bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1263: Targeting of CDCA8 suppresses hepatocellular carcinoma growth by restoring ATF3 tumor suppressor and inactivating oncogenic Akt signaling
Authors: Park Keon Uk , Ko Min Ji , Hwang Ilseon , Ryoo Hun-Mo , Lee Yun-Han 
Published: August 2019

Abstract
Background: Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide which remains a major challenge due to poor prognosis and limited treatment options. Cell division cycle associated 8 (CDCA8) is known as a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle and it is commonly overexpressed in human HCC. However, the functional role of CDCA8 in HCC progression remains to be clarified. In this study, we hypothesized if targeting of CDCA8 with small interfering (si) RNA could alter the course of HCC progression. We also investigated the molecular mechanism that mediates HCC cell death caused by CDCA8 silencing.
Methods: Human HCC cell lines, Huh1 and Huh7, were transfected with CDCA8 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and Western blotting. To obtain insights into the molecular changes in response to CDCA8 knockdown, global changes in gene expression were examined using RNA sequencing.
Results: siRNA silencing of CDCA8 inhibited HCC cell growth and long-term colony formation by blocking cell cycle progression and by inducing apoptotic cell death. RNA sequencing data showed that, representatively, the anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of tumor suppressive ATF3 and GADD34 genes and the downregulation of BGLAP, a key regulator of cell growth and invasiveness. Subsequent Western blot analysis affirmed that CDCA8 silencing induces the increase in the levels of ATF3 and GADD34 and the decrease in phosphorylated Akt in both Huh1 and Huh7 cells. Also, the same condition decreased the levels of PARP-1 and pro-caspase 3, accelerating apoptosis. Of importance, silencing of CDCA8 expression effectively suppressed HCC tumor growth in a murine xenograft model.
Conclusion: These findings suggest that targeting CDCA8 could be an attractive option for molecular therapy of HCC.
Citation Format: Keon Uk Park, Min Ji Ko, Ilseon Hwang, Hun-Mo Ryoo, Yun-Han Lee. Targeting of CDCA8 suppresses hepatocellular carcinoma growth by restoring ATF3 tumor suppressor and inactivating oncogenic Akt signaling [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 1263.
Abstract 1274: Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to channel antagonists
Authors: Granados Karol , Hüser Laura , Federico Aniello , Sachindra Sachindra , Wolff Gretchen , Umansky Viktor , Utikal Jochen 
Published: August 2019

Abstract
During melanoma progression, tumor cells undergo phenotypic switching, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). We propose a partial reprogramming model to target melanoma therapy resistance. Here we show that partially reprogrammed cells are a less proliferative and more dedifferentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate the development of resistance to MAPKi, cells were exposed to BRAF and MEK inhibitors. Partially reprogrammed cells become less sensitive to MAPKi, showing increased cell viability and decreased apoptosis. Based on genome expression data, we evaluated potential targets to restore sensitivity to MAPKi in partially reprogrammed cells. One of our candidates showed promising results by increasing apoptosis and differentiation after sequential treatment with BRAF and MEK inhibitors, in partially reprogrammed cells and human BRAFi-resistant cells. In summary, we show that partial reprogramming of melanoma cells is a feasible in vitro model to study resistance to MAPKi. Moreover, we suggest our candidate as a target to restore sensitivity of resistant cells to MAPKi which has significant clinical implications in the development of resistance to current treatments against melanoma.
Citation Format: Karol Granados, Laura Hüser, Aniello Federico, Sachindra Sachindra, Gretchen Wolff, Viktor Umansky, Jochen Utikal. Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to channel antagonists [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 1274.
Abstract 1276: Inhibition of lipid metabolism decreases proliferation and increases radiosensitvity in EGFR-TKI resistant NSCLC cells with bFGF secretion
Authors: Wang Wei , Peng Shunli , Wang Rong , Ma yueyun , Zhong Longhui 
Published: August 2019

