bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3211: Inhibition of autophagy potentiates cytotoxicity of CX-5461 treatment in chemoresistant epithelial ovarian cancer
Authors: Cornelison Robert , Llaneza Danielle C. , Petrova Yulia , Dobbin Zachary C. , Schneider David A. , Landen Charles N. 
Published: July 2017

Abstract
Epithelial ovarian cancer remains a deadly diagnosis with poor prognosis and patients succumbing to chemoresistant disease in 80% of cases. Mechanisms of chemoresistance are numerous, but we have identified ribosomal biogenesis basal machinery as being a common upregulated signaling network in response to chemotherapeutic insult. Tumors treated with chemotherapy showed dramatic increases in size and morphology of nucleoli, suggesting global changes in ribosomal synthesis with stress. We next sought to use the RNA Polymerase I inhibitor CX-5461 to identify biologic changes in targeting ribosomal machinery that may allow resensitization to chemotherapy. CX-5461 induced autophagy, senescence and mitotic catastrophe in ovarian cancer cell lines Overall, 13 ovarian cancer lines examined were highly sensitive to Pol I inhibition by MTT, with IC50s ranging from 25nM to 2μM, and chemoresistant lines were generally more sensitive to CX-5461. In p53 mutant cells CX-5461 appears to be primarily cytostatic with mitotic catastrophe being a relatively rare event accompanying cytokinesis failure. This could be indicative of the cells successfully using autophagy to decrease ribosome requirements and evade treatment. When treated in combination with chloroquine as an autophagy inhibitor IC50s decreased to 550nM in HeyA8 (from 2μM), 70nM for HeyA8MDR (from 191nM), 110nM in SKOV3 (from 595nM) and 60nM for SKOV3TR-ip2 (from 109nM) with abundant multinucleated cells, suggesting synergy between ribosomal synthesis and autophagy inhibitors in vitro. Chloroquine administration appears to push cell to mitotic catastrophe after co-administration with CX-5461, thereby enhancing cytotoxicity over cytostatic endpoints after treatment, even in multi-drug resistant cell populations. Inhibition of autophagy appears to enhance efficacy of RNA Polymerase I inhibition in both sensitive and chemoresistant populations, prompting a potential new approach to chemoresistant disease.
Citation Format: Robert Cornelison, Danielle C. Llaneza, Yulia Petrova, Zachary C. Dobbin, David A. Schneider, Charles N. Landen. Inhibition of autophagy potentiates cytotoxicity of CX-5461 treatment in chemoresistant epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3211. doi:10.1158/1538-7445.AM2017-3211
Abstract 3213: Antagonism of D2-like dopamine receptors plays a role in Onc201’s anticancer effects
Authors: Kline Christina Leah B. , Lulla Amriti , Wagner Jessica , Dicker David , Baumeister Marie , Oster Sophie , El-Deiry Wafik 
Published: July 2017

Abstract
ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response and inactivates both Akt and ERK. Its promising safety profile and broad spectrum efficacy in vitro has been confirmed in Phase I/II trials in several advanced malignancies. Biochemical and reporter assays have shown that ONC201 is a selective and competitive antagonist of the D2-like receptors, specifically, dopamine receptor D2 (DRD2) and dopamine receptor D3 (DRD3) with a KD value of ~3 µM. The theme that dopamine and dopamine receptors are important in cancer has emerged in the literature. We hypothesize that ONC201’s interaction with DRD2 is critical for ONC201’s anticancer effects. Co-treating HCT116 and RKO colorectal cancer cells with ONC201 and dopamine or the selective D2-like receptor agonist sumanirole partially abrogated ONC201-induced ATF4/CHOP expression and apoptosis. Knocking down DRD2 expression using siRNA negated ONC201’s effects on viable cell count. Overexpressing DRD2 in a cancer cell line that has very low levels of DRD2, increased ONC201-induced PARP cleavage. Quantitative RT-PCR analyses showed that cells that have acquired resistance to ONC201 did not express detectable mRNA levels of the D2-like receptors. To further determine the anti-tumor potential of targeting the D2-like receptor, we treated different cancer cell lines with other D2-like receptor antagonists. Similar to ONC201, the D2-selective antagonist L-741,626 decreased cell viability and induced apoptosis in a number of cancer cell lines. In contrast to ONC201, however, L-741,626 has a poor therapeutic index. Our findings show that the ability of ONC201 to inhibit D2-like receptors contributes to ONC201’s antiproliferative and pro-apoptotic activity. Ongoing work is aimed at elucidating the mechanisms by which antagonism of D2-like receptors can promote apoptotic cell death, especially with regard to ATF4/CHOP/DR5 and Akt/ERK/Foxo3a/TRAIL, which have been shown to be stimulated in ONC201-treated and -sensitive tumor cells.
Citation Format: Christina Leah B. Kline, Amriti Lulla, Jessica Wagner, David Dicker, Marie Baumeister, Sophie Oster, Wafik El-Deiry. Antagonism of D2-like dopamine receptors plays a role in Onc201’s anticancer effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3213. doi:10.1158/1538-7445.AM2017-3213
Abstract 3235: Development of potent and selective inhibitors for ATR: An adjuvant for DNA damage based chemotherapeutics
Authors: Kirubakaran Sivapriya , Thiruvenkatam Vijay Thiruvenkatam , Shaik Althaf 
Published: July 2017

