bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1820: Synergistic lethality of mAbs with an EMT reversal agent, Nintedanib, in epithelial ovarian cancer
Authors: Teo Jocelyn , Tan Heng Liang , Huang Ruby Yun-Ju , Choo Andre 
Published: July 2017

Abstract
Epithelial-mesenchymal transition (EMT) has long been associated with cancer progression and metastasis. As a reversible process, it has the potential to be a target for cancer therapy. However, this concept of reversing EMT has not yet been widely explored in current treatment strategies. With the identification of Nintedanib as an EMT reversal agent, we aim to broaden the utility of this triple angiokinase inhibitor by identifying agents that show synergistic lethality with it, using monoclonal antibodies (mAbs) as a combinatory therapeutic. Nintedanib alone is not significantly cytotoxic to cells, but it causes cell cycle arrest and reverses EMT. By selecting for this sub-population of cells that are sensitive to Nintedanib, their subsequent eradication can then be more intricately directed. Since the anti-cancer application of EMT reversal agents are not fully developed, it is vital to investigate mechanisms that sensitize cancer cells to cytotoxic agents following EMT reversal.Our group has generated panels of mAbs that are able to bind differentially to various breast and ovarian cancer cell lines along the EMT spectrum. Some mAbs preferentially bind to Epithelial lines, while some have stronger affinity to Mesenchymal lines. This implies that mAbs have the ability to differentiate between epithelial and mesenchymal phenotypes, uncovering a new dimension to the capability of mAbs which have yet to be explored.Using a mesenchymal ovarian cancer cell line as a starting model, Nintedanib-treated cells were screened with the mAbs and those showing a &gt;2-fold increase in binding were shortlisted for further validation. Based on this criteria, 26 mAbs were identified and further characterized in functional Antibody Drug Conjugate (ADC) assays with mAbs conjugated to a toxic drug, Saporin (or Zap). Mabs successfully internalizing and killing the cancer cells will then be further chosen for antigen characterization and in vivo functional studies. Ultimately, there is huge potential for mAbs to be discovered that shows synergy with Nintedanib to enhance lethality to various types of cancer cells. A novel clinical strategy, the application of EMT reversal in terms of utilising a synthetic lethality-like approach allows better design of combinatory therapeutics, increasing treatment efficacy that might revolutionalise cancer treatment.
Citation Format: Jocelyn Teo, Heng Liang Tan, Ruby Yun-Ju Huang, Andre Choo. Synergistic lethality of mAbs with an EMT reversal agent, Nintedanib, in epithelial ovarian 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 1820. doi:10.1158/1538-7445.AM2017-1820
Abstract 1825: Angiopoietin-Tie-2 functional axis in colorectal cancer liver metastasis (CRCLM) provides a new marker for stratification and evaluation of tumor progression
Authors: Ibrahim Nisreen S. 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer in Canadians, with liver metastases being the major cause of death from this disease. Tumors induce angiogenesis, a phenomenon known as the ‘angiogenic switch’, which is an essential step in tumor progression whereby the balance of pro- and anti-angiogenic factors are important for active angiogenesis. Clinical efficacy of targeted VEGF (anti-angiogenic) treatment has been validated as a cancer therapy. Our group, together with others, has identified unique histological growth patterns HGPs (desmoplastic, replacement and pushing) within liver metastases that have different responses to anti-angiogenic therapy. The patients with Desmoplastic HGP (DHGP) that received anti-angiogenic plus chemotherapy prior to resection had a significantly better pathologic response and survival than patients with Replacement HGP (RHGP). The aim of this study was to explore the role of Ang-1, Ang-2, Tie-2 and VEGF in the development and progression of CRCLM tumors with distinct HGPs. Here, human CRCLM tumor samples were analyzed by quantitative real-time PCR (Q-PCR) and immunohistochemistry (IHC) staining. The Q-PCR results demonstrated that the expression of Ang-2 was lower in RHGP tumor samples compared with DHGP tumor samples. This data was validated by IHC, were IHC scoring results showed that the ratio of Ang-2: Ang-1 expression in DHGP tumors was higher compared to RHGP tumors. VEGF and Tie2 proteins were expressed in both tumor patterns. Thus vascular quiescence maintained by constitutive Ang-1/Tie-2 signaling, found in RHGP tumors, prevails over destabilization and pro-inflammatory Ang-2/Tie-2 signaling, which is higher in the DHGP tumor samples. Since vascular remodelling is driven by Ang-2/Tie-2 in DHGP, which is dependent on VEGF we would expect anti-angiogenic therapy to be effective on DHGP. Furthermore, the RHGP had low levels of Ang-2 and high levels of Ang-1, together with the presence of Tie-2, and then one would predict that VEGF is not required for the growth of these tumors and thus would not respond to anti-angiogenic therapy, as has been shown in our patients’ cohort. Taken together, these data suggest that the Angiopoietin/Tie-2 functional axis is an important player in CRCLM tumor progression and can be a potential target for CRCLM cancer therapy with stratification of patients by HGPs.