Abstract
Primary and acquired EGFR-TKIs resistance restricts the benefit of EGFR-TKIs to EGFR mutant NSLCLC patients. Recent studies found that metabolic reprogramming might contribute to develop metastasis and drug resistance of tumor cells. Therefore, illustrating the metabolism change is meaningful and targeting the peculiar metabolic pathways might be considered as potential therapeutic strategies for EGFR-TKIs resistant NSCLC. We separated single clones from gefitnib resistant NSCLC cells, by exposing EGFR-mutant EGFR-TKIs sensitive PC-9 cells into increasing concentrations of gefitnib. Among the numerous clones, clone 5 was resistant to gefitinib or AZD9291 and named as PC-9GR-FGF because of high level of bFGF secretion. We found that bFGF promote the transcription of SREBP-1 and its downstream genes, acetyl-CoA carboxylase alpha (ACC), ATP citrate lyase (ACLY) and fatty acid synthase (FASN) in PC-9 cells. Compared to PC-9 cells, higher ACC expression was detected in PC-9GR-FGF cells. Basing on TCGA database (lung Adenocarcinoma, provisional), patients with high ACC expression showed significant shorter PFS (progression-free survival) and OS (overall survival) compared to those with low ACC expression in the EGFR-mutant NSCLC (p&lt;0.05, N=32). Down-regulation of ACC by siRNA or TOFA, a small molecular ACC inhibitor, mederately decreased the proliferation of PC-9 cells whereas strongly decreased proliferation of PC-9GR-FGF cells in vitro and in vivo. Moreover, Reactive oxygen species (ROS) and oxidative stress scavenger, NAC and ferrostatin-1, failed to reverse the effect of ACC inhibition in PC-9 and PC-9GR-FGF cells. Furthermore, after down-regulation or inhibition of ACC, stronger G2/M arrest and more accumulation of DNA damage marker, γH2AX, were found in PC-9GR-FGF cells compared with PC-9 cells. In addition, ACC expression were increased after irradiation of X-ray in PC-9GR-FGF cells, and inhibition of ACC increased accumulation of γH2AX induced by X-rays in PC-9GR-FGF cells. Our research gives a view sight into lipid metabolism changes in EGFR-mutant NSCLC cells before and after acquired EGFR-TKIs resistance, and explores the possibility of combination strategy with radiotherapy and anti-cancer lipid metabolism therapy.
Citation Format: Wei Wang, Shunli Peng, Rong Wang, yueyun Ma, Longhui Zhong. Inhibition of lipid metabolism decreases proliferation and increases radiosensitvity in EGFR-TKI resistant NSCLC cells with bFGF secretion [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 1276.
Abstract 1298: The anticancer effects of RX-5902 result from inhibition of phosphorylated p68-mediated β-catenin nuclear translocation
Authors: Lee Young B. , George Christina , Kim Deog J. 
Published: August 2019

Abstract
Phosphorylated p68 (p-p68 or phospho-DDX5) has been shown to be associated with cell transformation, epithelial mesenchymal transition (EMT) and cell migration, and furthermore play a vital role in cell proliferation and tumor/cancer progression by promoting the nuclear translocation of β-catenin. RX-5902 is an oral, small molecule inhibitor of β-catenin nuclear translocation mediated by p-p68. Previous studies have shown that RX-5902 inhibits the growth of cancer cells at low nanomolar IC50 (10 to 24nM) and disrupts the p-p68-β-catenin signaling pathway through an interaction with p-p68 on Tyr 593. By interfering with the p-p68-β-catenin signaling pathway cancer cells undergo apoptosis. In this study, we expanded our investigation to study the effect of RX-5902 on nuclear β-catenin in several types of cancer cell lines that include colon, gastric, hepatic, head and neck, melanoma, breast, pancreatic, ovarian, and prostate. Western blot data, in the cell lines tested, showed a decrease of nuclear β-catenin protein as well as p-p68 and c-myc in a concentration-dependent manner. Furthermore, an in vivo study of the MDA-MD-231 xenograft model demonstrated the ability of RX-5902 to inhibit the tumor growth by decreasing p-p68, β-catenin, cyclin D1 and c-myc proteins. Collectively our findings in both in vitro and in vivo studies support the potential therapeutic effect of RX-5902 in multiple cancer indications through the disruption of the phospho-p68/nuclear β-catenin interaction and blocking the nuclear translocation of β-catenin.
Citation Format: Young B. Lee, Christina George, Deog J. Kim. The anticancer effects of RX-5902 result from inhibition of phosphorylated p68-mediated β-catenin nuclear translocation [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 1298.
Abstract 1311: Inhibition of gankyrin-tumor suppressor protein interactions due to small molecule induced conformational change
Authors: Kabir Abbas , Muth Aaron 
Published: August 2019

