bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2034: Activation of cancer-associated fibroblasts via the transfer of miR-125b containing extracellular vesicles from tumor cells
Authors: Vu Luyen Tien , Peng Boya , Zhang Daniel Xin , Ma Victor , Grimson Andrew , Cho William C. , Lieberman Judy , Le Minh TN 
Published: August 2019

Abstract
Tumor cells secrete elevated amounts of extracellular vesicles (EVs) as a mean of communication between them and other cells in the tumor microenvironment. Here, we established a series of breast cancer cell lines releasing fluorescent EVs to identify the common cell types that receive tumor EVs within the tumor microenvironment. Among the different cell types, cancer-associated fibroblasts consistently take up the most EVs from cancer cells. Using next generation sequencing, we find that miR-125b is among the top enriched miRNAs in EVs released by mouse isogenic triple-negative breast cancer 4T1 and 4TO7 cell lines. Co-injection of 4TO7 cells with 4T1 EVs results in an upregulation of fibroblast activation in vivo while blockage of miR-125b in 4T1 EVs rescues the effect indicating that EV-delivery of miR-125b is crucial for the fibroblast activation in mouse breast cancer models. Moreover, EVs from human breast cancer cells also contain abundant miR-125b and fibroblasts within the xenografted tumor that take up these EVs gain higher levels of miR-125b and upregulation of cancer-associated fibroblast markers. Both mouse and human fibroblasts that are transfected with miR-125b mimics show an activated phenotype similar to the knockdown of established miR-125b targets. In summary, normal fibroblasts within the tumor microenvironment actively take up the miR-125b-containing EVs from breast cancer cells and develop into cancer-associated fibroblasts.
Citation Format: Luyen Tien Vu, Boya Peng, Daniel Xin Zhang, Victor Ma, Andrew Grimson, William C. Cho, Judy Lieberman, Minh TN Le. Activation of cancer-associated fibroblasts via the transfer of miR-125b containing extracellular vesicles from tumor 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 2034.
Abstract 205: BBI-608 enhances the activity of chemoradiotherapy in colorectal cancer pre-clinical models
Authors: Nagaraju Ganji Purnachandra , Balney Rajitha , Bethi Shipra R. , Govardhanagiri Sneha , Lesinski Gregory B. Lesinski B. , El-Rayes Bassel F. 
Published: August 2019

Abstract
Background: Chemoradiotherapy is a standard treatment modality for early stage rectal cancer (CRC). The pathologic complete response rate after chemoradiation in CRC remains low at 15%. Given the potential for BBI608 to elicit effects on multiple oncogenic cellular pathways, we hypothesized that BBI608 can sensitize colorectal cell lines to the effects of chemoradiotherapy. The aim of this study was to evaluate if BBI-608 enhances the response of chemoradiotherapy against CRC.
Methods: The combined effects of BBI-608 and chemoradiotherapy [5-FU + ionizing radiation (IR)] were evaluated in CRC cell lines (HCT 116 and HT-29) using Br-dU cell proliferation and clonogenic assays. Effects on the expression of DNA damage and repair (pATM, pATR, Rad51 and γ-H2AX) molecules and angiogenesis (pSTAT-3 and VEGF) pathways were examined by Western blot. Egg CAM assay was also performed to evaluate effects of the drugs on angiogenesis (quantification was performed by AngioQuant software). The in vivo efficacy of BBI-608 alone or combined with 5-FU + IR, was evaluated in nude mice bearing subcutaneous human HCT116 xenograft tumors
Results: The combination of BBI-608 and chemoradiotherapy significantly decreased cell proliferation (p&lt;0.001), colony formation (p&lt;0.001) and inhibited angiogenesis (p&lt;0.001) in CRC cell lines as compared to chemoradiotherapy. BBI-608 decreased angiogenesis as determined by both matrigel plug and egg CAM assays. Immunoblot analysis indicated BBI-608 and chemoradiotherapy also decreased expression of pSTAT-3, MDM2, Rad51 and VEGF while increasing pATM, γ-H2AX and p53, in comparison to chemoradiotherapy alone. In animal models, combined therapy with BBI-608 and 5-FU + IR led to significant inhibition of longitudinal tumor growth as compared to chemoradiotherapy alone (p&lt;0.001). No overt signs of systemic toxicity were evident and animals showed no loss of body weight in any of the treatment groups, indicating the combination was well-tolerated.
Conclusion: These observations provide preclinical proof-of-principle data that BBI-608 can enhance the anti-tumor effects of chemoradiotherapy. BBI608 plus chemoradiotherapy is a rational approach for potential future development in early stage rectal cancer.
Citation Format: Ganji Purnachandra Nagaraju, Rajitha Balney, Shipra R. Bethi, Sneha Govardhanagiri, Gregory B. Lesinski B. Lesinski, Bassel F. El-Rayes. BBI-608 enhances the activity of chemoradiotherapy in colorectal cancer pre-clinical models [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 205.
Abstract 2061: A novel small molecule inhibitor of MDM2-p53 (APG-115) has antitumor activity in gastric adenocarcinoma
Authors: Zhang Lin , Qiuyun Luo , Xianglei Yan , Wan Xueping , Yuan Luping , Zhang Yuxing , Zhou Suna , Pan Wentao , Pan Mengxian , Qiu Miaozhen , Mai Shijuan , Yang Dajun 
Published: August 2019