Abstract
Inhibition of DNA damage checkpoint and repair function has been a challenging as well a promising approach in cancer therapy. ATR kinase is one of the key mediator of DNA damage response which induces cell cycle arrest and DNA repair via its downstream proteins. Blocking ATR has proved to prevent the Chk1 pathway from stalled replication fork and enhances the replication stress and premature mitotic entry. In addition inhibition of ATR can selectively sensitize the cancer cell to radio and chemotherapy, due to defective DNA damage signaling through the loss of ATM or p53 mutation in cancer cell. Due to its inherent role in DDR, ATR has been explored as a potential target in enhancing the effect of radiation and chemo-therapy in addition enables highly selective targeting the cancer cell through synthetic lethality.
Despite the attractiveness of ATR inhibition in the cancer therapy, specific ATR inhibitors have remained indefinable. Further, there is a limited proof of concept data for ATR inhibition. Considering these facts and challenges we will be presenting some preliminary results with respect to In-silico design, synthesis and evolution of potential and selective inhibitors for ATR.
References
Llona-Minguez, S., Hoglund, A., Jacques, S. A., Koolmeister, T. & Helleday, T. Chemical strategies for development of ATR inhibitors. Expert Rev Mol Med 9, 10 (2014).
Wagner, J. M. & Kaufmann, S. H. Prospects for the Use of ATR Inhibitors to Treat Cancer. Pharmaceuticals 3, 1311-1334 (2010).
Liu, Q. et al. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res 73, 2574-2586 (2013).
Citation Format: Sivapriya Kirubakaran, Vijay Thiruvenkatam Thiruvenkatam, Althaf Shaik. Development of potent and selective inhibitors for ATR: An adjuvant for DNA damage based chemotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3235. doi:10.1158/1538-7445.AM2017-3235
Abstract 3247: Discovery of a novel drug that affects centrosome clustering
Authors: Jaunky Dilan B. , Larocque Kevin , Suardiaz Javier Porro , Yang Dan , Furze Emma J. , Forgione Pat , Piekny Alisa 
Published: July 2017