Abstract
Introduction: Gankyrin is a highly conserved, 25 kDa protein containing 7 ankyrin repeats that binds to the S6 ATPase subunit of the 26S proteasome. It plays a crucial role in cellular growth, proliferation and metastasis. It is found to be largely overexpressed in a variety of malignancies and its abnormal overexpression makes it a biomarker in certain cancers. Gankyrin promotes cellular growth and proliferation through a variety of protein-protein interactions. Specifically, it binds to and promotes degradation of numerous tumor suppressor proteins (TSPs) such as p53 and retinoblastoma protein by promoting their proteasomal degradation. In 2016, a small molecule binder of gankyrin (cjoc42), demonstrated an ability to inhibit gankyrin activity in a dose dependent manner by inhibiting gankyrin’s interaction with certain TSPs as well as the proteasome.
Methods: In this research, we hypothesize that small molecule binding of gankyrin brings about a conformational change that inhibits its interaction with certain TSPs as well as the proteasome. In order to test this hypothesis, we have performed a series of fluorescence based experiments. We investigated the effect cjoc42 binding to gankyrin has on its intrinsic tryptophan fluorescence as well as its effect on fluorescently conjugated gankyrin. Follow up experiments consisted of both simple western blotting and co-immunoprecipitation assays to further investigate the ability of cjoc42 to induce a conformational change in gankyrin.
Discussion: We observed a diminished fluorescence intensity for both the intrinsic and labeled gankyrin experiments when in the presence of cjoc42. Western blot and Co-IP experiments are currently underway to further support our findings.
Conclusion: Cjoc42, a small molecule binder of gankyrin, appears to induce a conformational change. This conformational change appears to play a prominent role in regulating certain protein-protein interactions. Furthermore, this suggests that gankyrin's binding to specific TSPs and the proteasome are modulated by this mechanism.
Citation Format: Abbas Kabir, Aaron Muth. Inhibition of gankyrin-tumor suppressor protein interactions due to small molecule induced conformational change [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 1311.
Abstract 1319: Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations
Authors: Deng Wei , Zhai Dayong , Zhang Xin , Lee Dong , Rogers Evan , Whitten Jeffrey , Cui J. Jean 
Published: August 2019

