bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-313: CXCR2 inhibitor Reparixin enhances local tumor control and reduces distant metastases in mouse tumor radiotherapy
Authors: Chang Chia-lun , Liang Yi-Hsin , Wu Szu-yuan 
Published: August 2018

Abstract
Inadequately irradiated primary tumor of primary Lewis lung carcinoma (LLC-LM) in vivo is a mechanism of radiation-enhanced LLC-LM cells in pulmonary metastasis. We observed a CXCL1/GRO alpha, is a member of the CXC family of chemokines is elevated after radiation therapy. CXCL1 protein is function with to bind the G-protein coupled receptor chemokine (C-X-C motif) receptor 2 (CXCR2) to recruit neutrophils. Reparixin is an inhibitor of CXCR2, and demonstrates activity against malignant behavior of human cancer cells xenografts. The effect of Reparixin on the radiotherapy of LLC-LM primary tumor and the effects on distant metastases have not been studied. The right thighs of C57BL/6 mice (n = 40) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of four groups: no irradiation, 10 Gy in one fraction, Reparixin (0.1mg/kg/day, for 5days) plus 10 Gy in one fraction, or Reparixin( 0.1mg/kg/day, for 5days) only . Tumors were clinically irradiated in each treatment group. All of the mice were killed within 21 days after the completion of radiation therapy. Examination of their lungs revealed &gt;13 (range, 13-22) surface metastases in the 10 Gy treated mice with 3 (range, 2-7) in the no irradiation mice, in Reparixin plus 10 Gy treated mice with 6(range, 4-13), in Reparixin treated mice with 2 (range, 2-6). The lung weights had increased from 0.22 g (range, 0.21-0.24 g) in the no irradiation mice to 0.43 g (range 0.37-0.61) in the 10 Gy treated mice, in Reparixin plus 10 Gy treated mice with 0.31(range, 0.26-0.41), in Reparixin treated mice with 0.23 (range, 0.2-0.25 g). In the surface metastases and lung weight, Reparixin plus irradiation treatment were statistically significant with P &lt; 0.001 when compare with irradiation alone. Other hand, the tumor growth curve also demonstrated that the Reparixin enhanced the tumor control of irradiation of LLC-LM tumor. In this model, the use of inadequately radiation to eradicate a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests that combining CXCR2 inhibitor with radiation therapy may enhance local tumor control and reduce distant metastases.
Citation Format: Chia-lun Chang, Yi-Hsin Liang, Szu-yuan Wu. CXCR2 inhibitor Reparixin enhances local tumor control and reduces distant metastases in mouse tumor radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-313.
Abstract LB-316: Dynamic live cell imaging of tumor migration and invasion
Authors: Booth Ross , Chen Cindy , Yeh Victor , Verma Deepika , Park Jun 
Published: August 2018

Abstract
Migration and invasion activities of metastasizing cancer cells are of immense significance to the field of cancer research, often leading to fatal spread of the disease. While much understanding has been gained regarding the underlying molecular and cellular mechanisms governing these processes, the direct observations of associate morphological and biochemical features are limited by the current methodologies which largely rely on endpoint micro-porous membrane-based assays or various live cell imaging assays performed on 2D/3D substrates- neither of which enable dynamic control over the tumor microenvironment. Microfluidic technologies enable high-resolution time-lapse imaging while providing exceptional experimental control to maintain a physiologically relevant microenvironment. Here we demonstrate the value of the CellASIC ONIX2 “dynamic live cell imaging system”, where microenvironmental parameters such as flowrates, the perfusion of nutrients and reagents, and temperature and gas compositions can be precisely controlled on demand by software during the entire duration of a given experiment. We now show the value of this system for imaging of metastatic processes with a novel microfluidic design comprising two parallel chambers separated by a micro-porous wall. One chamber contains MDA-MB-231 breast cancer cells embedded in 3D hydrogel culture or simply grown in 2D fashion, and the other chamber contains HUVEC endothelial cells in a monolayer. The device enables exceptionally clear real-time imaging of the migration of MDA-MB-231 cells, as well as invasion of these cells through and out of the gel into the “vascular” channel, enabling the monitoring of the adhesion and interaction of these cells with the HUVEC cells once the tumor cells had left the gel. Unlike the state-of-the-art endpoint or static culture imaging assays, the microfluidics system described herein enables the investigation of wider microenvironmental parameters and their interplay with cellular processes in unprecedented precision and permutations, and is also suitable for the studies of wider biological applications outside of cancer biology.
Citation Format: Ross Booth, Cindy Chen, Victor Yeh, Deepika Verma, Jun Park. Dynamic live cell imaging of tumor migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-316.
Abstract LB-325: New synergistic mTOR-based combinations for the treatment of Ewing sarcoma
Authors: Menegaz Brian A. , Cuglievan Branko , Admane Prasad S. , Yang Feng , Dimiter Dimitrov , Landesman Yosef , Cherradi Salah-Eddine Lamhamedi , Ludwig Joseph A. 
Published: August 2018

