bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 200: Long lasting inhibition of TGF-β receptor Type 1 inhibitor (TGF-β R1) for treatment of pancreatic cancer
Authors: Rodriguez-Aguayo Cristian , Bayraktar Emine , Shen Haifa , Lopez-Berestein Gabriel 
Published: July 2017

Abstract
Pancreatic cancer stroma is a high component of total tumor volume and activators of fibro-genesis such as Transforming growth factor-β (TGF-β) are abundantly secreted by pancreatic stellate cells (PSCs) to the tumor microenvironment. Aberrant TGF-β signaling pathways are associated with many human diseases, including bone diseases, immune-suppression, fibrosis, cancer progression and metastasis. However, the precise mechanism of this phenomenon in pancreatic cancer remains unclear. In this study we hypothesized that inhibition of TGF-β Type I receptor kinase (TGF-β R1) in pancreatic cancer and stellate cells regulates proliferation and fibrosis through the regulation of TGF-β R1 signaling pathway in PC cells, resulting in decreased migration, and decreased proliferation. We analyzed a TGF-β R1 data set of PC patients from the Cancer Genome Atlas. Furthermore, the analysis of a panel of pancreatic cancer cell lines showed that TGFR-B1 at mRNA and protein levels were higher in PC cells when compared with human pancreatic duct epithelial (HPDE) normal cells. In vitro cell viability, growth, cell-cycle progression, migration, invasion and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following the inhibition of TGF-β R1 in pancreatic cancer and stellate cells. The experimental validation identifies TGFR-β1 associated with PC survival. Significant inhibition of cell growth, invasion, migration, angiogenesis and fibro-genesis. Furthermore, treatment with LY-DMPC:DMPG-MSV inhibited growth of CAPAN-II tumors. These findings identify TGFR-β1 as a potential therapeutic target in pancreatic cancers expressing high levels of this oncogenic protein.
Note: This abstract was not presented at the meeting.
Citation Format: Cristian Rodriguez-Aguayo, Emine Bayraktar, Haifa Shen, Gabriel Lopez-Berestein. Long lasting inhibition of TGF-β receptor Type 1 inhibitor (TGF-β R1) for 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 200. doi:10.1158/1538-7445.AM2017-200
Abstract 2016: Novel dual cIAP1/XIAP antagonist ASTX660 activity in preclinical models of human papillomavirus(+) and (-) head and neck squamous cell carcinoma
Authors: Xiao Roy , An Yi , Derakhshan Adeeb , Chen Zhong , Schmitt Nicole C. , Waes Carter Van 
Published: July 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with a five-year survival of ~50%. HNSCC are linked to human papillomavirus (HPV+) or tobacco carcinogenesis (HPV-). The Cancer Genome Atlas recently analyzed 279 HNSCC, revealing that 30% overexpress FADD (Fas-Associated Death Domain), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), which are critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways that determine cell death or survival. The frequency of such mutations provides a window for potential therapeutics, as IAP antagonists have been shown to switch cancer cell TNFα signaling from being pro-survival to pro-apoptotic. We recently showed that birinapant, a second mitochondrial activator of caspases (SMAC) mimetic that promotes IAP degradation, sensitizes HNSCC to cell death by TNFα and eradicates tumors in combination with radiation in HPV- HNSCC models overexpressing FADD+/-BIRC2. ASTX660 (developed by Astex Pharmaceuticals) is a novel dual cIAP1/XIAP antagonist currently in clinical trials for treating advanced solid tumors and lymphomas. The objective of the present study is to determine the therapeutic effects of ASTX660 in HPV+/- HNSCC preclinical models. ASTX660 at nanomolar concentrations was found to potently inhibit cell proliferation (measured using XTT assays) and induce apoptosis (Annexin/7-AAD flow cytometry), and displayed combinatorial activity with TNFα, TRAIL, or cisplatin in multiple human HPV+/- HNSCC cell lines. Western blotting showed near complete degradation of cIAP1 expression at nanomolar concentrations in human HNSCC cell lines. Flow cytometry revealed that ASTX660 in combination with either TNFα or cisplatin reduced MHC-I expression and increased PD-L1 expression, suggesting that potential synergistic efficacy could be observed in combination with immune checkpoint inhibitors. Our results demonstrate that ASTX660 is a potential therapeutic agent for both HPV+/- HNSCC. Experiments evaluating the anti-tumor effects of ASTX660 as a monotherapy and in combination with radiation, cisplatin, and anti-PD-1 therapies are ongoing, using both human HNSCC xenograft and syngeneic mouse oral cancer (MOC) models. Supported by NIDCD intramural projects (ZIA-DC-000016, 73 and 74).