Citation Format: Nisreen S. Ibrahim. Angiopoietin-Tie-2 functional axis in colorectal cancer liver metastasis (CRCLM) provides a new marker for stratification and evaluation of tumor progression [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 1825. doi:10.1158/1538-7445.AM2017-1825
Abstract 1833: Imaging-guided brain tumor surgery strategy based on a triple-modality MRI-PET-fluorescence imaging probe and imaging analysis
Authors: Meng Hui , Jin Yushen , Zhang Shaowei , Zhang Shuai , Ma Xibo , Tian Jie 
Published: July 2017

Abstract
Precise brain tumor resection is valuable for increasing the 5-year survival rate. However, the delineation of tumor margin is a major challenge. Transferrin modified nanoprobes had the property of passing the blood-brain barrier (BBB). Here, we endeavored to use transferrin to fabricate a triple-modality magnetic resonance imaging-PET-fluorescence imaging molecule agent (MPF) which could improve diagnostic sensitivity and specificity of the brain tumors in the imaging acquisition and analysis. The localization of the tumor were determined by the MRI before surgery. Glucose metabolism was derived from PET imaging which would be an important influence factor for surgery strategy. Tumor margin was delineated using the quick segmentation methods according to the fluorescence imaging after craniotomy which could reduce residual tumor after resection. Finally, tissues were sliced and stained with hematoxylin and eosin every 5 mm. The histology results were processed into a whole image which can be used to evaluate the accuracy of intraoperative tumor margin. This three modality imaging-guided surgery strategy is a promising method which will probably achieve its application in clinical trials in near future.
Citation Format: Hui Meng, Yushen Jin, Shaowei Zhang, Shuai Zhang, Xibo Ma, Jie Tian. Imaging-guided brain tumor surgery strategy based on a triple-modality MRI-PET-fluorescence imaging probe and imaging analysis [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 1833. doi:10.1158/1538-7445.AM2017-1833
Abstract 1839: TGFBR1*6A mouse model mimics human breast cancer development and progression
Authors: Pennison Michael James , Wang Minghui , Jimenez Hugo , Pasche Boris 
Published: July 2017

Abstract
Transforming Growth Factor-ß (TGF-β) is one of the most commonly altered cellular signaling pathways in human cancer. Our group was the first to discover TGFBR1*6A (*6A), a common hypomorphic variant of the type I TGF-ß receptor (TGFBR1), which has been associated with increased risk for breast cancer in multiple epidemiological studies. Functional analysis also suggests that *6A is associated with decreased tumor suppressive TGF-β signaling in early tumor development and is involved with promoting tumorigenesis in advanced carcinomas. To better understand the functional impact of *6A and constitutively reduced TGF-ß signaling on breast cancer development and progression, we have recently developed a series of transgenic knock-in mouse model variants by replacing exon 1 of the mouse Tgfbr1 sequence with human exon 1 sequences harboring both *6A and wild-type (*9A) TGFBR1 variants and crossed them with MMTVneu mice.
We generated a total of 5 FVB double and/or triple transgenic mouse strains: MMTVneu;9A/9A, MMTVneu;6A/6A, MMTVneu;9A/6A, MMTVneu;*9A/-, and MMTVneu;6A/-. Following tumor development, measurements were performed three times per week to determine tumor volume. All mice were allowed to live up to 18 months (548 days) or until they died of natural causes. Specimens were collected for later analysis of blood, tumors, normal mammary tissue, and were evaluated for lung metastases. Statistical comparisons performed using Student’s t-test.