Abstract
Chromosome rearrangements of ROS1 have been identified as oncogenic drivers in many malignancies, especially non-small cell lung cancer (NSCLC). Crizotinib is the only approved treatment for ROS1+ NSCLC. The efficacy of crizotinib varies among different types of ROS1 fusion partners in patients with ROS1-rearranged NSCLC, and the most dominant fusion CD74-ROS1 was associated with a higher rate of brain metastases and shorter overall survival. Unfortunately, the emergence of drug resistance to crizotinib and other ROS1-targeted therapies represents a major obstacle. The most common resistance mutations to crizotinib in ROS1+ NSCLC are the solvent front mutation (SFM) ROS1 G2032R and gatekeeper mutation ROS1 L2026M. Repotrectinib was rationally designed to overcome resistance mutations. The activity of repotrectinib against multiple fusion ROS1s and corresponding resistance mutations is outlined in the Table. Repotrectinib potently inhibited both wildtype and mutated fusion ROS1s including SFMs and gatekeeper mutations. In cell growth assays using engineered Ba/F3 cells expressing ROS1 fusions with several different partners, such as SDC4, CD74, TPM3 and EZR, repotrectinib demonstrated superior potency in comparison to other ROS1 inhibitors against multiple ROS1 mutations, especially the solvent front and gatekeeper mutations. In xenograft tumor model studies, repotrectinib resulted in tumor regression in the tumors carrying WT or SFM ROS1 fusion genes. Overall, repotrectinib demonstrated a strong inhibition profile against WT and various mutated ROS1s across different fusion partners when compared to many other ROS1 TKIs. A Phase 1/2 clinical trial of repotrectinib is currently enrolling ROS1+ NSCLC patients (NCT03093116).
Ba/F3 Cell Proliferation IC50 (nM)No Kinase Domain MutationROS1 G2032RROS1 L2026MInhibitorCD74-ROS1SDC4-ROS1EZR-ROS1TPM3-ROS1CD74-ROS1SDC4-ROS1EZR-ROS1TPM3-ROS1EZR-ROS1TPM3-ROS1Repotrectinib&lt;0.20.2&lt;0.1&lt;0.13.33516.3&lt;0.2&lt;0.1Crizotinib14.619.619.431.1266.24661660500.695.6236.2Lorlatinib0.20.30.20.3160.7352.9190.5434.91.61.9Entrectinib10.5ND1.59.41813ND2947109313.340.7Ceritinib42.859.833.110513911883885.8543.712.666.5Brigatinib2138.725.86111721473360.6300024.441.3Cabozantinib0.530.44.511.3169.439.560.73.412.6Ensartinib39.5ND118.6433.1371.8ND17574814543.31463
Citation Format: Wei Deng, Dayong Zhai, Xin Zhang, Dong Lee, Evan Rogers, Jeffrey Whitten, J. Jean Cui. Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations [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 1319.
Abstract 132: Direct interactions of oral bacteria and oral squamous cell carcinoma cells
Authors: Kovac Stefan , Napier Tiara , Scoffield Jessica , Amm Hope 
Published: August 2019

Abstract
Head and neck cancers (HNC) are the sixth most common cancer worldwide with more than 90% being squamous cell carcinoma. HNC can occur in the oral cavity, oropharynx, larynx or hypopharynx, or nasal cavities. Oral squamous cell carcinoma (OSCC) is estimated to be diagnosed in 50,000 patients this year with an overall 5-year survival rate of 64%. The tumor microenvironment has been shown to play a vital role in the progression of many human cancers, including OSCC. Given the complexity of the oral microbiome, we hypothesize that OSCC and oral bacteria interact to affect the tumorigenic properties of OSCC.
Methods: OSCC cells were cultured in the presence of oral pathogenic (Streptococcus mutans, Enterococcus faecalis, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans) and non-pathogenic (Streptococcus parasanguinis) bacteria. OSCC cells (A253, Cal27, FaDu, SCC-4, SCC- 9, SCC-25, SCC-152) were assessed for changes in cell proliferation, gene expression, and capacity to invade.
Results: Pathogenic oral bacteria increased proliferation in A253 OSCC cells. Enterococcus faecalis increased proliferation of SCC-4, SCC-25 and SCC-152 cells. No increase in proliferation was seen in FaDu and Cal27 cells. When examining changes in gene expression, oral bacteria increased MMP2 expression in A253 cells.Enterococcus faecalis increased JAG1, markers of hedgehog signaling (GLI1, GLI2), cell proliferation (CCDN1, CDKN1A), and cell invasion (MMP2) in SCC-4. In SCC-25 cells, Enterococcus faecalis increased JAG1, GLI1, and GLI2. Despite having no effect in total proliferation, Enterococcus faecalis increased HES1 (a marker of Notch activity), GLI1, and GLI2 in Cal27 cells. In SCC-9 cells, GLI1 expression was increased with all treatments. Streptococcus mutans increased MMP9 and HES1. Aggregatibacter actinomycetemcomitans increased MMP2 and MMP9. Enterococcus faecalis and Fusobacterium nucleatum also increased HES1.
Conclusions: Both the chemical and spatial interactions between OSCC and oral bacterium may play a role in tumor progression and migration by regulating proliferation of cancer cells and cellular signaling. A direct infection model, as opposed to interactions with bacterial spent media, showed more potential in terms of affecting cell viability and likely gene regulation as well. Future experiments will further explore the interactions, including the complexity of the oral biofilm in cancer patients and the presence of multiple bacteria.
Citation Format: Stefan Kovac, Tiara Napier, Jessica Scoffield, Hope Amm. Direct interactions of oral bacteria and oral squamous cell carcinoma 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 132.
Abstract 1327: UM-9107: A selective wild-type and T315I Bcr-Abl inhibitor with in vivo activity against chronic myelogenous leukemia
Authors: Phadke Sameer , Lopez-Barcons Lluis , Johnson Taylor K. , Lachacz Eric J. , Merajver Sofia D. , Soellner Matthew B. 
Published: August 2019