Citation Format: Roy Xiao, Yi An, Adeeb Derakhshan, Zhong Chen, Nicole C. Schmitt, Carter Van Waes. Novel dual cIAP1/XIAP antagonist ASTX660 activity in preclinical models of human papillomavirus(+) and (-) head and neck squamous cell 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 2016. doi:10.1158/1538-7445.AM2017-2016
Abstract 202: Comprehensive spatial mapping by MALDI imaging mass spectrometry of the N-glycan tissue glycome and database generation for eighteen tumor types
Authors: Drake Richard R. , Talbot Kacey , Norris-Caneda Kim , Bruner Evelyn , Angel Peggi M. 
Published: July 2017

Abstract
Glycoproteins account for approximately 80% of the proteins located at the cell surface and in the extracellular environment, and serve as binding ligands for cell adhesion, extracellular matrix molecules, signaling receptors, immune cells, lectins and pathogens. Alterations and changes in cell surface glycosylation during tumorigenesis are well documented, including the major N-linked glycan class of glycosylated proteins. We have recently developed a MALDI imaging mass spectrometry (MALDI-IMS) method to spatially profile N-linked glycans in frozen and formalin-fixed paraffin-embedded (FFPE) tissue sections and tissue microarrays (TMAs). In order to facilitate method development and maximize glycome determinations for many cancer types, we have generated two custom TMAs comprised of multiple tissue core pairs of non-tumor and tumor regions representing eighteen different tumor types (pancreatic, colon, prostate, breast, lung, melanoma, sarcoma, head/neck, kidney, liver, glioma, ovarian, thyroid, uterine, cervical, testicular, gastric, bladder). Tissues are incubated with a molecular coating of peptide N-glycosidase, and released N-glycans are detected directly using MALDI-FTICR imaging, linked directly with tissue histopathology. The method is able to simultaneously identify and distinguish 50 or more components of the N-glycome on a single slide. The approach allows comparison of the similarities and differences in N-glycome compositions across each tumor tissue type, as well determine the relative abundance of each individual glycan across all tumor types. For example, an increase in high mannose glycans is common to many tumor types. From the TMA data, this glycan class is consistently elevated for colon, prostate, lung, breast and bladder cancers, while the other tumor types are variable. Differences in branching complexity, bisecting N-acetylglucs0amine, and the degree of fucosylation and sialylation are also readily evaluable. Additionally, data from each of the TMA core pairs is being compared systematically to the N-glycans detected in the source FFPE blocks. The goal is to generate an extensible reference database of expected N-glycans for each tumor tissue type. This will also provide a framework to expand to other classes of glycans, and complementary glycan data generated by other methods on the same TMA cores.
Citation Format: Richard R. Drake, Kacey Talbot, Kim Norris-Caneda, Evelyn Bruner, Peggi M. Angel. Comprehensive spatial mapping by MALDI imaging mass spectrometry of the N-glycan tissue glycome and database generation for eighteen tumor types [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 202. doi:10.1158/1538-7445.AM2017-202
Abstract 2028: PDE3A modulation for cancer therapy
Authors: Wu Xiaoyun , Lewis Timothy , Waal Luc de , Gao Galen , Zhang Jian , Schenone Monica , Garvie Colin , Diamond Brett , Lorrey Selena , Cherniack Andrew , Corsello Steven , Burgin Alex , Golub Todd , Schreiber Stuart , Meyerson Matthew , Greulich Heidi 
Published: July 2017

Abstract
In a differential cytotoxicity screen, we identified a novel small molecule modulator of phosphodiesterase 3A (PDE3A) that kills cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal, Nat Chem Biol, 2016). Treatment with this cell-selective cytotoxic small molecule, DNMDP, induces complex formation between PDE3A and SLFN12, resulting in apoptosis. Inhibition of PDE3A enzymatic activity is not sufficient for cancer cell killing, and expression of both PDE3A and SLFN12 are required. Although the mechanism of signaling to the apoptosis machinery remains unclear, we examined more closely the role of the PDE3A-SLFN12 complex in cancer cell killing mediated by DNMDP. We found that cancer cell lines made resistant to DNMDP by persistent exposure downregulated SLFN12 expression and that re-expression of SLFN12 was sufficient to restore sensitivity. Furthermore, ectopic expression of PDE3A and SLFN12 are sufficient to sensitize cancer cells to DNMDP. These data underscore the tight correlation of PDE3A-SLFN12 complex formation and cancer cell killing mediated by DNMDP.