Only 34.4% of MMTVneu;9A/9A mice (11/32) developed mammary tumors, while 80% of MMTVneu;6A/6A mice (24/30; p=0.0002) and 62.5% of MMTVneu;6A/- mice (19/32, p=0.046) developed tumors. The percentage of MMTVneu;9A/6A and MMTVneu;*9A/- mice that developed tumors was higher than MMTVneu;9A/9A mice (48.3% and 50%, respectively) but was not statistically significant. Additionally, 66.7% of MMTVneu;6A/6A mice (20/30) developed 2 or more tumors, while only 25% of MMTVneu;9A/9A mice (8/32) developed multiple tumors (p=0.0007).
Our data suggests that we have developed transgenic mouse strains that accurately mimic human breast cancer susceptibility associated with *6A and constitutively decreased TGFBR1 expression in humans, as evidenced by other studies. These mouse models may be a tool to provide invaluable insight to better understand the role of TGFBR1 variants in the development and progression of breast cancer.
Citation Format: Michael James Pennison, Minghui Wang, Hugo Jimenez, Boris Pasche. TGFBR1*6A mouse model mimics human breast cancer development and progression [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 1839. doi:10.1158/1538-7445.AM2017-1839
Abstract 1844: Investigating the role of amphiregulin in breast cancer
Authors: Chiang Serena P. , Karagiannis George S. , Condeelis John S. , Segall Jeffrey E. 
Published: July 2017

Abstract
Breast cancer is the most prevalent cancer in women worldwide and afflicts more than 3.1 million women in the US alone. The epidermal growth factor receptor (EGFR) is frequently overexpressed in breast cancer and is associated with poor clinical outcome. Several therapies involving anti-EGFR agents have been developed to target breast cancer. However, clinical trials have shown mixed outcomes with these therapies. Amphiregulin (AREG) is a ligand for EGFR that mediates estrogen-induced mammary ductal morphogenesis during development. Expression of AREG is enriched in invasive breast carcinomas, particularly ERα-positive breast tumors. Studies have shown that AREG increases the in vitro invasiveness of breast cancer cells. Furthermore, suppression of AREG expression in transformed human breast epithelial cells reduces tumor formation when injected in nude mice. These observations suggest that AREG plays an important role in breast cancer development and progression. To investigate the role of AREG in breast cancer development and progression, we utilized a spontaneous mammary tumor mouse model where oncogenesis is driven by expression of the polyoma middle T oncoprotein (PyMT) through the mouse mammary tumor virus (MMTV) promoter. We have crossed AREG knockout mice with the MMTV-PyMT mice to generate AREG KO mice that spontaneously form mammary tumors. Tumors in AREG KO PyMT mice initially grow more quickly but eventually reach 2 cm in diameter at a relatively time as compared to tumors formed in AREG WT PyMT mice. Histologically, AREG KO tumors appear more differentiated and display a greater proportion of tumor stroma. This prompted us to further hypothesize that AREG may have diverse effects in the tumoral or stromal compartment of developing tumors. To individually assess the effects of AREG knockout in the tumor cells and the stroma, we utilized a transplantation model in which we prepared tumor chunks from AREG WT and KO PyMT tumors and transplanted them into AREG WT and KO mice. Through this model, we have found that AREG expression in the tumor has a greater impact on tumor growth and progression than the tumor stroma. Regardless of the AREG status of the recipient mice, AREG KO tumors display a significant growth impairment and reduced transplant efficiency. In summary, these results demonstrate that AREG is important for mammary tumor progression.