Abstract
Ewing sarcoma (ES), an aggressive bone cancer in children and young adults, is dependent upon the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) cell-signaling axis for malignancy, survival, and metastasis. Individual targeting of mTOR has negligible anti-tumor activity in ES, and single-agent IGF-1R targeting leads to only transient effects that benefit only 10-14% of patients. Co-targeting strategies using IGF-1R Abs combined with mTOR inhibitors were shown in 2012 to increase response rates to 29% but the high toxicity profile limited subsequent clinical development. While an ongoing COG protocol combines IGF-1R Abs with standard-of-care cytotoxic chemotherapy in newly diagnosed ES patients harboring metastatic disease, this combination is unlikely to benefit those who have recurred or developed chemoresistant disease. Herein, we present several highly synergistic drug combinations using novel biologically-targeted therapies aimed at the IGF-1R/mTOR pathway. A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody (m708.5), which binds human IGF-1 and IGF-2 with high pico-molar affinity, potently inhibited phosphorylation of the IGF-1R and the insulin receptor (IR) in an EW5 xenograft animal model of ES. In concert with mTOR inhibitors (e.g., everolimus or ridaforolimus), m708.5 demonstrated striking tumor regression and prolonged mouse survival. Additionally, we expand upon the synergistic role of CRM1 (XPO1) in combating ES tumor growth. A small molecule inhibitor of this protein (KPT-330) was previously shown to attenuate IGF-1-induced activation of IGF-1R when combined with a small-molecule inhibitor of IGF-1R and IR (Linsitinib, OSI906). Our results indicate superior preclinical anti-tumor activity when it is combined with everolimus in our xenograft ES models. Though these combinations have not yet been assessed in the clinical setting, early-phase clinical trials have begun testing KPT-330 in select sarcoma subtypes, and a host of mTOR inhibitors are FDA-approved and widely available. Our data supports several novel drug combinations that could rapidly be explored in the clinic to improve survival of ES patients.
SELC & JAL: Co-senior Authors
Citation Format: Brian A. Menegaz, Branko Cuglievan, Prasad S. Admane, Feng Yang, Dimitrov Dimiter, Yosef Landesman, Salah-Eddine Lamhamedi Cherradi, Joseph A. Ludwig. New synergistic mTOR-based combinations for the treatment of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-325.
Abstract LB-329: Multiple-resolution characterization of tumor heterogeneity as associated with disease progression in a mouse model of colorectal cancer
Authors: Farhoud Mohammed , Leystra Alyssa , Albrecht Dawn M. , Brevard Mathew , Dimant Hemi , Holt Robert , Halberg Richard B. 
Published: August 2018

Abstract
The ability to engineer models to express endogenous fluorophores has become an invaluable tool for studying tumor biology. The utility of these models is limited by the sensitivity and resolution of currently available imaging platforms. In vivo techniques enable longitudinal studies in which changes in fluorescent markers, tumors, and whole organs can be monitored over time. In vivo fluorescence suffers from poor sensitivity and resolution owing to the high absorption and scatter of light in biological tissue. While ex vivo fluorescence techniques allow for high resolution evaluation and characterization, these techniques typically only focus on a small samples of tissue instead of whole animals. Using a Cryo-Fluorescence Tomography (CFT) imaging approach, an imaging modality based on serial slicing and off-the-block fluorescence imaging, we can bridge the gap between in vivo and ex vivo resolution of the entire animal. As proof of concept, a novel mouse model expressing fluorophores was evaluated and characterized. Individual cells were labeled with either EGFP or tdTomato prior to tumor initiation. Intestinal tumors were induced through loss of Apc, the activation of PI3K, or both. Tumor heterogeneity and grade were assessed by traditional histopathology, individual-tissue CFT, and whole-animal CFT. Using CFT, serial sectioning and 3D-reconstruction of whole tissues were achieved at 10-50 µm resolution.The multi-resolution imaging approach of this model enabled visualization of molecular and histopathological information from a common in vivo resolution (1mm) to whole-tissue resolution. The CFT platform enabled a 3D data set at a resolution that was not previously available in traditional histopathology. CFT as a molecular tissue imaging technique has proven its utility as a complimentary assay in preclinical oncology studies allowing several characteristics of tumors including heterogeneity, growth, and malignant spread to be readily assessed.
Citation Format: Mohammed Farhoud, Alyssa Leystra, Dawn M. Albrecht, Mathew Brevard, Hemi Dimant, Robert Holt, Richard B. Halberg. Multiple-resolution characterization of tumor heterogeneity as associated with disease progression in a mouse model of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-329.
Abstract LB-330: Investigating how extracellular signals contribute to single cancer cell heterogeneity using near-infrared quantum dots
Authors: Le Phuong , Baculis Brian C. , Chung Hee Jung , Kilian Kristpher , Smith Andrew M. 
Published: August 2018