Citation Format: Xiaoyun Wu, Timothy Lewis, Luc de Waal, Galen Gao, Jian Zhang, Monica Schenone, Colin Garvie, Brett Diamond, Selena Lorrey, Andrew Cherniack, Steven Corsello, Alex Burgin, Todd Golub, Stuart Schreiber, Matthew Meyerson, Heidi Greulich. PDE3A modulation for cancer therapy [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 2028. doi:10.1158/1538-7445.AM2017-2028
Abstract 2055: Therapeutic resistance to BET bromodomain inhibition in prostate cancer
Authors: Engelke Carl G. , Malik Rohit , Kregel Steven , Asangani Irfan A. , Wilder-Romans Kari , Jiang Xia , Cao Xuhong , Speers Corey , Chinnaiyan Arul M. 
Published: July 2017

Abstract
Prostate cancer is the most common cancer among men and a leading cause of cancer-related death in North America. Current therapies include radical prostatectomy and radiotherapy for localized disease, and androgen deprivation therapy (i.e. surgical or medical castration) for metastatic disease. Recently, we described the use of inhibitors of bromodomain and extraterminal (BET) proteins for the treatment of castration-resistant prostate cancer (CRPC), which have since undergone investigation in clinical trials. In anticipation of patients refractory to treatment with BET inhibitors, we explored the development of resistance to a clinical-grade BET inhibitor in four cell line models—VCaP, LNCaP, LNCaP-AR, and 22Rv1—by serially passaging cells in increasing concentrations of drug with matched controls in DMSO. All resistance models displayed several-fold increased IC50 values relative to control in in vitro cell viability assays. Additionally, we have modeled resistance to BET inhibition in vivo by serially passaging cell line- and patient-derived xenografts in animals treated with BET inhibition. Interrogating these models through traditional molecular techniques and next-generation sequencing, we discovered several putative mechanisms of resistance to BET inhibition that we are currently validating in our laboratory.
Note: This abstract was not presented at the meeting.
Citation Format: Carl G. Engelke, Rohit Malik, Steven Kregel, Irfan A. Asangani, Kari Wilder-Romans, Xia Jiang, Xuhong Cao, Corey Speers, Arul M. Chinnaiyan. Therapeutic resistance to BET bromodomain inhibition in 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 2055. doi:10.1158/1538-7445.AM2017-2055
Abstract 2058: Co-treatment of NVP-BSK805 highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition
Authors: Park Yu Jin , Cheon Ji Hyun , Son Ji Yeon , Yoon Sung Pil , Kim Hyung Sik 
Published: July 2017

Abstract
The high expression of P-glycoprotein (P-gp) is consistently observed in multidrug resistance (MDR) cancer cells. The purpose of our study is to identify conditions that could increase the sensitivity of P-gp-overexpressing the drug-resistant KBV20C cancer cell line. We have used the commercially-available epigenetic library, which includes 128 compounds. Using the cellular viability test, we also identified that NVP-BSK805 is highly sensitized to KBV20C-resistant cells and vincristine treatment. However, NVP-BSK805-induced sensitization was not observed in vincristine-treated sensitive KB parent cells, suggesting that the effects are specific to resistant cancer cells. Using FACS analysis, western blot, and Annexin V staining, we identified that NVP-BSK805 sensitized vincristine-treated KBV20C cells arrest via apoptosis and G2. Furthermore, sensitization potency of NVP-BSK805, in combination with vincristine, was measured in KBV20C cells when comparing them with P-gp inhibitor verapamil or another Jak2 inhibitor CEP-33779. We further investigated the mechanisms of NVP-BSK805 against sensitization of vincristine-treated KBV20C cells. The sensitization mechanism of NVP-BSK805 was mainly dependent on the inhibition of P-gp. In addition, ATPase activity was conducted to identify its potential role in NVP-BSK805 for P-gp inhibition. Both NVP-BSK805 and CEP-33779 showed high binding affinity docking scores -9.1 and -7.4, respectively, against the ABCB1 receptor protein. Collectively, inhibition of P-gp by NVP-BSK805 can increase vincristine-sensitivity in MDR cancer cells through increased apoptosis and G2 arrest. Our findings indicate that the Jak2 inhibitor may be a promising target in the treatment of patients resistant to antimitotic drugs.