Citation Format: Serena P. Chiang, George S. Karagiannis, John S. Condeelis, Jeffrey E. Segall. Investigating the role of amphiregulin in breast 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 1844. doi:10.1158/1538-7445.AM2017-1844
Abstract 1855: Developed operation method for patient-drived orthotopic xenograft model of hepatocellular carcinoma
Authors: Byeon Hye Rim , Seo YunSung , Kong Sun-Young , Lee Seung Duk 
Published: July 2017

Abstract
Patient-drived xenograft(PDX) model is a biological organized platform and a patient substitute. Recent studies use the ectopic model for hepatocellular carcinoma(HCC) but this model don’t reflect likewise the tumor state of patient. For exact prognosis, it is need to establish patient-derived orthotopic xenograft(PDOX) mouse model of hepatocellular carcinoma using direct injection technique. Additionally, secretion of growth factor from bone marrow stem cells is promoted after partial hepatectomy. This mechanism is helpful to not only general liver regeneration but also tumorigenesis. Based on former PDX research, we develop the new protocol using direct injection technique. From January 2015 to June 2016, consent about getting tumor pieces to the patient of hepatocellular carcinoma. The pieces is stored in RPMI1640 and moved from operation room to research room immediately. For PDOX and PDX to subcutaneous model, 8~10weeks old NOD SCID and NSG male mouse is used. The tumor pieces cutted to the cube size 1mm. For stop the bleeding, inferior vena cava is blocked using Bulldog Clamp and the cube is directly injected median lobe to 3 places randomly. After clear the Bulldog Clamp, a left lobe is removed using tie and weighted. After 3 months, the PDOX mouse is checked for cancer growth using MRI or PET-CT. Successful PDOX or PDX to subcutaneous model is sacrificed and succeeded a generation to another Balb/C-nude male mouse 8~10weeks old. The rate of success of PDOX model and PDX to subcutaneous model is about 10% respectively. Formed tumor is verified by H&E staining. Based on protocol established, further study plan is required for improving on the rate of success to establish PDOX model and clinical application.
Note: This abstract was not presented at the meeting.
Citation Format: Hye Rim Byeon, YunSung Seo, Sun-Young Kong, Seung Duk Lee. Developed operation method for patient-drived orthotopic xenograft model of hepatocellular carcinoma [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 1855. doi:10.1158/1538-7445.AM2017-1855
Abstract 1858: Theranostic nanoparticles for detection and treatment of pancreatic cancer
Authors: Chuong Phillip , Bhutiani Neal , McNally Lacey R. 
Published: July 2017

Abstract
Background: Despite continued efforts to improve early detection and treatment of pancreatic adenocarcinoma, the disease still carries a poor prognosis. The combination of multispectral optoacoustic tomography (MSOT) and theranostic nanoparticles offers a possible solution by providing tumor targeting using fluorescent dyes and treatment through drug delivery. We describe a 40 nm colloidal mesoporous silica nanoparticle (CMS) with vermiform pores and a chitosan coating and tagged with the V7 peptide to provide pH-specific dual targeting to deliver a contrast agent in a tumor-specific fashion.
Methods: CMSs were synthesized using a modified Stober method, coated with chitosan, and conjugated with a V7 peptide, resulting in a dual acidic pH targeting system. Particle characterization was performed using transmission electron microscopy (TEM), UV-vis spectrophotometry, Zeta potential, and dynamic light scattering . To determine acidic pH specificity of V7-CMS, Panc1 and S2VP10 cell lines were incubated in cell culture medium at either pH 7.4 or 6.6 followed by treatment with V7-CMS. Particle uptake was determined using near infrared (NIR) fluorescence and tissue phantoms. Finally, for in vivo testing, the same CMSNs were injected into mice bearing S2VP10 pancreatic tumors. MSOT imaging was performed 8 hours after CMS injection.
Results: TEM images demonstrated successful synthesis of approximately 40 nm V7-CMSs with vermiform pores. On NIR imaging, V7-CMS demonstrated acidic pH specificity in both S2VP10 and Panc 1 cells at pH 6.6, with particle localization and signal intensity 8-fold and 5-fold higher, respectively, than that observed at pH 7.4. In tissue phantoms, increased pH specificity was also observed in both S2VP10 and Panc 1 cells at pH 6.6. Particle location and signal intensity on MSOT was 20-fold and 4-fold higher, respectively, than that observed at pH 7.4. In the murine orthotopic S2VP10 pancreatic tumor model, MSOT imaging 8 hours after IV CMS injection demonstrated V7-CMS accumulation specifically within pancreatic tumors.
Conclusion: The acidic pH specific dual targeting system using chitosan-coated and pHLIP V7-tagged CMSs results in tumor specificity. Preferential binding and dye release was increased as much as 20-fold at pH 6.6 as compared to pH 7.4 in tissue phantoms. MSOT was able to detect tumor specific accumulation of V7-CMS in vivo. These small, pH specific particles hold significant promise for effectively identifying pancreatic tumors with high sensitivity and specificity and for targeted drug delivery.