Abstract
Background: The amplification of Murine Double Minute 2 (MDM2) and mutation of P53 are significant processes in the incidence of gastric cancer. APG-115, a small molecular inhibitor of MDM2-P53, is a novel potential anticancer agent. We aim to investigate the anticancer effect of APG-115 in gastric cancer.
Methods: We selected 87 pairs of gastric cancer tissues (primary tumors and metastatic tissues). Using Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH), we examined the expression and amplification of MDM2 and P53. Using MTS, we examined the anti-proliferation activity of APG-115 in five gastric cancer cell lines (AGS, MKN-45, BGC-823, NCI-N87, NUGC-3) by CCK-8 assay. We used western blot analysis and siRNA interference for mechanism exploration to examine the anti-cancer activity of APG-115 in p53 wild type gastric cancer cell lines. Gastric cancer cell xenograft nude mice models were used for in vivo efficacy evaluation.
Results: We examined 87 pairs of gastric cancer tissues in IHC. The results suggested that the primary tumors and metastatic tissues with high expression of MDM2 and P53 have shortened survival. The proliferation inhibition of APG-115 on p53 wild-type gastric cancer cells of AGS and MKN45 was concentration and time dependent. APG-115 induced apoptosis in gastric cancer cells. APG-115 can induced cell-cycle arrest in G1/G0 phase in the p53 wild-type of gastric cancer cells. APG-115 exhibited potent antitumor activity against established human gastric cancer xenografts.
Conclusions: APG-115 can inhibitor tumor growth in p53 wild-type gastric cancer cells by inducing apoptosis and cell cycle arrest both in vitro and vivo. APG-115 can serve as an effective and precise therapeutic strategy for gastric cancer.
Citation Format: Lin Zhang, Luo Qiuyun, Yan Xianglei, Xueping Wan, Luping Yuan, Yuxing Zhang, Suna Zhou, Wentao Pan, Mengxian Pan, Miaozhen Qiu, Shijuan Mai, Dajun Yang. A novel small molecule inhibitor of MDM2-p53 (APG-115) has antitumor activity in gastric adenocarcinoma [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 2061.
Abstract 2063A: Glucolipotoxicity and altered oxidative stress responses in cancer cells
Authors: Al-Nahdi Arwa MT , John Annie , Raza Haider 
Published: August 2019

