bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4266: Endoplasmic reticulum (ER), a potential therapeutic target for mutant p53 colorectal cancer
Authors: Tyagi Ashish , chandrasekaran Balaji , Kolluru Venkatesh , Baby Becca V. , Houda Alatassi , Ramisetti Srinivasa , Sharma Arun , Ankem Murali , Damodaran Chendil 
Published: August 2019

Abstract
Introduction: Inactivating p53 mutations contribute to tumor progression and treatment-resistance, resulting in poor patient survival in colorectal cancer patients (CRC). The goal of this study is to identify novel small molecules that therapeutically target mutant p53 in CRC.
Methods: We analyzed the effects of small molecule (ASR458) on p53-wild type (p53-wt; HCT116) and mutant p53 (p53-mut; SW620) colon cancer cells by phenotypic, molecular and in vivo assays.
Results: ASR458 treatment significantly inhibited the proliferation of both HCT116 and SW620 cells at nM concentrations. In p53-wt HCT116 cells, ASR458 caused induction of p53 that resulted in caspase-mediated cell death in both in vitro and in vivo models. On the contrary, ASR458 treatment induced ER-stress signaling (i.e., phosphorylation of ERK and eIF2-α) in p53-mut SW620 cells, which triggered ATF4 activation and subsequent induction of cascade of autophagy events (Atg family proteins, LC3B and Lamp1), causing autophagy-mediated cell death. Silencing ER stress marker ATF-4, a key regulator of autophagy, caused resistance to ASR458 and abrogated autophagy signaling in SW620 cells. This suggested that induction of ER-stress is critical for the cytotoxic effects of ASR458 in p53-mut CRC. Preliminary knockdown studies indicate that silencing of ER markers causes resistance to ASR458 in vitro, further confirming ER-stress as the mechanism of ASR458 action in p53-mut CRC. ASR458 significantly inhibited the growth of SW620 tumors in xenograft. Tissue analysis confirmed the ER-stress signaling observed in vitro.
Conclusion: Our results demonstrate ASR458 as a potential therapeutic agent with distinct targets in p53-wt and p53-mut CRC. This study also suggests that ATF4 mediated autophagy in unmanaged ER stress can reduce CRC pathogenesis. Further investigation into the pharmacokinetics and pharmacodynamics of ASR458 should help clinical translation of this agent.
Citation Format: Ashish Tyagi, Balaji chandrasekaran, Venkatesh Kolluru, Becca V. Baby, Alatassi Houda, Srinivasa Ramisetti, Arun Sharma, Murali Ankem, Chendil Damodaran. Endoplasmic reticulum (ER), a potential therapeutic target for mutant p53 colorectal cancer [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 4266.
Abstract 4278: A comparison of drug sensitivity in isogenic tumor cell lines confirms that cytoprotective autophagy confers intrinsic resistance to cisplatin
Authors: Xu Jingwen , Patel Nipa , Saleh Tareq , Wu Yingliang , Lima Santiago , Gewirtz David A. 
Published: August 2019

Abstract
Although autophagy inhibition often increases tumor cell sensitivity to chemotherapy and radiation, these observations do not provide definitive proof that autophagy is actually an intrinsic mechanism of resistance since virtually all tumor cells undergo autophagy in response to therapy. To directly address whether autophagy induction can confer chemoresistance, the current studies utilized a paired set of isogenic cell lines in which (cisplatin-induced) autophagy was either cytoprotective (crp53 cells where p53 was knocked out) or nonprotective (parental p53 wt cells) in function, but where the overall extent of autophagy was essentially identical. Cisplatin sensitivity was significantly lower in the crp53 cells where cisplatin-induced autophagy was protective compared to the parental p53 wt cells where cisplatin-induced autophagy was nonprotective, in support of the premise that cytoprotective autophagy could confer a relative degree of intrinsic resistance to chemotherapy. Accordingly, we can draw the following conclusions: (i) radiation and chemotherapy can promote both protective and nonprotective autophagy in tumor cells; (ii) although p53 can act as an autophagic switch, it cannot be reliably predicted whether autophagy will be protective or nonprotective based solely on p53 function; and (iii) even in the case(s) where autophagy is cytoprotective, it cannot be assumed that autophagy will confer drug or radiation resistance, but only that autophagy inhibition may, in select cases, increase drug or radiation sensitivity. These findings highlight the complexity of efforts to exploit autophagy inhibition as a therapeutic strategy to enhance tumor response to chemotherapy and radiation.
Citation Format: Jingwen Xu, Nipa Patel, Tareq Saleh, Yingliang Wu, Santiago Lima, David A. Gewirtz. A comparison of drug sensitivity in isogenic tumor cell lines confirms that cytoprotective autophagy confers intrinsic resistance to cisplatin [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 4278.
Abstract 4284: Targeting notch signaling in glioblastoma cancer stem cells through modulation of Connexin43 function
Authors: Lunski Michael , Smyth James , Vaughn Jennifer , Sheng Zhi , Gourdie Robert , Purow Benjamin , Lamouille Samy 
Published: August 2019

