bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2001: Inhibiting voltage-gated sodium channel activity in medullary thyroid cancer using small molecule compounds
Authors: Ahuja Paras , Guenter Rachael , Cowan Jaden , Shihab Yazen , Whitt Jason , Chen Herbert , Velu Sadanandan , Jaskula-Sztul Renata 
Published: August 2019

Abstract
Medullary thyroid cancer (MTC) is a type of neuroendocrine cancer (NE) with increasing incidence worldwide. Compared with well-differentiated thyroid cancers, distant metastases are more commonly observed in MTC patients, ranging from 7-23%. The inability to treat metastatic MTC contributes to a decreased patient survival rate. Currently, at least nine mammalian voltage-gated sodium channels (VGSCs) named Nav1.1-Nav1.9 have been identified as potential safe drug targets for treating metastasis in various cancers. Herein, we investigate the effects of targeting VGSCs in MTC using small molecule inhibitors. Two MTC cell lines, TT and MZ, were treated with four compounds and the changes in mRNA and protein expression of VGSC isoform Nav1.7 were assessed through RT-PCR and western blotting. Treatment by one of the compounds exhibited a 28-fold decrease in mRNA expression of VGSC isoform 1.7. Furthermore, a cell proliferation assay, proliferation assay (MTT) a MTT, assay to study cell proliferation after treatment showed decreasing cell viability resulted from the treatment. and Additionally, morphological changes characteristic of apoptosis in fluorescently labeled MTC cell lines after 48 hours of treatment with VGSC inhibitory compounds were observed. A Boyden chamber assay was also performed on MTC cell lines to examine changes in migration and invasion after administering the potential inhibitory compounds. This study has generated preliminary evidence that voltage-gated sodium channels (VGSCs) may indeed be potential targets for treating metastatic MTC. The results may be translated to future studies focused on controlling metastasis through specified drug treatment in MTC, leading to the limitation of cancer progression by means of targeting VGSCs.
Citation Format: Paras Ahuja, Rachael Guenter, Jaden Cowan, Yazen Shihab, Jason Whitt, Herbert Chen, Sadanandan Velu, Renata Jaskula-Sztul. Inhibiting voltage-gated sodium channel activity in medullary thyroid cancer using small molecule compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2001.
Abstract 2014: A novel small molecule inhibitor to suppress Notch1 activation in CRC
Authors: Damodaran Chendil , Tyagi Ashish , Chandrasekaran Balaji , Kolluru Venkatesh , Jojua Ibrahim , Ramisetti Srinivasa , Sharma Arun K. , Ankem Murali K. 
Published: August 2019

Abstract
Introduction: Earlier we reported that aberrant overexpression of Notch1 in colon cancer patients is responsible for aggressiveness and progression of the disease. Current, therapeutic interventions of notch1 inhibitors that binds catalytic unit of γ-secretase and disrupts the cleavage activity cause gastrointestinal toxicity in clinical trial. Therefore, our study aims to develop a small molecule inhibitor, which inhibits Notch1 signaling but binds outside of γ-secretase’s catalytic unit thereby substantially reducing associated toxicity attributes. Through structure-activity relationship (SAR) studies based on naturally occurring Withaferin A (WA) structure, we have recently identified a WA-difuroate analog ASR458 as one such small molecule.
Methods: To analyze the effect of ASR490 on HCT116 and HCT116/Notch1 cells, we performed phenotypic, western blot and in vivo analysis.
Results: Notch1 overexpressing CRC cells (HCT/Notch1) showed aggressive cell growth (42%) as compared to HCT116 cells, however, ASR490 treatment inhibited cell growth in both HCT116 (IC50: 600 nM) as well as HCT/Notch1 cells (IC50: 850 nM). ASR458 significantly inhibited Notch1 expression and its downstream events in both the transfected cell lines. As a result, we observed shutdown of pro-survival machinery and induction of pro-apoptotic events (Bax, caspases and PARP) resulting in apoptotic cell death in ASR456 treated HCT116 and Notch1/HCT116 cells. Since Notch1 is responsible for epithelial mesenchyme transition (EMT); we analyzed EMT drivers and readout invasion/migration assays. ASR458 treatment reversed the mesenchymal characteristics by restoring the function of E-cadherin, which resulted in the suppression of invasion and migration in readout assays of HCT116 transfectants. Our ongoing Xenotransplanted mice experiments may suggest whether ASR458 inhibits the growth of HCT116 and HCT116/Notch1 tumors.
Conclusion: Restrained gastrointestinal toxicity of Notch1 targeting therapeutics is achievable with novel small molecules displaying a differential binding affinity to γ-secretase. ASR458 inhibits cell growth in Notch1 overexpressing cells and abrogates Notch1 induced EMT. Ongoing molecular docking and in vivo studies may confirm ASR458 binding sites in γ-secretase and validate our in vitro findings respectively.
Citation Format: Chendil Damodaran, Ashish Tyagi, Balaji Chandrasekaran, Venkatesh Kolluru, Ibrahim Jojua, Srinivasa Ramisetti, Arun K. Sharma, Murali K. Ankem. A novel small molecule inhibitor to suppress Notch1 activation in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2014.
Abstract 2015: Downregulation of MZB1 by aminoguanidine, APOE mimetic and nitroxyl compounds associated with reduction in invasive breast tumor volume and metastasis
Authors: Cheng Yuk Sing Robert , Basudhar Debashree , Lisa Rdinour , Somasundaram Veena , Wink David 
Published: August 2019