Citation Format: Yu Jin Park, Ji Hyun Cheon, Ji Yeon Son, Sung Pil Yoon, Hyung Sik Kim. Co-treatment of NVP-BSK805 highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition [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 2058. doi:10.1158/1538-7445.AM2017-2058
Abstract 2074: Targeting SHP-1 mediated VEGF signaling to block the migration of human triple negative breast cancer
Authors: Su Jung-Chen , Mar Ai-Chung , Liu Chun-Yu , Chen Kuen-Feng , Shiau Chung-Wai 
Published: July 2017

Abstract
Patients with triple-negative breast cancer (TNBC) had an increased likelihood of distant recurrence and death, as compared with those with non-TNBC subtype. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting oncogenesis and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recently, scientists have suggested that regorafenib also acts as a SHP-1 phosphatase agonist. In this study, we aimed to investigate the role of regorafenib in suppressing metastasis of TNBC cells through targeting the SHP-1/p-STAT3/VEGF-A axis. We first observed a significant correlation between migration ability and SHP-1/p-STAT3/VEGF-A expression in several human TNBC cell lines. Importantly, we also demonstrated that VEGF-A expression is correlated with worse disease-free and distant metastasis-free survival in clinical TNBC patients. Furthermore, we showed that regorafenib could inhibit the migration of human TNBC cells, which was related to downregulation of p-STAT3 and VEGF-A. To exclude the role of RTK inhibition in regorafenib-induced anti-metastasis, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1 activation. SC-78 demonstrated superior in vitro and in vivo anti-migration to regorafenib. This study indicated that the SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC, and SC-78 may be a promising lead compound for suppressing metastasis of TNBC. (Grant supported by MOST 104-2628-B-075-001-MY3, MOST 105-2325-B-010-007, 105F026 )
Citation Format: Jung-Chen Su, Ai-Chung Mar, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau. Targeting SHP-1 mediated VEGF signaling to block the migration of human triple negative 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 2074. doi:10.1158/1538-7445.AM2017-2074
Abstract 2076: Targeting the FGFR pathway in androgen receptor negative castration resistant prostate cancer
Authors: Morrissey Colm , Corey Eva , Brown Lisha , Coleman Ilsa , Nguyen Holly , Schweizer Michael , Nelson Peter 
Published: July 2017

Abstract
Metastatic castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. The continued importance of androgen receptor (AR) signaling as a growth and survival pathway in most advanced prostate cancer (PC) has prompted the development of therapeutics directed toward further suppressing AR ligands or the AR itself. However, total androgen blockade can give rise to AR-negative PC and currently there are no effective therapies for AR-negative PC. We have developed two novel patient-derived xenograft (PDX) models from a liver metastasis and a rib metastasis of a patient with CRPC: LuCaP 173.1 (Neuroendocrine; NE) and LuCaP 173.2 (Double negative: DN (AR-negative and NE-negative)). Using RNA-Seq we observed that both of these lines express high levels of fibroblast growth factors (FGF’s) and downstream effectors. We hypothesized that FGF signaling promotes survival and proliferation of NEPC and DNPC. To determine if blocking the FGFR survival pathway can attenuate the growth of NEPC/DNPC tumors, to characterize the molecular response and resistance to FGF signaling inhibition, and to support further evaluation in the clinic, we treated both PDX models with the FGFR inhibitor CH5183284. CH5183284 significantly reduced LuCaP 173.2 tumor volume (TV) (p&lt;0.0001). The reduction in TV in CH5183284-treated animals bearing LuCaP 173.1 tumors was not as significant. To address this difference, we analyzed FGFR1 expression at the transcript and protein levels. Analysis of the FGFRs in the LuCaP 173.1 PDX model revealed a loss of FGFR1 expression. FGFR2 and FGFR3 transcripts were expressed at similar levels in both PDXs. The loss of FGFR1 expression may explain the low efficacy of CH5183284 in the LuCaP 173.1 PDX model. We are currently assessing the molecular pathways impacted by FGFR inhibition and mechanisms of resistance to treatment in these studies. We have demonstrated that FGFR inhibition attenuated tumor growth in FGFhigh AR-negative PC. We intend to target the FGFR survival pathway in additional NE and DNPC PDX models to investigate tumor heterogeneity in response to therapy and identify mechanisms of resistance. These studies will provide translational evidence that FGFR inhibitors could represent a new therapy for CRPC patients with AR-negative PC.