Abstract
Glioblastoma (GBM) is a highly malignant and lethal cancer of the central nervous system for which there has been limited progress in improving patient outcomes despite intensive research efforts. The current multimodal therapy for newly diagnosed GBM patients includes surgical resection, radiotherapy and cytotoxic chemotherapy with temozolomide (TMZ), conferring a median survival time of just 14.6 months. Failure to generate more effective treatment strategies is due to 1) the infiltrative nature of GBM tumor cells preventing complete surgical resection, and 2) the cellular heterogeneity within GBM tumors, which often comprise a sub-population of GBM cancer stem cells (GSCs) characterized by self-renewal characteristics and resistance to chemotherapeutic alkylating agents including TMZ. Multiple signaling pathways, including Notch, participate to the formation and maintenance of GSCs. Recent studies, including our research, have shown that increased levels of gap junction protein Connexin43 (Cx43) correlate with TMZ resistance in GBM cells and inversely correlated with GBM patient survival. Importantly, Cx43 has also been associated with anti-proliferative effects in glioma, and reduced levels of Cx43 protein occur in high-grade gliomas. Therefore, we hypothesized that altering Cx43 localization and/or activity rather than Cx43 expression represents a potent strategy for GBM treatment. Regulating Cx43 function is primarily associated with the multiple sites for post-translational modifications and protein-protein interactions within the Cx43 carboxy-terminus. Our research identifies crosstalk between Cx43 and Notch signaling in GSCs. Using a Cx43 carboxy-terminus mimetic peptide that modulates non-junctional functions of Cx43, we observe a decrease in Notch1 protein expression and reduced transcription of its downstream targets Hes1 and Hey1 in GSCs derived from patient tumors. Most importantly, our Cx43 mimetic peptide decreases cell survival in TMZ-resistant GSCs, limits GSC neurosphere formation in vitro, and inhibits GSC-derived tumor growth in vivo. Our current research aims at dissecting the molecular mechanisms of Cx43 functions on Notch signaling in GSCs using this Cx43 mimetic peptide. In conclusion, we have identified a novel therapeutic opportunity to decrease the tumorigenic potential of GSCs through altering Cx43 activity and Notch signaling to target chemoresistant GSCs in GBM treatment.
Citation Format: Michael Lunski, James Smyth, Jennifer Vaughn, Zhi Sheng, Robert Gourdie, Benjamin Purow, Samy Lamouille. Targeting notch signaling in glioblastoma cancer stem cells through modulation of Connexin43 function [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 4284.
Abstract 4291: p85α alters Gab2 phosphorylation profile in ovarian cancer
Authors: Li Xinran , Mak Victor CY , Cheung Annie NY , Mills Gordon B. , Cheung Lydia WT 
Published: August 2019