Abstract
Cancer cells heterogeneity presents a major roadblock in clinical diagnostics and therapy. Investigations of tumor cell heterogeneity using single-cell analytical techniques have revealed not only the presence of multiple clonal subpopulations but also phenotypic variability among genetically identical cells. This heterogeneity plays a critical role in therapeutics, as population extrema, rather than cells near the ensemble mean, can dominate pathogenesis as well as drug resistance. To characterize single cell heterogeneity, multiple techniques quantifying single-cell gene expression have been developed. However, there's a lack of experimental techniques to measure how cellular decision-making processes underlying population variability derive from extracellular biochemical input signals, such as peptide growth factors, which cannot be measured at the single-cell level. Here, to digitally count growth factors in single cells, we develop a novel method combining fluorescent quantum dots and calibrated three-dimensional deconvolution microscopy (QDC-3DM). Using quantum dots with near-infrared emission to overcome intrinsic cellular autofluorescence, we were able to detect and accurately count individual quantum dots conjugated to epidermal growth factor (EGF) using their fluorescent intensities. Analyzing triple-negative breast cancer cells (MDA-MB-231) with QDC-3DM, we observed that single-cell heterogeneity in growth factor stimulation led to heterogeneity in receptor activation. When treating cells with increasing concentration of phamarcological inhibitor blocking receptor activation, we observed a proportional increase in receptor activation heterogeneity. Together, our results indicate that external stimulation contributes to signaling variation and drug response variation at the single-cell level. We anticipate that QDC-3DM can be applied to any peptidic ligands to study how extracellular signaling stimulation contributes to phenotypic variability to provide new insight into cancer cell heterogeneity that plays a critical role in therapeutic resistance.
Citation Format: Phuong Le, Brian C. Baculis, Hee Jung Chung, Kristpher Kilian, Andrew M. Smith. Investigating how extracellular signals contribute to single cancer cell heterogeneity using near-infrared quantum dots [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-330.
Abstract LB-332: Evidence for cutaneous squamous tumors derived from carcinogen-exposed bone marrow
Authors: Lad Sonali , Johnson Kelly , Boland Kelsey , Readio Nyssa , Schuster Todd , Li Yong , Gordon Derek , Morris Rebecca J. 
Published: August 2018

Abstract
Cytokeratins are frequently found in the blood and bone marrow of patients with epithelial cancers and are attributed to metastasis. We wondered whether we could find keratin expression in blood and bone marrow in untreated adult mice. To address this problem, we have used classical immunoreactivity, Krt1-14;mTmG transgenic mice together with fluorescence activated cell sorting, and quantitative reverse transcriptase polymerase chain reaction. We have made several novel findings. First, we discovered, rare but distinctive, keratin-14 and keratin-15 immunoreactive cells the size of small lymphocytes in blood and bone marrow of untreated mice. Second, using Krt1-14;mTmG transgenic mice, we found low (8.6 GFP positive cells per 10^6 cells analyzed), but significant numbers (p&lt0.0005) of GFP positive cells in bone marrow of normal adult mice when compared with negative controls. Third, qRT-PCR demonstrated very low but reproducibly detectable expression of keratin-14 mRNA in blood and bone marrow when compared with epidermal keratinocytes: with blood expressing one thousand times, and bone marrow, one hundred thousand times, less than epidermal keratinocytes. Moreover, FACS analysis of fresh bone marrow disclosed a subpopulation of keratin-14 immunoreactive cells that was negative for hematopoietic lineage markers. Furthermore, and even more curious, recipients of bone marrow transplants from DMBA-treated UBC/GFP mice (“toxic bone marrow”) developed GFP-immunoreactive skin tumors upon TPA tumor promotion: four of fifteen mice developed GFP-immunoreactive skin tumors. Of these tumors, four were squamous papillomas, and one was a squamous cell carcinoma. None of the ten control mice receiving normal whole bone marrow developed any skin tumors upon tumor promotion. We conclude from these observations that keratin-14 protein and mRNA are expressed at low, but detectable levels in the blood and bone marrow of mice, and that a subset of “toxic bone marrow” derived cells can be recruited to form epithelial benign and malignant squamous tumors. Building upon these observations should open new avenues of understanding for cutaneous biology, non-melanoma skin cancer, and other epithelia and their cancers.
Citation Format: Sonali Lad, Kelly Johnson, Kelsey Boland, Nyssa Readio, Todd Schuster, Yong Li, Derek Gordon, Rebecca J. Morris. Evidence for cutaneous squamous tumors derived from carcinogen-exposed bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-332.
Abstract LB-338: SHP2 inhibition enhances sensitivity to MEK inhibitors in multiple resistant cancer models
Authors: Fedele Carmine , Tang Kwan Ho , Ran Hao , Wei Wei , Diskin Brian , Miller George , Neel Benjamin G. 
Published: August 2018