Abstract
Alterations in energy metabolism, such as aerobic glycolysis and lactic acid production, and mitochondrial bioenergetics are the key metabolic changes associated with increased glucose uptake in cancer cells (Warburg effect). Metabolic adaptation, inflammatory responses and oxidative stress have been implicated in cancer etiology and pathology. Both experimental and epidemiological studies have suggested that caloric restriction is beneficial in reducing the complications of cancer cells. Studies have also suggested that increased availability of energy metabolites, such as glucose and fatty acids, as also seen in obesity and diabetes, which induces inflammatory and oxidative stress responses, may also be key factors in cancer development. In the present study, we have used human hepatoma, HepG2 and rodent pancreatic cancer derived Rin-5F cells to investigate the effects of high glucose (25mM) and high palmitic acid (up to 0.3mM) on cell survival and cell death along with the metabolic, inflammatory and oxidative stress associated alterations in these cells. Our results have shown that both increased glucose and fatty acids induce DNA damage and caspase-dependent apoptosis and mitochondrial respiratory dysfunction. Glucolipotoxicity in these cells, due to increased ROS production and oxidative stress has been suggested to be involved in altering the mitochondrial membrane potential and bioenergetics. Altered Nrf-2/NFk-B/AMPK/mTOR-dependent cell signaling and inflammatory (IL6/PGE2) responses have also been observed when cells were treated with high glucose and palmitic acid. Interestingly, pretreatment with N-acetyl cysteine (NAC, 10mM), a GSH precursor, resulted in partial recovery from the oxidative stress-induced glucolipotoxicity. Our results suggest that the presence of high energy metabolites enhance inflammatory and oxidative stress responses that may be responsible for alterations in cancer cell signaling and metabolism.
Citation Format: Arwa MT Al-Nahdi, Annie John, Haider Raza. Glucolipotoxicity and altered oxidative stress responses in cancer 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 2063A.
Abstract 2075: MAPK pathway expression in platinum-treated cancers
Authors: Georgiadis Rebecca A. , Stark Amy , Hummon Amanda B. 
Published: August 2019

Abstract
The Mitogen-Activated Protein Kinase (MAPK) Pathway is a critical cell signaling pathway in normal cell function. It is involved in cell proliferation, cell survival, and differentiation. It is a common pathway that is mutated in many cancers, and drug targets have already been developed and tested in clinical trials for many components of this pathway. Further understanding of how gene expression in this pathway is altered by treatment of chemotherapeutic agents can potentially impact resistance to chemotherapeutic agents. The half-maximal inhibitory concentration (IC50) was found for A549 cultured lung adenocarcinoma cells treated with cisplatin and for DLD1 cultured colorectal adenocarcinoma cells and HCT116 colorectal carcinoma cells treated with cisplatin and oxaliplatin. The IC50 concentration of cisplatin-treated A549 cells was 5.429 µM, of DLD1 cells was 5.017 µM, and of HCT116 cells was 4.42 µM. The IC50 concentration of oxaliplatin-treated DLD1 cells was 37.53 µM, as compared to 10.36 µM for HCT116 cells. Therefore, the HCT116 cell type is more sensitive to both chemotherapies. qPCR was then conducted on platinum-treated A549 cultured cells, DLD1 cultured cells, and HCT116 cultured cells to evaluate expression of 6 MAPK pathway genes: RAF1, MAP2K1, MAPK1, STAT1, CREB1, and LAMTOR3. A different pattern of induced gene expression was observed across all three cell types. The 24 hour time point of cisplatin-treatment of A549 cells demonstrated a consistent upregulation of expression in all genes, which is starkly contrasted with a significant downregulation at the 48 hour time point. In HCT116 cells, cisplatin treatment led to the opposite trend, as there was downregulation at the 18 hour time point and significant upregulation at the 48 hour time point. DLD1 had inconsistent results. This demonstrates that level of expression of genes in the pathway is cell-type dependent and time-dependent. Naringenin is a flavonoid that has been implicated in MAPK signalling. We tested this compound as an inhibitor to determine the effect on platinum induced gene expression in lung and colorectal cells. These results have implications for treatment of multiple cancers, especially lung and colorectal cancer.
Citation Format: Rebecca A. Georgiadis, Amy Stark, Amanda B. Hummon. MAPK pathway expression in platinum-treated cancers [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 2075.
Abstract 2077: A novel assay for PARP-DNA trapping provides insights into the mechanism of action (MoA) of clinical PARP inhibitors (PARPi)
Authors: Illuzzi Giuditta , O'Connor Mark J , Leo Elisabetta 
Published: August 2019

