bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2122: Downregulation of RGS10 induces PI3K/mTOR inhibitor resistance by Ras activation in glioblastoma
Authors: Li Xiaolong , Wu Shaofang , Koul Dimpy , Yung. W.K. Alfred 
Published: July 2016

Abstract
Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer in adults. The prognosis of affected patients is poor and median survival is only one year. The essential role of PI3K signaling in GBM proliferation, metabolism and differentiation has been highlighted. The major mechanism for the oncogenic activity of PI3K is by preventing apoptosis through the downstream activation of Akt and mTOR. The importance of mTOR in the regulation of cell survival downstream of PI3K signaling provides a strong rationale for the use of dual PI3K/mTOR inhibitor. However, the limited effect of dual PI3K/mTOR inhibitor used as single agent is most likely due to activation of collateral pathways, suggesting that additional refinement of this overall approach is necessary. We investigated potential bypass mechanisms to PI3K/mTOR inhibition as a single agent and generated three resistant cell lines to PI3K/mTOR inhibitor with 3 to 5-fold increase in IC50 value and with an aim to identify the potential bypass of survival to PI3K/mTOR inhibitor. We show that the IC50 of the resistant cell lines and parental lines is correlated with s6 phosphorylation and the three resistant cell lines express increased level of phosphorylated ERK1/2, p70S6K and p90RSK protein levels. Further investigation show that RGS10, a regulator of G protein signaling, is down regulated in the resistant cell lines. Down regulation of RGS10 increases the GTP-bound Ras, implying that Ras activation defines the acquired resistance by activating the ERK/p90RSK pathway. Knockdown RGS10 in the parental cells induces ERK1/2, p70S6K and p90RSK phosphorylation and the resistance to PI3K/mTOR inhibitor. Raf1 or p90RSK knockdown can re-sensitize resistant cell lines to PI3K/mTOR inhibition. Combination of PI3K/mTOR inhibitor with Raf inhibitor Sorafinib efficiently inhibited the growth of the resistant cell lines showing Ras/Raf activation serves as an escape mechanism to PI3K/mTOR inhibition.
These observations suggest that Ras/Raf signaling serves as an survival signal upon PI3K/mTOR inhibition and provides a strong rationale for the combined use of PI3K/mTOR and Raf1 inhibition to induce lethal growth inhibition in human GBM.
Citation Format: Xiaolong Li, Shaofang Wu, Dimpy Koul, W.K. Alfred Yung. Downregulation of RGS10 induces PI3K/mTOR inhibitor resistance by Ras activation in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2122.
Abstract 2126: Androgen receptor expression is associated with sunitinib resistance in renal cell carcinoma models
Authors: Adelaiye-Ogala Remi M. , Chintala Sreenivasulu , Orillion Ashley , Pettazzoni Piergiorgio , Elbanna May , Elzey Bennett , Miles Kiersten Marie , Kao Chinghai , Draetta Giulio F. , Pili Roberto 
Published: July 2016

Abstract
Background: Androgen receptor (AR) expression has been reported in renal cell carcinoma but its biological role remains elusive. Sunitinib is a potent anti-angiogenic drug approved for the treatment of advanced renal cell carcinoma (RCC). However, eventually RCC tumors develop drug resistance. We have hypothesized that tumor cells resistance to sunitinib is associated with kinome reprograming and anti-apoptotic genes upregulation. To date, there is no report on the association between AR expression and resistance to TKI such as sunitinib in RCC. Our study was designed to investigate the role of AR in sunitinib resistance in RCC. We used our previously reported sunitinib resistant ccRCC cells and patient derived xenograft models. Methods: Human RCC cell lines; 786-0, 786-0R (sunitinib resistant), C2, C2R (sunitinib resistant), ACHN and Caki 2 were utilized to determine sensitivity or resistance to sunitinib. Patient derived xenograft (PDX) models of advance and metastatic RCC and RCC cell lines, sensitive and resistant tumors were used to detect AR expression by qRT-PCR, immunohistochemistry and Western blot analysis. Reverse phase protein array (RPPA) was used to assess 249 protein including AR in sunitinib sensitive and resistant tumors. Results: Our qRT-PCR data showed an increase by 1000 folds in mRNA levels of AR in our sunitinib resistant cell lines. Similarly, RPPA data revealed AR to be increased in sunitinib resistant RCC PDX tumors. This observation was confirmed by Western blot analysis. Conclusion: Overall our data suggest the potential role of AR and its association with resistance to sunitinib. Ongoing studies are testing the in vitro and in vivo combination treatment of RCC models with sunitinib and AR antagonists.
Citation Format: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, Piergiorgio Pettazzoni, May Elbanna, Bennett Elzey, Kiersten Marie Miles, Chinghai Kao, Giulio F. Draetta, Roberto Pili. Androgen receptor expression is associated with sunitinib resistance in renal cell carcinoma models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2126.
Abstract 2139: RNA nanoparticles as a two-in-one siRNA delivery carrier synergistically suppress drug-resistance cancer via combination therapy with doxorubicin
Authors: Ahn Hyung Jun 
Published: July 2016