Abstract
Dysregulation of phosphatidylinositol 3-kinase (PI3K), which is essential for various cellular processes, is a common event in cancers. PIK3R1 encodes the PI3K class IA regulatory subunit p85α, which binds the p110 catalytic subunit forming heterodimeric PI3K complex. The PI3K associates with receptor tyrosine kinase, for example through the docking protein Gab2, to initiate downstream signaling events. Downregulation of p85α is frequently seen in cancers. However, the signaling changes driven by the downregulation remain to be elucidated. Our data herein indicate that reduced p85α expression leads to changes in the phosphorylation status of Gab2 at multiple amino acid residues. PIK3R1 siRNA decreased the levels of phosphorylated Y452 (a site implicated in binding p85α) and S210 (a site that may mediate negative feedback of Gab2 activity). Meanwhile, we observed an increase in phosphorylated S623, which was shown to involve in STAT activation. These findings provide mechanistic insights on the pathway activation upon downregulation of p85α in cancer.
Citation Format: Xinran Li, Victor CY Mak, Annie NY Cheung, Gordon B. Mills, Lydia WT Cheung. p85α alters Gab2 phosphorylation profile in ovarian cancer [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 4291.
Abstract 4294: C6 Ceramide potentiates paclitaxel and gemcitabine mediated antitumor effects against pancreatic cancer via inhibition of prosurvival PI3k/AKT/mTOR and ERK pathways
Authors: Wanebo Harold J. 
Published: August 2019

Abstract
The 5% survival of pancreatic cancer emphasizes need for new treatment strategies. Our studies suggest potential value of C6Ceramide (C6Cer) as a chemotherapeutic adjunct. The current study demonstrates that combination chemotherapy of Paclitaxel with adjunct C6Cer significantly increased cell death (apoptosis) in pancreatic cancer cell lines (L3.6,PANC-1, MIA (PaCa-2) in vitro as well as in vivo - enhancing tumor regression in SCID mice bearing L3.6 transplants. A similar synergistic effect was observed with addition of C6Cer to cetuximab which is not effective in KRAS mutant Pancreatic or Colorectal cancer and thus is not used clinically. At the molecular level combining C6Cer with Gemcitabine or Paclitaxel resulted in significant decreased p-AKT and p-GSK-a/b(PI3K/AKT (survival)pathway in L3.6 cells.
Conclusion: C6Cer significantly inhibited key cancer survival pathways resulting in significant synergism with chemotherapeutics in therapy of Pan Ca and KRAS mutant CRC.
Citation Format: Harold J. Wanebo. C6 Ceramide potentiates paclitaxel and gemcitabine mediated antitumor effects against pancreatic cancer via inhibition of prosurvival PI3k/AKT/mTOR and ERK pathways [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 4294.
Abstract 4299: Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived xenografts in vivo
Authors: Song Mengqiu , Zhao Ran , Xie Hua , Chen Hanyong , Liu Kangdong , Bode Ann M. , Lee Mee-Hyun , Dong Zigang 
Published: August 2019

Abstract
Esophageal cancer is the sixth leading cause of cancer death worldwide and has low survival rates with poor prognosis. Hyperactivation of AKT has been reported to modulate cell growth, survival, and gene expression in various solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacologic and physiologic properties, including antitumor, antibacterial, and anti-inflammatory effects. In this study, we aimed to investigate the effects of oridonin on the proliferation and growth of ESCC and to elucidate its underlying mechanisms of action. We found that oridonin is an inhibitor of AKT and induces cell cycle arrest and apoptosis in ESCC cells and attenuates growth of patient derived xenograft (PDX) tumors in vivo by interfering with AKT signaling pathways through MTT assay, anchorage-independent cell growth assay and Cell cycle and apoptosis analyses. AKT was developed as a dierctly target of oridonin by in vitro kinase assay, ex vivo and in vitro pull-down assay and computational docking model. Mechanistically, oridonin diminished the phosphorylation and activation of AKT and supressed the downstream of p-GSK-3β, p-mTOR and NF-kB activity. Moreover, a combination of oridonin and 5-fluorouracil or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. Overall, our study suggests that oridonin can inhibit progression of ESCC tumors in vitro and in vivo by suppressing AKT signaling through its direct targeting of AKT. Thus, this study might provide useful information in the clinical application of oridonin for ESCC chemotherapy.
Citation Format: Mengqiu Song, Ran Zhao, Hua Xie, Hanyong Chen, Kangdong Liu, Ann M. Bode, Mee-Hyun Lee, Zigang Dong. Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived xenografts in vivo [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 4299.
Abstract 4302: AR signaling promotes prostate carcinogenesis
Authors: Cheng Siyuan , Yang Shu , Connelly Zachary M. , Chen Fenghua , Yu Xiuping 
Published: August 2019