Abstract
Our goal is to identify molecular regulators of a mechanism that occurs uniquely in cancer cells, and to develop a selective anti-cancer drug. Most chemotherapies are non-selective, causing severe side-effects. In additions, cancers often develop resistance to some of the more commonly used chemotherapies. To expand the repertoire of available drugs, and to design drugs that are selective, we need to identify molecules that regulate the physiological changes that occur primarily in cancer cells. For example, cancer cells in many hard-to-treat cancers have aberrant centrosomes, which may be supernumerary or fragmented. During mitosis, these aberrant centrosomes must cluster to form bipolar spindles for successful division. Thus, targeting a process like centrosome clustering is ideal, since it is not necessary in healthy cells. We synthesized a small, stable scaffold with amenability to structure-activity-relationship studies, and found several analogues with IC50 values &lt; 50 nM, depending on the cancer cell line. Preliminary tests showed that these compounds prevent tumors from forming and/or cause their regression in vitro. We performed cell biological studies to characterize their mechanism of action. In several different types of cancer cells, these compounds cause mitotic arrest and centrosome declustering at concentrations where they have little affect on non-cancerous cells. Live imaging revealed that within minutes of adding the compounds to HeLa cells expressing GFP-tagged tubulin, we observed rapid microtubule depolymerization and centrosome declustering. After washing out the compound, microtubule polymerization recovered, but the mitotic spindles were multipolar. Adding similar concentrations of Nocodazole, a microtubule-depolymerizing drug, also caused rapid microtubule depolymerization, but after washing out the drug, the spindles were bipolar. We are in the process of identifying the molecular target of these compounds to provide crucial insight to the mechanism governing centrosome clustering, and are continuing to perform SAR studies to obtain compounds with higher efficacy and selectivity.
Citation Format: Dilan B. Jaunky, Kevin Larocque, Javier Porro Suardiaz, Dan Yang, Emma J. Furze, Pat Forgione, Alisa Piekny. Discovery of a novel drug that affects centrosome clustering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3247. doi:10.1158/1538-7445.AM2017-3247
Abstract 3258: Genomic analyses define molecular subtype of lung squamous cell carcinoma
Authors: lee Ji won , kim Ahreum , shin Jong-Yeon , kim Young Tae , Seo Jeong-Sun 
Published: July 2017

Abstract
Lung squamous cell carcinoma, which account for 25 percent of all lung cancers, have not been well characterized owing to a lack of systematic understanding of molecular pathogenesis. We performed the whole-exome and transcriptome sequencing from 101 tumors and matched normal samples from Korean patients. Somatic mutations and gene expression defined two intrinsic subtypes: (1) classical subtype; (2) immunogenic subtype. Classical subtype displayed upregulation of cell cycle related genes and enriched for gene mutations (TP53, NAV3, NFE2L2, CDKN2A, PIK2CA, KEAP1 and RB1) involved in cell proliferation, squamous differentiation and oxidative stress. Immunogenic subtype had more tumor-infiltrating immune cells than classical type. More proportion of adaptive immune cells was also detected in immunogenic subtype. Immune genes, involved in adaptive immune response, were also upregulated in immunogenic subtype. Taken together, our finding revealed that each subtype has different immune mechanisms in lung squamous cell carcinoma and provides potential opportunities for therapeutic development.
Citation Format: Ji won lee, Ahreum kim, Jong-Yeon shin, Young Tae kim, Jeong-Sun Seo. Genomic analyses define molecular subtype of lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3258. doi:10.1158/1538-7445.AM2017-3258
Abstract 3282: Common chronic medical conditions in pancreatic cancer: impact on overall survival
Authors: Abousamra Ahmed O. , Fogelman David , Rallapalli Vijayashri , Shalaby Akram , Javle Milind , Lenzi Renato , Ho Linus , Li Donghui , Hassan Manal 
Published: July 2017

Abstract
Background: We aimed to categorize the most common comorbid medical conditions in pancreatic cancer (PC) patients and to determine whether these conditions have impact on the overall survival (OS).
Methods: Between January 2000 and 2014, 2165 patients with pathologically confirmed adenocarcinoma of the pancreas consented to participate in a clinico-epidemiological study at the University of Texas MD Anderson Cancer Center. We reviewed the electronic medical records of all patients to identify the prevalence of four chronic medical conditions, including systemic hypertension, hyperlipidemia, type 2 diabetes, and altered morphology of the pancreas. Prevalence of each chronic disease was assessed and median survival was estimated by using the Kaplan-Meier product-limit method, and significant differences between the survival times were determined by using the log-rank test.
Results: Among all patients, 950 (43.9%) had history of hypertension, 516 (23.8%) had hyperlipidemia, 585 (27%) had type 2 diabetes. Radiological and pathological records indicted presence of steatosis (0.4%), fibrosis (1.9%), and pancreatitis (9.9%). The prevalence of hyperlipidemia and diabetes was significantly higher in men (27.9%, 30.2%) than in women (18.2%, 22.8%) respectively; P value &lt;.01. We found no significant variation in the prevalence of hypertension and altered pancreatic morphology between men and women. Hypertension was more frequent among African American patients while diabetes was more common among Hispanics and African Americans. No significant variations in the distribution of other conditions by ethnicity. Median survivals of PC patients by comorbidities are presented in table 1.
Conclusion: Chronic medical conditions are commonly reported by PC patients and the prevalence of these conditions may vary by gender. However, the impact of these conditions may not significantly affect the survival of the patients. The interaction treatment choices with these conditions still needs to be elaborated in future studies.
OS (months), 95%CI of PC patients by comorbiditiesComorbidityYesNoP valueHypertension10.9 (10-11.7)11.6 (10.7-12.4).09Hyperlipidemia12 (11.8-13.1)10.9 (10.2-11.6).4Diabetes Mellitus9.7 (8.4-11.1)11.4 (10.7-12.1).1
Note: This abstract was not presented at the meeting.
Citation Format: Ahmed O. Abousamra, David Fogelman, Vijayashri Rallapalli, Akram Shalaby, Milind Javle, Renato Lenzi, Linus Ho, Donghui Li, Manal Hassan. Common chronic medical conditions in pancreatic cancer: impact on overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3282. doi:10.1158/1538-7445.AM2017-3282
Abstract 3305: Autophagic induction through upregulation of sestrin-2 transcription and mRNA stability mediates the anticancer effect of new compound ChlA-F
Authors: Hua Xiaohui , Huang Chuanshu , Wu Xueru , Li Jingxia 
Published: July 2017