Abstract
Treatments with PARPi in cancers with impaired DNA repair mechanisms (i.e. with Homologous Recombination Repair Deficiency, HRD) causes unsupportable genomic instability resulting in tumor cell death. PARPi act via a dual mechanism: 1) they block PARylation activity that normally occurs in response to DNA damage; 2) they trap PARP onto DNA lesions creating potentially cytotoxic PARP-DNA complexes. The longer PARP is inhibited and trapped onto the DNA, the greater the cytotoxic effect of PARPi in preclinical models. However, differences in preclinical PARP trapping potency have not translated into increased clinical efficacy with standard clinical doses used. Therefore, the ability to assess PARP-chromatin trapping in cancer models is critical for understanding the MoA of existing clinical PARPi. To date, this has been achieved by low throughput assays in non-HRD models using high PARPi concentrations and the addition of exogenous DNA damage.
Here, we describe the development of a novel assay, a high throughput in situ cell extraction platform, where PARP-chromatin trapping is monitored by immunofluorescence and can be multiplexed with the analysis of other relevant biomarkers. Our novel assay has several advantages compared to conventional methods: the overall experimental process is simpler and less time consuming with results being quantitative and less error prone. Most importantly, the higher throughput allows a thorough evaluation of PARP1-chromatin trapping kinetics and their effects with dose-response in a time-dependent manner for clinical PARPi following both continuous treatment or after a wash out of drug.
Using this new assay, we tested the kinetics in isogenic cell line pairs (BRCA2-/- and WT) and followed in parallel the appearance of biomarkers of DNA damage (e.g. γ-H2AX). The data have revealed important elements of differentiation between the MoA of clinical PARPi including the important insight that the strongest PARP trapper (talazoparib) has clearly reduced cytotoxic specificity for HRD cells, which likely explains the significantly reduced dose used in the clinic compared to other PARPi. These along with other data presented highlight how this next generation PARP trapping assays can provide important insights into PARPi MoA.
Citation Format: Giuditta Illuzzi, Mark J O'Connor, Elisabetta Leo. A novel assay for PARP-DNA trapping provides insights into the mechanism of action (MoA) of clinical PARP inhibitors (PARPi) [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 2077.
Abstract 2086: Targeting the MNK effector hnRNPA1 enhances the efficacy of BET inhibitors in cancer cells
Authors: Pham Thao , Stempel Sophie , Shields Mario , Spaulding Christina , Kumar Krishan , Bentrem David , Munshi Hidayatullah 
Published: August 2019

Abstract
Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. While a number of BET inhibitors are currently in preclinical development or in early phase clinical trials, BET inhibitors show limited single-agent activity. Thus, there is increasing interest in identifying combination regimens to enhance the efficacy of BET inhibitors. Since MNK kinases can enhance the efficacy of BET inhibitors in vitro and in vivo, in this report we evaluated whether targeting effectors downstream of MNK kinases can enhance the efficacy of BET inhibitors. We show that there is co-expression of the BET protein BRD4 and the MNK effector hnRNPA1 in human tumors. We show that hnRNPA1 knockdown can potentiate the effects of BET inhibitors, with enhanced apoptosis and suppression of proliferation and sphere-forming ability by cancer cells. We also show that the plant flavonoid Quercetin, which reduces hnRNPA1 protein levels in cancer cells, can enhance the efficacy of BET inhibitors. Co-treatment with BET inhibitors and Quercetin results in enhanced apoptosis, further suppression of proliferation, and decreased sphere-forming ability by cancer cells. Significantly, Quercetin synergizes with BET inhibitors at suppressing tumor growth in vivo. Together, these results demonstrate that targeting the MNK effector hnRNPA1 can enhance the efficacy of BET inhibitors, and we identify combination therapy with BET inhibitors and Quercetin for the treatment of cancer patients.
Citation Format: Thao Pham, Sophie Stempel, Mario Shields, Christina Spaulding, Krishan Kumar, David Bentrem, Hidayatullah Munshi. Targeting the MNK effector hnRNPA1 enhances the efficacy of BET inhibitors in cancer 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 2086.
Abstract 209: Metastatic colonization in the perivascular niche: A mechanotransduction perspective
Authors: Er Ekrem Emrah , Tello-Lafoz Maria , Hu Jing , Huse Morgan , Massagué Joan 
Published: August 2019