Abstract
Targeting tumors with kinase inhibitors induces complex adaptive programs that enable the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. Most tumors developing resistance to MEK inhibitors upregulate and/or activation of at least one of several different receptor tyrosine kinases (RTKs), which drive resistance. Notably, different RTKs or RTK combinations are upregulated in different cancer cells, even those from the same histotype. SHP2 (encoded by PTPN11) is required for RAS/ERK pathway activation downstream of most RTKs, suggesting that it might provide a common targetable resistance node in multiple resistant cancer cell lines. We show that the addition of a newly identified SHP2 inhibitor, SHP099, to MEK therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cancer models in vitro and in vivo. These effects occurred in a wide range of malignancies, including KRAS mutant pancreas, lung cancer, triple negative breast cancer, and serous ovarian cancer cell lines, as well as in PDX and GEMM models. SHP099 effects were overcome by expressing an SHP2 mutant that loses drug binding but retain catalytic activity and regulation, demonstrating that on target effects of the inhibitor. Mechanistic studies across multiple cellular cancer models suggest that SHP2 inhibition by SHP099 prevents the compensatory RAS and ERK1/2 reactivation in response to MEK therapy and impedes the engagement of the ERK1/2 transcriptional programs (i.e., MYC, ETV1, FOSL1, etc.) and signaling outputs that characterize the drug-tolerant state. Combining full doses of MEK inhibitors and SHP099 causes significant toxicity in mice, but non-toxic, efficacious dosing regimens can be achieved. Our findings suggest that SHP099, in combination with MEK inhibition is a promising therapeutic strategy for enhancing the effectiveness of targeted therapies.
Citation Format: Carmine Fedele, Kwan Ho Tang, Hao Ran, Wei Wei, Brian Diskin, George Miller, Benjamin G. Neel. SHP2 inhibition enhances sensitivity to MEK inhibitors in multiple resistant cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-338.
Abstract LB-350: IgG4 expressing B cells associate with poor survival in triple negative breast cancer
Authors: Flynn Nicole , Amadi Ugochukwu , Somasundaram Rajasekharan , Sims-Mourtada Jennifer 
Published: August 2018

Abstract
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with high levels of lymphocyte infiltration. Although high levels of infiltrating B cells are present in TNBC, their role in progression of this disease is unclear. IgG4 is one of four subclasses of IgG and is the least abundant in healthy human serum. IgG4 has been found at higher percentages in both tissue and serum in cases of chronic inflammation, which promotes class switching to IgG4. Expression and secretion of IgG4 by B cells may be non-beneficial and potentially harmful in the cancer setting. Unlike the other subclasses of IgG, IgG4 does not activate complement dependent cytotoxicity and has a lower affinity for FcγR, thus resulting in a poor ability to engage immune effector cells and activate antibody-depended cell-mediated cytotoxicity. Additionally, IgG4 can compete with other IgG subclasses by binding to antigens and can sequestering IgG through Fc-Fc interactions, thus impairing potential anti-tumor antibody-mediated responses. As IgG4 expressing B cells have been shown to be associated with poor outcomes in other aggressive cancers such melanoma, glioblastoma and pancreatic cancer, we sought to determine the expression of IgG4 in TNBC. We performed immunohistological staining of IgG4 in paraffin-embedded tissue microarrays from 75 treatment-naive TNBC specimens obtained from women who underwent surgical resection of their tumors at the Helen F Graham Cancer Center and Research Institute from 2006-2007. We found that 69 % of TNBC cases contain IgG4+ cell infiltration. Moreover, the presence of IgG4+ cells is significantly correlated with poorer progression free (p&lt;0.0003) and overall survival (p&lt;0.0001) as determined by a Log-rank (Mantel-Cox) test. These findings indicate the presence of an immunosuppressive B cell population. Further study is needed to characterize these cells and to determine the significance of IgG4+ tumor infiltrating B cells, and their potential immunosuppressive role in the progression of TNBC.
Citation Format: Nicole Flynn, Ugochukwu Amadi, Rajasekharan Somasundaram, Jennifer Sims-Mourtada. IgG4 expressing B cells associate with poor survival in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-350.