Citation Format: Colm Morrissey, Eva Corey, Lisha Brown, Ilsa Coleman, Holly Nguyen, Michael Schweizer, Peter Nelson. Targeting the FGFR pathway in androgen receptor negative castration resistant 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 2076. doi:10.1158/1538-7445.AM2017-2076
Abstract 2085: Development of a novel targeted therapy for malignant mesothelioma carcinoma by a midkine inhibitor
Authors: Fukazawa Takuya , Maeda Yuitaka , Yamatsuji Tomoki , Takaoka Munenori , Yoshida Masakazu , Ishida Naomasa , Iwai Miki , Yokota Etsuko , Yukawa Takuro , Haisa Minoru , Miyake Noriko , Ikeda Tomoko , Takigawa Nagio , Whitsett Jeffery , Naomoto Yoshio 
Published: July 2017

Abstract
Malignant pleural mesothelioma is an aggressive tumor of mesenchymal origin and is increasing worldwide as a result of widespread exposure to asbestos. The median survival of patients with mesothelioma from time of diagnosis ranges between 1 and 2 years. The mortality is expected to increase, at least until 2020, which is mainly due to the long latency (30-50 years) of the disease. Despite considerable advances in the understanding of its pathogenesis and etiology, malignant mesothelioma remains largely unresponsive to standard modalities of cancer therapy. Thus, there is an urgent need for new therapeutic options for mesothelioma.Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. We have previously reported that a MDK inhibitor, iMDK, suppresses non-small cell lung cancer expressing MDK without harming normal cells. Importantly, iMDK inhibits the PI3 kinase / Akt pathway and induces apoptosis in MDK expressing non-small cell lung cancer cells. In the present study, we have investigated the antitumor effect of iMDK against malignant mesothelioma both in vitro and in vivo. 48 hours after treatment, iMDK dose-dependently inhibited cell growth of MDK expressing malignant mesothelioma cells. iMDK also suppressed colony formation of MSTO-211H mesothelioma cells. TUNEL positive cells were significantly increased in MSTO-211H cells 48 hours after iMDK treatment in a dose-dependent manner, confirming the induction of apoptosis in mesothelioma cells by iMDK. Combination treatment of iMDK and Bcl-2 inhibitor ABT-263 is more effective than each drug alone in MSTO-211H mesothelioma cells. Moreover, systemic administration of iMDK significantly inhibited tumor growth in a mesothelioma xenograft tumor in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of malignant mesothelioma that is driven by MDK.
Citation Format: Takuya Fukazawa, Yuitaka Maeda, Tomoki Yamatsuji, Munenori Takaoka, Masakazu Yoshida, Naomasa Ishida, Miki Iwai, Etsuko Yokota, Takuro Yukawa, Minoru Haisa, Noriko Miyake, Tomoko Ikeda, Nagio Takigawa, Jeffery Whitsett, Yoshio Naomoto. Development of a novel targeted therapy for malignant mesothelioma carcinoma by a midkine 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 2085. doi:10.1158/1538-7445.AM2017-2085