of cells were PDGFRa or PDGFRb-positive. Preliminary data demonstrate extracellular expression of RTKs on PBMC and intracellular expression of RTKs in TILs. The study will be continued. Citation Format: Dmitry Khochenkov, Maria Volkova, Ilya Tsimafeyeu. Identification of receptor tyrosine kinases (RTKs) expression in tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMC) [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 3995. doi:10.1158/1538-7445.AM2017-3995
Evaluation of Mena isoforms as a surrogate for epithelial mesenchymal transformation and erlotinib resistance in breast carcinoma
Authors: C. M. Ghiuzeli, E. T. Roussos, J. B. Wyckoff, D. Sun, Y. Wang, T. Patsialou, S. Goswami, F. B. Gertler, J. S. Condeelis
Journal: Journal of Clinical Oncology (2009)

1078 Background: Epithelial to mesenchymal transition (EMT) is an important step in invasiveness and has been shown to correlate with metastatic potential in several cancer cell lines, including breast carcinoma. However, given the heterogeneity of tumors in vivo, EMT has not been a reliable marker of metastatic potential in cancer patients. Mena, a member of the enabled (ena)/vasodilator-stimulated phophoprotein (VASP) family, which controls cell motility, is upregulated in the invasive subpopulation of breast cancer cells. Mena is alternatively spliced to include one of four exons: +, ++, invasive (INV), or 11a. In the presence of Mena INV , tumor cells are able to invade even at epidermal growth factor (EGF) concentrations that would otherwise be undetectable by the tumor cells. Currently, there are several clinical and genetic characteristics which can predict sensitivity to erlotinib, an EGF receptor inhibitor, but further studies are necessary. Methods: The animal models used were the polyoma middle T antigen (PyMT) transgenic mouse and severe combined immunodeficiency (SCID) xenografted tumors derived from injection with a human breast carcinoma line, MDA-MB-231, and a rat adenocarcinoma line, MTLn3, with forced expression of Mena INV and Mena11a. Invasive cells and average primary tumor cells were collected using the in vivo invasion assay and Fluorescence activated cell sorting (FACS), respectively, and imaged via immunofluorescence. Results: We show that in both the PyMT and MDA-MB-231 animal models, invasive cells are significantly more mesenchymal than average primary tumor cells, indicating they have undergone EMT. The MTLn3-Mena INV cells are more mesenchymal-like, whereas the Mena11a are more epithelial-like. We also expect that cells with a high Mena INV /11a ratio invade despite the presence of erlotinib. No significant financial relationships to disclose.
Abstract 5009: Self-renewal of hypoxic glioma stem-like cells is facilitated by secretion-mediated STAT3 activation
Authors: Damian A. Almiron Bonnin, Matthew C. Havrda, Huan Liu, Myung Chang Lee, Matthew H. Ung, Chao Cheng, Mark A. Israel
Journal: Cancer Research (2017)

Abstract Glioblastoma, a type of high-grade glioma, is the most common and the most aggressive primary brain tumor of adults. The median survival is 12-15 months. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven at least partly by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a pathway dependent upon tumor hypoxia, a commonly found pathologic feature of GBM, that promotes self-renewal through the HIF1α-JAK1/2-STAT3 axis. Under hypoxic conditions, the expression of HIF1α is greatly increased in GBM stem-like cells leading to the activation of JAK1/2-STAT3 which mediates enhanced tumor stem-like cell self-renewal. Our data further demonstrate the importance of VEGF secretion for this pathway of hypoxia-mediated self-renewal. Using tumor stem-like cells derived from the S100β-v-erbB/p53-/- mouse model of spontaneous high-grade glioma, we have discovered that the activation of STAT3 through hypoxia-mediated VEGF secretion is required for self-renewal of glioma stem-like cells. Media conditioned by these S100β-v-erbB/p53-/- tumor sphere cells cultured under hypoxic conditions promoted self-renewal in S100β-v-erbB/p53-/- glioma stem-like cells and depletion of VEGF from this media was sufficient to inhibit STAT3 phosphorylation. Moreover, we have been able to identify two drugs: Brefeldin A and EHT-1864, that significantly inhibit VEGF secretion, decrease stem cell self-renewal, inhibit tumor growth, and increase the survival of mice allografted with S100β-v-erbB/p53-/- glioma stem-like cells. Cells treated with these drugs express molecular signatures that correlated strongly with the increased survival of GBM patients. These findings suggest a novel treatment strategy to inhibit hypoxia-mediated self-renewal of glioma stem-like cells in high-grade gliomas by targeting the secretion of extracellular, paracrine mediators of self-renewal. Citation Format: Damian A. Almiron Bonnin, Matthew C. Havrda, Huan Liu, Myung Chang Lee, Matthew H. Ung, Chao Cheng, Mark A. Israel. Self-renewal of hypoxic glioma stem-like cells is facilitated by secretion-mediated STAT3 activation [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 5009. doi:10.1158/1538-7445.AM2017-5009
Abstract 1341: Talin plays an important role in cell-cell interactions
Authors: Devang M. Patel, Akhilesh Kumar, William Morgan, Michael D. Birnbaum, Chaunhua Jiang, Fangliang Zhang
Journal: Cancer Research (2017)