Abstract
ChlA-F is a novel conformation-derivative of Cheliensisin A (Chel A), which is a new styryl-lactone isolated from Chinese Herb Goniothalamus cheliensis Huand shows potent antitumor potential effect both in vitro and in vivo. However, the anticancer activity and its potential mechanisms underlying ChlA-F action have never been explored. In present study, we evaluated the potency of ChlA-F on anchorage-independent growth and its association with autophagic responses in human high grade invasive bladder cancer cells. We found that ChlA-F significantly inhibited anchorage-independent growth of human bladder cancer cells by induction of autophagy in a sestrin2(SESN2)-dependent Fashion. Our results revealed that ChlA-F treatment specifically induced SESN2 expression via increasing its both gene transcription and mRNA stability. On the one hand, ChlA-F treatment markedly attenuated Dicer protein abundance, and in turn abolished miR-27a maturation and further relieved miR-27a directly binding to SESN2 mRNA 3’UTR, thereby promoting SESN2 mRNA stabilization. On the other hand,ChlA-F treatment promoted Sp1 abundance and consequently mediated SESN2 transcription. Moreover, either knockdown of Sp-1 or ectopic expression of miR-27a could abolish the autophagic response and reversed the inhibition of anchorage-independent growth in human bladder cancer cells. These results demonstrate that anticancer effect of ChlA-F is mediated by its activating autophagic pathway through promoting both SESN2 mRNA transcription and stabilization,which offers novel insights into the anticancer effect of ChlA-F on bladder cancer and provides a therapeutic alternative against human bladder cancer.
Citation Format: Xiaohui Hua, Chuanshu Huang, Xueru Wu, Jingxia Li. Autophagic induction through upregulation of sestrin-2 transcription and mRNA stability mediates the anticancer effect of new compound ChlA-F [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3305. doi:10.1158/1538-7445.AM2017-3305
Abstract 3307: Induction of autophagy as a mechanism of therapeutic resistance in head and neck cancer
Authors: Eckers Jaimee C. , Swick Adam D. , Fowler Tyler , Skiba Justin , Nickel Kwangok P. , Kimple Randall J. 
Published: July 2017