Abstract
Triple negative breast cancer (TNBC) is notoriously known for poor prognosis due to a lack of actionable molecular target(s). Remarkably, the majority of TNBC patients suffer the cancer relapse even they receive treatment given for early stage breast cancers. Up-to-date, lots of therapeutic agents have been developed and actionable molecular targets have been proposed. Nevertheless, the survival rate for metastatic invasive breast cancer is low because of poor prognosis. In this study, we determined whether different classes of chemo-agents (or compounds) interact with different cellular and molecular pathways they might share some common pathway(s) if their therapeutic outcome is similar. We first tested the effect of aminoguanidine (AG), APOE mimetics (COG), and nitroxyl (HNO) compounds on carcinogenesis and metastasis using an orthotopic breast cancer model. In vivo imaging analysis indicated that these compounds significantly reduced the tumor loading in the xenografts (MDA-MB-231-GFP). Moreover, compounds AG and COG are able to reduce brain metastasis significantly. RNA-Seq analysis identified only one gene which is commonly altered in all treatment groups. This gene encodes marginal zone B and B1 cell specific protein (MZB1). MZB1 was downregulated after treatment and its expression was inversely correlated with the efficacy of brain metastasis. In addition, pathway comparison analysis of RNA-Seq data revealed there are three top canonical pathways including (1) Role of NFAT in Regulation of the Immune Response, (2) PKC theta Signaling in T Lymphocytes, and (3) iCOS-iCOSL Signaling in T Helper Cells, downregulated in all treatment groups. In conclusion, our findings demonstrated three different classes of compounds can reduce not only tumor loading but metastasis. MZB1, identified from our transcriptome analysis, may serve as an actionable molecular target for TNBC. All-in-all, it provides new insights into the development of new therapeutic targets and biomarkers for TNBC.
Citation Format: Yuk Sing Robert Cheng, Debashree Basudhar, Rdinour Lisa, Veena Somasundaram, David Wink. Downregulation of MZB1 by aminoguanidine, APOE mimetic and nitroxyl compounds associated with reduction in invasive breast tumor volume and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2015.
Abstract 2020: Adipocytes up-regulates CD36 expression, fatty acid uptake and oxidation enhancing breast cancer cell progression
Authors: Choi Junjeong , Gyamfi Jones 
Published: August 2019