Abstract
Prostate cancer (PCa) is the most common non-skin cancer in American men. Each year, about 164,690 new patients will be diagnosed and about 29,430 men will die from this disease in 2018. Studies have identified several factors that increase the risk of PCa, including age, race, family history, and some diet factors. However, the exact cause of PCa remains unclear. Prostate is an androgen dependent organ and the growth of PCa also dependents on androgen and AR signaling. It is well established that AR signaling is the central player in promoting PCa progression. Here, we explore if AR signaling also plays a role in prostate carcinogenesis. We found that activation of AR signaling in normal prostate epithelial cells suppressed their cell proliferation in vitro but induced carcinogenesis in vivo. To explore the mechanisms that contribute to the differential effects of AR in vitro and in vivo, we examined if AR signaling induces genome instability in prostate epithelial cells, resulting in carcinogenesis and tumor progression. Senescence-associated beta-galactosidase staining results indicated that androgen treatment induced cellular senescence of prostate epithelial cells. Also, we found that the cells that survived the cellular senescence had altered genome ploidy and increased expression of active DNA-PK, suggesting that non-homologous end joining repair pathway is active in these cells. Our data support that AR signaling promotes genome instability in prostate epithelial cells, contributing to carcinogenesis. This may explain the high frequency of cancer developed in hormone-regulated organs such as prostate, mammary gland, and liver.
Funding: This study was supported by: FWCC/Foundation Legacy Funds, DOD New Investigator Award, The Office of Research SEED awards, The Department of Biochemistry & Molecular Biology.
Citation Format: Siyuan Cheng, Shu Yang, Zachary M. Connelly, Fenghua Chen, Xiuping Yu. AR signaling promotes prostate carcinogenesis [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 4302.
Abstract 431: Semi-automated detection, isolation and molecular analysis of single disseminated melanoma cells from lymph nodes
Authors: Alberter Barbara , Scheitler Sebastian , Feliciello Giancarlo , Ferrarini Alberto , Werner-Klein Melanie , Haferkamp Sebastian , Klein Christoph A. , Polzer Bernhard 
Published: August 2019

Abstract
We recently showed that lymph node disaggregation followed by immunocytology enables precise quantification of disseminated cancer cells (DCCs) and demonstrated that this approach has a 20-fold higher sensitivity to detect melanoma DCCs than routine histopathology (Ulmer et al., PLoS Medicine, 2014). Moreover, genetic profiling of single melanoma DCCs identified a colonization signature consisting of specific copy number alterations and point mutations that identify patients with high risk of progression (Werner-Klein et al., Nature Communications 2018). Here, we present the adaptation of this method to a semi-automated workflow for detection, isolation and molecular analysis of single melanoma DCCs. The developed workflow includes a mechanical disaggregation of lymph node tissue and collection of the mononuclear cells, immunofluorescence staining against melanoma-associated markers gp100 and MCSP and depletion of CD45-positive cells. Individual melanoma cells are then detected and isolated by DEPArrayTM technology enabling single cell whole genome amplification (Ampli1TM) for subsequent molecular analysis. In total, we processed 20 lymph nodes of melanoma patients and detected melanoma DCCs in 11/20 samples (55%). The quality of isolated cells was checked by Ampli1TM QC and 174 isolated single cells were further analyzed by Sanger sequencing for specific point mutations (BRAF, NRAS and cKIT) and Ampli1TM low pass kit for Illumina for copy number variation (CNV). Successful molecular analysis was correlated with genome integrity score (GII) as determined by Ampli1TM QC, with more than 95% of cells with GII 3-4 showing good performance in low pass sequencing. In conclusion, a new DepArrayTM based application for marker-dependent single cell isolation from malignant melanoma lymph nodes was successfully established and tested on a cohort of 20 melanoma patients. Molecular analyses of isolated single cells confirmed the tumor origin by CNV profiling and mutational analysis of melanoma-associated mutations. In the future, this approach could help to select individualized therapies for melanoma patients.
Citation Format: Barbara Alberter, Sebastian Scheitler, Giancarlo Feliciello, Alberto Ferrarini, Melanie Werner-Klein, Sebastian Haferkamp, Christoph A. Klein, Bernhard Polzer. Semi-automated detection, isolation and molecular analysis of single disseminated melanoma cells from lymph nodes [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 431.
Abstract 4311: Mechanisms responsible for the inflammatory polarization of monocytes by subclinical low-dose LPS
Authors: Pradhan Kisha 
Published: August 2019