Abstract
Purpose: Long-term treatment of chronic myelogenous leukemia (CML) with the Bcr-Abl inhibitor imatinib, is initially successful but gives rise to several drug-resistant mutations. The most prevalent of these is the T315I ‘gatekeeper’ mutation that is sensitive to the second-line therapy, ponatinib. However, ponatinib causes serious vascular adverse events, including fatalities, in over 25% of patients, in part due to its target promiscuity. We have designed a novel Bcr-Abl inhibitor (UM-9107) that shows significant in vitro and in vivo anti-CML activity against wild-type and drug-resistant mutants, including the gatekeeper mutant. Furthermore, UM-9107 has excellent selectivity across the kinome and in vitro surrogate toxicity assessment models demonstrate a low likelihood of vascular adverse events as compared to ponatinib.
Experimental Design: We designed a series of compounds to specifically interact with a specific kinked conformation of the phosphate-binding loop of Abl. Since only a small proportion of kinases display this kinked conformation, we hypothesized that our compounds would be selective for Abl. We have analyzed the compound series biochemically and in vitro. The most potent compound, UM-9107, has been comprehensively characterized including: biochemical inhibition, cellular target engagement, kinome-wide profiling, in vitro cell proliferation, pharmacokinetic studies, and in vivo activity in xenograft models of CML.
Results: We demonstrate that UM-9107 potently inhibits all clinical mutants of Bcr-Abl, including the T315I gatekeeper mutant. UM-9107 shows robust activity against CML cell lines, comparable to ponatinib, with significantly fewer off-targets, as determined by kinome-wide profiling. Phenotypic profiling of UM-9107 in human primary cells shows low risk of vascular adverse events as indicated by specific biomarker readouts. UM-9107 demonstrates good oral bioavailability and in vivo activity in xenograft models of CML, with low toxicity.
Conclusions: The success of imatinib has been revolutionary and has led to an increase in the number of patients on long-term therapy. This inevitably gives rise to drug resistance through point mutations in the Bcr-Abl protein. Our results suggest that UM-9107 is a safe and efficacious preclinical candidate for the treatment of imatinib-resistant CML.
Citation Format: Sameer Phadke, Lluis Lopez-Barcons, Taylor K. Johnson, Eric J. Lachacz, Sofia D. Merajver, Matthew B. Soellner. UM-9107: A selective wild-type and T315I Bcr-Abl inhibitor with in vivo activity against chronic myelogenous leukemia [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 1327.
Abstract 1333: Isolation, characterization and expansion of circulating tumor cells in solid cancers
Authors: Kulasinghe Arutha , Kapeleris Joanna , Kenny Liz , Warkiani Majid , Vela Ian , Thiery Jean-Paul , O'Byrne Ken , Punyadeera Chamindie 
Published: August 2019

Abstract
Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types.
Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=300) and lung cancer (n=80) patients were recruited to investigate the prognostic role of CTCs.
We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, inertial microfluidics) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (PFS) (Hazard ratio [HR]: 4.946; 95% confidence internal [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485).
In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Recently, we have preliminary data that suggests that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit from immunotherapy-a current unmet clinical need. Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies.
Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Majid Warkiani, Ian Vela, Jean-Paul Thiery, Ken O'Byrne, Chamindie Punyadeera. Isolation, characterization and expansion of circulating tumor cells in solid 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 1333.