Abstract
The role of the tumor microenvironment in tumor progression has recently gained enormous attention, with studies reporting heterogeneous interactions between tumor cells and tumor stroma cells driving tumor progression. The breast cancer microenvironment is unique since the breast tissue within which the tumor originates comprises predominantly of adipocytes. This makes adipocytes a unique component in the breast cancer microenvironment. Adipocytes secrete various growth factors and cytokines that influence tumor progression by induction of epithelial-mesenchymal transition (EMT) which enhances cancer cell migration, invasion and metastasis. This study presents an alternative approach by which adipocytes may enhance cancer progression via the transfer of free-fatty acids from tumor-associated adipocytes to breast cancer cells. The uptake of free fatty acid subsequently serves as a secondary source of energy to drive breast cancer progression. The study aimed to provide an in-depth understanding of the molecular mechanism by which free fatty acid are imported and metabolized in cancer cells in an adipocyte-rich microenvironment. Human adipocytes were co-cultured with cancer cells and the fatty acid (FA) translocase (CD36) activity was inhibited by the chemical inhibitor sulfosuccinimidyl oleate (SSO). Silencing RNA and expression plasmids were used to evaluate CD36 activity in cancer cells. Expression levels of key genes and proteins involved in lipid transfer and metabolism were evaluated by qtPCR and western blot. Inhibition of CD36 reduces free fatty acid uptake and induces intracellular lipogenesis with upregulation of fatty acid synthase (FASN). Breast cancer cells co-cultured with human adipocytes express high levels of the CD36 facilitating free fatty acid uptake from adipocytes. Co-cultured cells had increased levels of fatty acid oxidation (FAO) and oxygen consumption, with increased migration and invasion characteristics. We also observed a significant increase in the expression of CPT1A required for mitochondrial fatty acid import and ATGL required for triglyceride metabolism. Our findings indicate an enhanced dependence on FAO in co-cultured cancer cell. Indicating a potential bioenergetic adaptation of breast cancer cells to the adipocyte-rich microenvironment. Inhibition of CD36 and CPT1 significantly decreased breast cancer cell migration and invasion. These results suggest that cancer-associated adipocytes induce free fatty acid uptake via upregulation of CD36 and reprogram breast cancer cell metabolism. Thus, targeting CD36 may have a potential targeted therapy.
Citation Format: Junjeong Choi, Jones Gyamfi. Adipocytes up-regulates CD36 expression, fatty acid uptake and oxidation enhancing breast cancer cell progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2020.
Abstract 2021: Role of MMP1-PAR-1 crosstalk in the pro-tumorigenic senescent fibroblasts in large cell carcinoma of the lung
Authors: Gabasa Marta , Ikemori Rafael , Radisky Evette , Reguart Noemí , Radisky Derek , Alcaraz Jordi 
Published: August 2019

Abstract
Tumor associated fibroblasts (TAFs) are key effector cells of cancer progression. Intriguingly, senescent TAFs have been reported in a growing list of agressive cancer subtypes including large cell carcinoma (LCC) of the lung. We previously reported that LCC cells induce fibroblast senescence in indirect co-cultures with transwells, revealing that paracrine signaling must be involved. A follow-up study identified MMP1 as an important regulatory protein in fibroblast senescence, since knocking-down MMP1 in LCC cells was sufficient to abrogate the induction of fibroblast senescence in co-cultures as well as the growth and invasion enhancement elicited by the conditioned medium of fibroblasts in LCC cells. Here we examined the potential role of the protease activated protein 1 (PAR-1) in fibroblast senescence by MMP1, since PAR-1 can be activated by MMP1 and has been reported in the stroma of lung cancer patients. We found that PAR-1 expression was down-regulated in fibroblasts that become senescent upon co-culture with LCC cells. In addition, forcing a reduced PAR-1 expression in fibroblasts by siRNA increased their expression of markers of the senescence associated secretory phenotype (SASP) during co-culture with LCC cells, whereas the percentage of senescence-associated beta-galactosidase positive fibroblasts remained largely unaffected. These results suggest that fibroblast senescence elicited by MMP1 secreted by LCC cells is mediated by processes other than PAR-1 activation and/or overexpression in fibroblasts.
Citation Format: Marta Gabasa, Rafael Ikemori, Evette Radisky, Noemí Reguart, Derek Radisky, Jordi Alcaraz. Role of MMP1-PAR-1 crosstalk in the pro-tumorigenic senescent fibroblasts in large cell carcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2021.
Abstract 2028: CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype
Authors: Song Erwei , Chen Jianing , Su Shicheng 
Published: August 2019