Abstract
Dynamic polarizations of innate leukocytes such as monocytes and macrophages have been increasingly recognized to play key roles in the pathogenesis and/or treatment of human disease. However, mechanisms responsible for distinct polarizations of monocytes are not well understood. Our previous studies indicate that monocytes can be persistently polarized into a low-grade inflammatory state by subclinical super-low dose LPS (bacterial lipopolysaccharide). In this current study, we further characterized the unique polarization of monocytes by super-low dose LPS and its underlying mechanisms. We observed that super-low dose LPS preferentially induced the expression of inflammatory mediators such as MCP-1 while potently suppressed the expression of homeostatic mediators such as Catalase and FPN. Super-low dose LPS activated the inflammatory signaling molecules such as p38, CamKII, and NFkB. In contrast, super-low dose LPS suppressed the basal activation of immune suppressing molecules such as AMPK and SIRT3. Taken together, our data reveal novel insights regarding the persistent polarization of inflammatory monocyte, an emerging key player in various human diseases including cancer.
Citation Format: Kisha Pradhan. Mechanisms responsible for the inflammatory polarization of monocytes by subclinical low-dose LPS [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 4311.
Abstract 4328: Epigenetic modulation of SSTR2 expression provides the potential to broaden PEN-221 treatment population
Authors: Perino Samantha , Quinn James , Freda Jessica , White Brian , Bailey Scott , Bhatia Viren , Sweryda-Krawiec Beata , Bilodeau Mark , Bloss Jeffrey D. , Whalen Kerry , Wooster Richard 
Published: August 2019

Abstract
The expression of somatostatin receptor subtype 2 (SSTR2) is increased in up to 80% of neuroendocrine tumors (NETs), 20-40% of small cell lung cancers (SCLC) and a number of other tumor types. As a cell surface receptor, SSTR2 is a logical target for a drug conjugate. However, marginal, or loss of, expression of SSTR2 in tumor tissues has potential to limit the benefit from such conjugates.
Recent published preclinical studies have demonstrated that epigenetic modulators, such as HDAC inhibitors, can result in increased SSTR2 expression with treatment. Given that the expression of SSTR2 can be variable from patient to patient and in some cases low to absent, we hypothesized that the combination of epigenetic modulators with an SSTR2 target therapy may provide a benefit for patients who are not eligible for these targeted approaches on their own.
PEN-221 is a miniature drug conjugate of an SSTR2 targeting peptide attached to the potent cytotoxic DM1 through a cleavable disulfide linker. PEN-221, currently in Phase 1/2a (NCT02936323), is designed as a potent and selective anticancer agent to treat patients whose tumors express SSTR2. The targeting peptide of PEN-221 selectively binds to SSTR2, triggers receptor internalization leading to the accumulation of the DM1 to provide antitumor activity by disrupting microtubule networks causing apoptosis and mitotic catastrophe. In preclinical studies, single agent PEN-221 treatment leads to complete and sustained tumor regression in xenograft models that over-express SSTR2. We hypothesize that increased expression of SSTR2 as a result of epigenetic modulation from HDAC or other epigenetic modulators, may allow for the broadening of PEN-221 treatable tumors.
To evaluate these hypotheses, we have combined PEN-221 and epigenetic modulators in preclinical models of cancer. Efficacy studies were carried out in models expressing various degrees of SSTR2, and combinations resulted in greater efficacy than that of the single agent. In addition, a pharmacodynamic assessment of epigenetic modulator treatment on SSTR2 expression levels was performed. These data demonstrate that combination of PEN-221 and epigenetic modulators provide greater efficacy than single agent activity alone and support the evaluation of such combinations in the clinical setting.
Citation Format: Samantha Perino, James Quinn, Jessica Freda, Brian White, Scott Bailey, Viren Bhatia, Beata Sweryda-Krawiec, Mark Bilodeau, Jeffrey D. Bloss, Kerry Whalen, Richard Wooster. Epigenetic modulation of SSTR2 expression provides the potential to broaden PEN-221 treatment population [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 4328.