Abstract
Background: In the curative setting for head and neck cancer (HNC) a commonly used treatment is radiation combined with the anti-EGFR monoclonal antibody cetuximab (CTX). However, despite decades of research into improved treatments, therapeutic resistance remains a major challenge for this malignancy with roughly 40% of patients developing recurrent disease. We are studying the molecular mechanisms by which radiation and cetuximab induce autophagy and how this process can be modulated to improve the efficacy of therapy.
Methods: We evaluated a panel of both human papillomavirus (HPV) positive and negative HNC cell lines for autophagic response to both CTX treatment and ionizing radiation (XRT). Induction of autophagy was detected by immunoblot flux assays for LC3 and p62 and by immunofluorescent staining of autophagic vesicles. siRNA knockdown of EGFR, LAMPT4B, ULK1, Beclin1 and others was used to probe the involvement of different signaling molecules. The addition of specific autophagy inhibitors, such as the ULK1 inhibitor SBI-0206965, to CTX or XRT treatment was tested to determine whether the reduction of autophagic response reduced cell survival in a clonogenic survival assay. Induction of apoptosis was analyzed by immunoblot against cleaved Caspase and PARP and AnnexinV staining.
Results: Flux assays revealed that both CTX and XRT induced autophagy in a time and dose dependent manner. Immunofluorescent staining of LC3 to identify autophagic vesicles showed that a relatively small fraction of the total cell population is able to induce this response. Specific siRNA knockdown of EGFR and LAMPT4B was able to abrogate the induction of autophagy in response to both CTX and XRT. Involvement of alternative downstream pathways involving either ULK1 and Beclin1 or p53 in response to either treatment is under investigation. To determine whether blockade of cytoprotective autophagy can help overcome therapeutic resistance, we tested specific autophagy inhibitors in combination with either CTX or XRT treatment. The addition of the ULK1 inhibitor to CTX or XRT induced apoptosis as shown by caspase activity, AnnexinV staining, and reduced cell survival in clonogenic assays.
Conclusions: Autophagy may play a critical and protective role in how head and neck cancers respond to therapeutic stress. The addition of specific autophagy inhibitors to standard treatments may provide a way to overcome resistance to therapy.
Citation Format: Jaimee C. Eckers, Adam D. Swick, Tyler Fowler, Justin Skiba, Kwangok P. Nickel, Randall J. Kimple. Induction of autophagy as a mechanism of therapeutic resistance in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3307. doi:10.1158/1538-7445.AM2017-3307
Abstract 3325: Ginkgetin, a biflavonoid derived from leaves of Ginkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62
Authors: Lou Jian Shu , Bi Cathy , Chan Gallant , Dong Tina , Tsim Karl 
Published: July 2017

Abstract
Chemotherapeutic drugs in the treatment of non-small-cell lung carcinoma (NSCLC) are usually mediated by induction of apoptosis; this usually results in drug resistant during the therapy. Many compounds from natural resource have been shown to trigger autophagy in promoting cell death, and therefore which could be a novel treatment for cancer. Ginkgetin, a biflavonoid from Ginkgo biloba leaves (Ginkgoaceae), was shown its anticancer effects recently. The leaf of G. biloba is being recorded as a safe herbal drug in Pharmacopoeia from China and Europe. Here, the possible development of ginkgetin as an anticancer drug was demonstrated. Ginkgetin induced the death in A549 (NSCLC) with an IC50 lower than that of cisplatin. This anticancer effect of ginkgetin was also illustrated in NSCLC xenograft nude mice model. Transmission electronic microscope revealed that ginkgetin-induced autophagy was the main cause of cell death. Autophagy inhibitors, 3-methyladenine and chloroquine but not apoptosis inhibitor Z-VAD-FMK, rescued ginkgetin-induced cell death. Reciprocally, the induction of autophagy by rapamycin promoted ginkgetin-induced cell death, as well as the formation of p62-TRAF6-mTOR. During autophagy, p62 is hypothesized to be a target of ginkgetin-induced autophagic cell death. This notion is supported by several lines of evidence. The application of ginkgetin blocked fully the expression of p62 in cultured A549, and in contrast the over expression of p62 reduced ginkgetin-induced autophagy and cell death concomitantly with the decline on autophagosome formation. In parallel, the modulation on p62 expression could regulate Nrf2 activity and ROS level in the presence of ginkgetin. Thus, autophagy could act as an inducer in ginkgetin-induced cell death, and p62 was proposed to be a possible target during this process. Here, ginkgetin exhibited promising anticancer effect in NSCLC via autophagy, a signaling very different to orthodox chemotherapeutic drug cisplatin. Besides, ginkgetin is a phytochemical from G. biloba that is considered as a safe herbal supplement, and no obvious toxicity was observed in xenograft nude mice. Therefore, ginkgetin is proposed to be a potential compound for the development of novel anticancer drug. Acknowledgements: This study was supported by Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), GRF (663012, 662713, M-HKUST604/13), TUYF15SC01 and Foundation of The Awareness of Nature (TAON12SC01) to Karl Tsim.
Citation Format: Jian Shu Lou, Cathy Bi, Gallant Chan, Tina Dong, Karl Tsim. Ginkgetin, a biflavonoid derived from leaves of Ginkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3325. doi:10.1158/1538-7445.AM2017-3325