Abstract
Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment critically involved in cancer progression. Our recent study identified a specific CAFs subset by two cell-surface molecules, CD10 and GPR77. We proved that CD10+GPR77+CAFs could promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). However, their origin and underlying activating initiation mechanism are unclear. Tumor-associated macrophages (TAMs) are the most abundant immune-related stromal cells and the important source of inflammatory cytokine. Here, we demonstrated that CCL18 secreted by TAMs could induces the activation of normal breast fibroblasts into a CD10+GPR77+CAFs phenotype, which are not only resistant to chemotherapy themselves, but also can induce chemoresistance in cancer cells by abundantly producing IL-8 and IL-6 and enriching the population of cancer stem cells. In conclusion, our studies have identified an inflammatory signaling network in the interaction of different kind of stroma cells in tumor microenvironment and highlighted its potential values as predictive markers and therapeutic targets to abrogate tumor formation and improve chemotherapeutic efficacy.
Note: This abstract was not presented at the meeting.
Citation Format: Erwei Song, Jianing Chen, Shicheng Su. CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2028.
Abstract 2029: Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression
Authors: Enomoto Atsushi , Mizutani Yasuyuki , Kobayashi Hiroki , Iida Tadashi , Woods Susan L. , Worthley Daniel L. , Takahashi Masahide 
Published: August 2019

Abstract
Cancer-associated fibroblasts (CAFs) constitute a major component of the cancer stroma. They can promote cancer progression through a variety of mechanisms including the production of growth factors, chemo/cytokines, and extracellular matrix (ECM). Recent observations from genetically engineered mouse models and clinical studies have suggested that there may exist at least two subpopulations of CAFs, i.e., cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). Although various pCAF markers have been identified, the identity of rCAFs is unknown due to a lack of specific rCAF marker(s). Here, we show that Meflin, a glycosylphosphatidylinositol (GPI)-anchored protein that maintains the undifferentiated state of mesenchymal stromal/stem cells (MSCs) (Maeda et al., Sci Rep, 6:22288, 2016), is a marker of pancreatic stellate cells (PSCs). We find that Meflin-positive CAFs represent rCAFs in pancreatic ductal adenocarcinoma (PDAC). Infiltration of Meflin-positive CAFs correlated with favourable prognosis in patients with PDAC, consistent with our observation that Meflin deficiency led to tumour progression with poorly differentiated histology in a PDAC mouse model. Notably, Meflin-positive cells gave rise to α-smooth muscle actin (SMA)-positive CAFs during cancer progression. Both genetic ablation of Meflin-positive CAFs and delivery of a Meflin-expressing lentivirus into the stroma suppressed xenografted tumour differentiation and growth, respectively. Mechanistically, Meflin interacts with lysyl oxidase (Lox) to inhibit collagen crosslinking activity, and Meflin deficiency led to straightened and wide stromal collagen fibers as demonstrated by a second harmonic generation microscopy. These data demonstrate the presence of rCAFs in the cancer stroma and the significance of their differentiation to pCAFs in cancer progression, which may be exploited for the development of therapeutic strategies to specifically target pCAFs or reprogram them into rCAFs.
Citation Format: Atsushi Enomoto, Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Susan L. Woods, Daniel L. Worthley, Masahide Takahashi. Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2029.
Abstract 2037: Macrophage Inflammatory Protein-3 beta (MIP-3β) from cancer-associated fibroblasts promote the proliferation of melanoma cells
Authors: Fujikawa Heishiro , Yashiro Masakazu , Hatano Takaharu , Maeda Shusaku , Motomura Hisashi 
Published: August 2019