Abstract Appropriate cell adhesion is necessary for numerous physiological processes and can be deranged in many diseases, including cancer. It has long been recognized that the cadherins mediated cell-cell adhesion receptor is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis. Recently a role for the C-terminal region of talin (the VAD fragment) in cadherin mediated cell-cell attachment has been suggested, but its molecular mechanism remained unclear. Here, we identified a small region of the VAD fragment required for its localization to cadherin-mediated cell-cell junctions and also found that its localization to cell-cell junctions is independent of its actin binding properties. To identify the binding partner of the VAD fragment at cell-cell junctions we utilized immune-pulldown and found that it interacts with catenins, an important component of cadherin-mediated cell-cell junction. Based on our data, we proposed that the VAD-fragment of talin stabilized and/or stimulated the cell-cell junction by interacting with catenins. Citation Format: Devang M. Patel, Akhilesh Kumar, William Morgan, Michael D. Birnbaum, Chaunhua Jiang, Fangliang Zhang. Talin plays an important role in cell-cell interactions [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 1341. doi:10.1158/1538-7445.AM2017-1341
Abstract 695: Targeted nanoparticle therapy for poor prognosis Ewing’s sarcoma
Authors: HyungGyoo Kang, Jon Nagy, Julia Samulak, Timothy Triche
Journal: Cancer Research (2017)

Abstract Targeted nanoparticles have shown the potential to deliver anticancer drugs to cancer cells selectively and thus to overcome unexpected cytotoxicity and limited efficacy of chemotherapy caused by non-selective delivery to normal cells. However, the optimal formulation of targeted nanoparticles for actual translational applications has not been established. By refining early formulations and after extensive testing, we have created an optimized targeted delivery system, HPLNs (Hybrid Polymerized Liposomal Nanoparticles) and demonstrated that this new, targeted nanoparticle technology overcomes many of these deficiencies. This technology has tremendous potential for treating virtually any type of cancer. The goal of our present study was to determine the efficacy and toxicity of this novel targeted nanoparticle in the treatment of Ewing’s Sarcoma, a rare and highly lethal cancer of children and young adults. The efficacy of this targeted delivery system was compared to 1) administration of the free drug and 2) the drug in untargeted nanoparticle form. Our studies have shown that HPLN-Dox targeted with human antiCD99 antibodies can successfully inhibit the growth of Ewing’s Sarcoma in murine models without any detectable off-target toxicity. The deliverable for our study was to demonstrate that the effectiveness of doxorubicin in the treatment of recurrent Ewing’s sarcoma could be dramatically improved when encapsulated in human antiCD99 antibody targeted HPLNs. At the same time, toxic side effects normally seen with free drug was not detectable. Success with human anti-CD99 antibodies targeted HPLNs containing Doxorubicin was then easily adapted to other tumor types (Leukemia, Prostate or Pancreatic cancers) and other payloads such as irinotecan, EWS-FLI1 specific ASOs, siRNA and CRISPR/Cas9 targeting the ETS domain of the chimeric EWS-ets gene found in all Ewing sarcoma. In conclusion, our study showed a potential of targeted HPLN as a selective delivery vehicle of cytotoxic payloads to cancers and this technology is then easily adapted to other tumor types and virtually any small molecule therapeutic. Citation Format: HyungGyoo Kang, Jon Nagy, Julia Samulak, Timothy Triche. Targeted nanoparticle therapy for poor prognosis Ewing’s sarcoma [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 695. doi:10.1158/1538-7445.AM2017-695
Abstract 1976: Dried blood imaging and immunoassay: Spot formation, particle migration, and tumor cell detection
Authors: Quanxu Shen, Bin Hong
Journal: Cancer Research (2017)

Abstract Blood droplet, when dried, forms a structured sedimentation pattern with central flat, corona ring and peripheral rim. This pattern can be fine-tuned with the blood formula. Surfactant is critical to promote the gelation process, eliminate the film cracking and delamination, and hence, suppress the coffee-ring effect. Additionally, surfactant restrains the shrinkage of the dried film. Without surfactant, the contraction was 100~150µm for 20µL of blood; decreased with surfactant added; fully stopped at 10% of concentration. Drying at room temperature with surfactant formed a flat disc-shaped deposit, while at 37°C, volcanic protuberance was developed. The size of the protuberance depended on the concentration of the surfactant primarily, and the anticoagulant type, evaporation velocity, and blood volume. To monitor the dynamic desiccation process, video recording of the evaporating drop was employed. It revealed a quick dislocation of the leukocyte-resembling beads to the outer region of the blood spot, reportedly at velocity of 10µm/sec. The use of 1 and 10µm sized beads further demonstrated layered convective flow below the surface. Beads migrated outward primarily before gelation, inward slightly during solidification, and ultimately settled down across the spot. The movement of beads was found in the range of a few hundred microns to millimeters before and after desiccation for a 50µL drop. Notably, plasma proteins and saline have influenced the bead distribution more than the surfactant. After plasma removal and mixing with surfactant, the majority of beads were dragged to the periphery, compared with many beads for no plasma and surfactant, some for whole blood with surfactant, and none for whole blood without surfactant. For a thick blood film, detection of embedded cells and beads can be difficult. Experiments showed that beam of longer wavelength, 532nm, was capable of visualizing all fluorescent cells and beads. Dried blood spot (DBS) assay has been widely used for newborn metabolic testing and DNA analysis. To detect rare tumor cells in DBS, the dried pattern was optimized to eliminate the artifacts, stabilize the cells, and enrich the targeted cell. DBS assay holds greater potential for cancer detection when the medical resource is limited. Note: This abstract was not presented at the meeting. Citation Format: Quanxu Shen, Bin Hong. Dried blood imaging and immunoassay: Spot formation, particle migration, and tumor cell detection [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 1976. doi:10.1158/1538-7445.AM2017-1976