Abstract
Metastases are responsible for majority cancer related deaths. Disseminated tumor cells (DTCs) gain a diverse array of metastatic traits in order to adapt to and survive within different microenvironments, making them very difficult to therapeutically target. Remarkably, regardless of the secondary organ, DTCs survive and thrive in perivascular niches. Using xenograft and syngeneic models of metastasis in mouse, we found that upon extravasation, neuronal cell adhesion molecule L1 (L1CAM) expressed by DTCs engages the vascular basal lamina in order to amplify integrin β1 and integrin linked kinase (ILK) signaling in DTCs. ILK promotes actin polymerization for cell spreading and subsequent activation of mechanotransduction effector transcription factors YAP and MRTF. We found that activation of YAP and MRTF coincides with DTCs ability to dislodge resident pericytes from the perivascular niche and is an essential step in the metastatic colonization regardless of dormancy state. Therefore, these results provided us a unifying molecular mechanism that governs cancer progression from metastatic seeding to overt colonization. Ongoing studies will determine how mechanotransduction and pericyte-DTC interactions can be manipulated to prevent metastatic colonization by potentiating the immune response and exposing their biophysical vulnerabilities.
Citation Format: Ekrem Emrah Er, Maria Tello-Lafoz, Jing Hu, Morgan Huse, Joan Massagué. Metastatic colonization in the perivascular niche: A mechanotransduction perspective [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 209.
Abstract 2095: AsiDNATM, a targeted therapy with no acquired resistance
Authors: Jdey Wael , Kozlac Maria , Alekseev Sergey , Johnson Danielle , Bono françoise , bhaskara Srividya , thomas frederic , Dutreix Marie 
Published: August 2019

Abstract
The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection, i.e. treatment toxicity place the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we demonstrate that AsiDNA, the first antitumor drug with an agonist activity, can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long term exposure of cancer cells to the strong alarm signal, generated by the AsiDNATM DNA repair inhibitors, did not promote resistance emergence. It induces a stable new state characterized by the down regulation of the targeted pathways that persists for months after treatments. This property is due to the original mechanism of action of AsiDNATM, which acts by over-activating a “false” signaling of DNA damage through DNA-PK and PARP enzymes, and is not observed with other DNA repair inhibitors such as the PARP inhibitors olaparib and talazoparib. Transcriptomic analysis of AsiDNATM treated independent populations derived from lung and breast cancers revealed the common evolution of independent AsiDNA-treated samples, resulting in a general down-regulation of enzymes involved in DNA repair and oncogenesis, and a specific down regulation of DNA-PK targets. Similar down regulation of DNA-PK targets was observed in xenografted tumor in animal models after three cycles of AsiDNA treatment. Chromatin analysis revealed a major change in AsiDNATM treated populations with an increased nucleosome stability that could be responsible for the epigenetic modification observed. Long term treatment with AsiDNATM induces a new “alarm down” state in the tumor cells that increase its efficacy. These results suggest that agonist drugs such as AsiDNATM could promote a state-dependent tumor cell evolution by lowering their ability to respond to damage signal as predicted by the ecological and evolutionary “smoke detector principle”.
Citation Format: Wael Jdey, Maria Kozlac, Sergey Alekseev, Danielle Johnson, françoise Bono, Srividya bhaskara, frederic thomas, Marie Dutreix. AsiDNATM, a targeted therapy with no acquired resistance [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 2095.