Abstract
Introduction: Malignant tumors are composed of cancer cells and various types of stromal cells, including fibroblasts, vascular endothelial cells, and immune cells. It has been reported that fibroblasts in the tumor stroma termed as cancer-associated fibroblasts (CAFs) may affect cancer progression. However, the currently available evidence regarding the function of CAFs remains controversial, with some studies reporting stimulatory activity and some studies reporting inhibitory activity in malignant melanoma cells. Previously, we reported that CAFs possibly exert a stimulatory effect on the proliferation of melanoma cells. In this study, we identified a factor from CAFs that are involved in melanoma progression.
Materials and Methods: We used three malignant melanoma cell lines, namely MMAc, COLO679, and A375. Three CAFs and one type of non-affected fibroblasts (NAFs) were established from sebaceous carcinoma/skin malignant melanoma and normal skin, respectively. Serum-free conditioned medium from CAFs (CAF-CM) was prepared as follows: CAFs were seeded into 100-mm plastic dishes with 10 ml of Dulbecco's modification of Eagle medium (DMEM) containing 5% fetal calf serum. To obtain CAF-CM, CAFs were washed using phosphate-buffered saline and subsequently incubated for 3 days with serum-free DMEM, and the conditioned medium was collected as CAF-CM. Additionally, we obtained NAF-CM from NAFs using the same procedure. These fibroblasts were cultured and used before the 15th passage. The cytokines included in each conditioned medium were determined using cytokine assay. Subsequently, we selected some cytokines, which were released more abundantly in CAFs than in NAFs, as potential factors affecting the proliferation of melanoma cells. The effects of these cytokines on the proliferation of melanoma cells were determined using MTT assay and cytometry assay using a Coulter Counter.
Results: CAF-CM contained significantly high concentration of MIP-3β, in compared with that in NAF-CM. In addition, MIP-3β significantly increases in the proliferation of melanoma cells, A375 and COLO679, at 48 h and 72 h culture.
Conclusion: CAFs from skin cancer might promote the proliferation of malignant melanoma cells via MIP-3β signaling.
Citation Format: Heishiro Fujikawa, Masakazu Yashiro, Takaharu Hatano, Shusaku Maeda, Hisashi Motomura. Macrophage Inflammatory Protein-3 beta (MIP-3β) from cancer-associated fibroblasts promote the proliferation of melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2037.
Abstract 2056: Combined FLT3 and Pim kinase inhibitor treatment downregulates c-Myc early in apoptosis induction in acute myeloid leukemia with FLT3-ITD
Authors: Lee Jonelle K. , Scarpa Mario , Kapoor Shivani , Baer Maria R. 
Published: August 2019

Abstract
Background: fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in acute myeloid leukemia (AML) in 30 % of patients, with poor treatment outcomes due to rapid relapse. FLT3 inhibitors have limited activity and rapid onset of resistance. The oncogenic serine/threonine kinase proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is upregulated downstream of FLT3-ITD and phosphorylates and stabilizes FLT3 in a positive feedback loop in cells with FLT3-ITD. Dual inhibition of FLT3 and Pim kinases is therefore a promising treatment strategy for AML with FLT3-ITD. The proto-oncogene c-Myc, upregulated in many cancer types, drives proliferation and causes resistance to apoptosis. We previously showed that concurrent FLT3 and Pim inhibition in cells with FLT3-ITD increases apoptosis through downregulation of the anti-apoptotic protein Mcl-1. Here we demonstrate downregulation of c-Myc upstream of Mcl-1.
Methods: Ba/F3-ITD and MV4-11 cells, with FLT3-ITD, were cultured with the FLT3 inhibitors gilteritinib (15 nM) or quizartinib (1 nM) and the pan-Pim inhibitor AZD1208 (1 μM) alone and in combination, and with DMSO control. c-Myc and Mcl-1 protein expression was measured by immunoblotting and c-Myc mRNA by qPCR using SybrGreen. Cells were cultured with cycloheximide (100 μg/mL) with and without the proteasome inhibitor MG-132 (20 μM). Ba/F3-ITD cells were stably transfected with a lentiviral c-Myc plasmid or a retroviral Mcl-1 plasmid and corresponding empty vectors. Apoptosis was detected by Annexin V and propidium iodine staining, measured by flow cytometry.
Results: Combined FLT3 and Pim inhibitor treatment decreased c-Myc protein expression in Ba/F3-ITD and MV4-11 cells within 30 minutes, preceding Mcl-1 downregulation. c-Myc mRNA levels did not change, but c-Myc protein half-life decreased with combination treatment, and this decrease was abrogated by proteasome inhibitionMcl-1 overexpression did not abrogate c-Myc downregulation by combination treatment, and c-Myc overexpression decreased apoptosis induction by combination treatment from 65% to 45%.
Conclusion: Combined FLT3 and Pim kinase inhibitor treatment enhances apoptosis in FLT3-ITD cells through c-Myc downregulation, which precedes Mcl-1 downregulation. c-Myc downregulation is post-translational, via increased proteasomal degradation.
Citation Format: Jonelle K. Lee, Mario Scarpa, Shivani Kapoor, Maria R. Baer. Combined FLT3 and Pim kinase inhibitor treatment downregulates c-Myc early in apoptosis induction in acute myeloid leukemia with FLT3-ITD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2056.