Note: This abstract was not presented at the meeting.
Citation Format: Phillip Chuong, Neal Bhutiani, Lacey R. McNally. Theranostic nanoparticles for detection and treatment of pancreatic 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 1858. doi:10.1158/1538-7445.AM2017-1858
Abstract 1872: Fluorescence-guided surgery in the tumor microenvironment in a syngeneic mouse model of EL-4 lymphoma
Authors: Hasegawa Kosuke , Suetsugu Atsushi , Nakamura Miki , Matsumoto Takuro , Kunisada Takahiro , Shimizu Masahito , Saji Shigetoyo , Moriwaki Hisataka , Bouvet Michael , Hoffman Robert M. 
Published: July 2017

Abstract
We report fluorescence-guided surgery (FGS) of the tumor microenvironment of the EL-4-RFP lymphoma cells growing subcutaneously in C57/BL6 GFP transgenic mice. Using a portable hand-held Dino-Lite digital imaging system, subcutaneous tumors were resected by FGS. The tumor surface contained both RFP cancer cells and GFP stromal cells. The tumor microenvironment was clearly visualized and resected with the Dino-Lite. Host stromal cells, including adipocyte-like cells and blood vessels with lymphocytes, were observed along the tumor by confocal microscopy in addition to cancer cells by color-coded confocal imaging. Stromal cells were within the tumor and that cancer cells also invaded the TME. Color-coded FGS, which distinguished cancer and stroma, significantly prevented local recurrence, which bright-light surgery or single-color FGS could not.
Citation Format: Kosuke Hasegawa, Atsushi Suetsugu, Miki Nakamura, Takuro Matsumoto, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman. Fluorescence-guided surgery in the tumor microenvironment in a syngeneic mouse model of EL-4 lymphoma [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 1872. doi:10.1158/1538-7445.AM2017-1872
Abstract 1874: First demonstration that hypoxia targeting with radiation improves tumor control in a mammal tumor model
Authors: Halpern Howard J. , Epe; Boris , Maggio Matthew C. , Krzykawska-Serda Martyna , Redler Gage H. , Miller Richard C. , Barth Eugene D. , Weichselbaum Ralph R. 
Published: July 2017

Abstract
For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local lack of molecular oxygen, or low pO2. The focus of this research has been to validate the hypothesis that has been assumed, but not proven over the past century, that radiation treatment focused specifically on hypoxic regions of tumors would improve tumor curability. This research used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO2 images in volume elements or voxels of murine tumors with 1 torr pO2 resolution and 0.7 mm spatial resolution in FSa fibrosarcomas in the legs of C3H mice. We define hypoxic regions of tumors as those whose image subvolumes or voxels have low pO2, voxels less than 10 torr. We have established EPR pO2 imaging as a reliable locator of relevant radiobiologically relevant hypoxia. To determine if pO2 based dose painting improves tumor cure, we implemented the XRAD225Cx system to deliver gantry based x-ray treatments to mouse tumors accurately registered with EPR pO2 images. All tumors were pretreated with a dose of radiation that had been determined in separate experiments to cure 30% of tumors, a TCD30. Conclusive failure to demonstrate a difference between treating crude spherical volumes including ~ 85% of hypoxic voxels with an additional curative dose compared with treatment with shells of radiation avoiding hypoxia (anti-boosts) proved tenets of radiation biology: a few surviving hypoxic clonogens cause radiation treatment failure. In response, we implemented rapid 3D printing Tungsten loaded, highly conformal plastic blocks to compare treating ~100% of hypoxic tumor voxels with hypoxia avoidance, treating similar volumes of well oxygenated tumor. Only then did we observe significant (p&lt;0.01) tumor control differences between hypoxic boosts and anti-boosts. This is the first validation of the curative effectiveness of focusing hypoxia based dose painting in mammalian tumors.
Citation Format: Howard J. Halpern, Boris Epe;, Matthew C. Maggio, Martyna Krzykawska-Serda, Gage H. Redler, Richard C. Miller, Eugene D. Barth, Ralph R. Weichselbaum. First demonstration that hypoxia targeting with radiation improves tumor control in a mammal tumor model [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 1874. doi:10.1158/1538-7445.AM2017-1874