Abstract
To overcome multi-drug resistance (MDR) caused by malfunction of genes in chemotherapy, we synthesize RNA nanoparticles (RNA NPs) as a “two-in-one” siRNA delivery system for MDR1 siRNA and BCL2 siRNA by using rolling circle transcription and base-pairing with folate-DNA-cholesterol fragments. The resulting RNA nanoparticles (Dsi RNPs), which contain multiple tandem copies of two siRNA sequences, form the self-assembled structure with about 100 nm of diameter, and simultaneously suppress pump and non-pump phenotypes in the same cancer cells. Using Dsi RNPs, we show that there exists an optimal time point within the window of time at which the synchronous silencing of MDR1 and BCL2 gene markedly enhances the chemosensitivity of MDR cancer cells to doxorubicin. Accordingly, a two-step sequential treatment of MDR cancer cells with Dsi RNPs and doxorubicin leads to the optimal synergistic cancer suppression. Finally, we demonstrate that such a synergism is attributed to the synchronous silencing of both genes, as well as to the precisely controlled timings of drugs and Dsi RNPs treatment. RNA NPs exhibit the folate receptor-specific cellular uptake, lowering the risk of severe adverse side effects. Also, RNA NPs do not induce innate immunostimulatory response and their highly condensed structure reveals the enhanced stability against nuclease attack in bloodstream. Therefore, RNA NPs delivery system provides an alternative tool as a two-in-one siRNA carrier that is suitable for the spatial-temporal synchronization of double gene silencing, and also, Dsi RNPs have great potential as combination chemotherapeutics with traditional anticancer drugs for suppression of MDR cancer.
Citation Format: Hyung Jun Ahn. RNA nanoparticles as a two-in-one siRNA delivery carrier synergistically suppress drug-resistance cancer via combination therapy with doxorubicin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2139.
Abstract 2149: The anti-EGFR antibody mixture Sym004 overcomes acquired resistance to cetuximab in colorectal cancer
Authors: Sanchez-Martin Francisco J. , Dalmases Alba , Bellosillo Beatriz , Argiles Guillem , Gelabert Mariona , Cañadas Israel , Vidal Joana , Siravegna Giulia , Arena Sabrina , Koefoed Klaus , Visa Laura , Arpí Oriol , Horak Ivan D. , Iglesias Mar , Stroh Christopher , Kragh Michael , Rovira Ana , Albanell Joan , Bardelli Alberto , Tabernero Josep , Montagut Clara 
Published: July 2016

Abstract
The anti-EGFR monoclonal antibodies (MoAbs) cetuximab and panitumumab are used to treat ‘RAS’ wild type metastatic colorectal cancer (MCRC), providing significant clinical benefit in patients. However, all patients ultimately develop disease progression, driven by acquisition of mutations in downstream effectors and in the extracellular domain (ECD) of EGFR, in approximately 25% of the cases. Sym004 is a novel 1:1 mixture of two non-overlapping anti-EGFR MoAbs that has recently shown promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored an EGFR mutation in the post-cetuximab tumor sample. Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring EGFR ECD mutations maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As a proof of principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. These data suggest that Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. Overall, EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials.
Citation Format: Francisco J. Sanchez-Martin, Alba Dalmases, Beatriz Bellosillo, Guillem Argiles, Mariona Gelabert, Israel Cañadas, Joana Vidal, Giulia Siravegna, Sabrina Arena, Klaus Koefoed, Laura Visa, Oriol Arpí, Ivan D. Horak, Mar Iglesias, Christopher Stroh, Michael Kragh, Ana Rovira, Joan Albanell, Alberto Bardelli, Josep Tabernero, Clara Montagut. The anti-EGFR antibody mixture Sym004 overcomes acquired resistance to cetuximab in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2149.
Abstract 2158: Pharmacologic, pharmacodynamic action of MELK kinase inhibitor OTS167 in cancer cells
Authors: Chung Suyoun , Kijima Kyoko , Harada Yosuke , Takamatsu Naofumi , Miyamoto Takashi , Matsuo Yo , Nakamura Yusuke 
Published: July 2016

Abstract
Cancer is the second most common cause of death in US in 2015 and has been the leading cause of death in Japan since 1981. Despite of improved therapeutic strategies in cancer, only limited treatment options can still be available to a subset of patients. Many efforts have been made to develop molecular targeted drugs, but the success rate did not reach to patients’ expectation. Unlike the conventional chemotherapy, the use of maximum tolerated dose (MTD) and the measurement of bulk tumor volume are not always appropriate for the clinical evaluation of molecular targeted drugs. To optimize and personalize the dosing for targeted agents, detailed molecular pathway and biomarkers that are affected by the drug should be elucidated. OTS167 was developed as a novel and potent MELK kinase inhibitor that we previously reported. The expression of MELK is elevated in various human cancers both in solid and hematological tumor and MELK is known to be associated with cancer progression and poor prognosis. Because MELK is indicated its critical roles in cancer stem cell proliferation as well, targeting MELK is an attractive and promising therapeutic strategy for cancer patient.
Here, we report the molecular mechanism of action of OTS167 in preclinical model. OTS167 suppressed MELK activity and promoted MELK protein degradation by inhibition of autophosphorylation. OTS167-treated cells showed drastic morphological transformation with the induction of p53 and p21 expression. We also investigated the expression of stem cell markers to elucidate whether OTS167 suppresses cancer stem-like properties through inhibition of MELK. Furthermore, we evaluated antitumor activity of OTS167 using human xenograft model and molecular changes in tumor tissue. The expression of MELK and downstream molecules were decreased in OTS167-treated xenograft tumor tissues by IHC. The change of expression and pharmacological effect were well correlated. Our data provide the evidence for the concept that OTS167 suppresses tumor growth through the inhibition of MELK signaling pathway and suggest the possibility of biomarkers for the assessment of clinical efficacy.
Citation Format: Suyoun Chung, Kyoko Kijima, Yosuke Harada, Naofumi Takamatsu, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura. Pharmacologic, pharmacodynamic action of MELK kinase inhibitor OTS167 in cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2158.
Abstract 2169: High content screening in MCF7 and MCF10A cells show differential responses depending on oxygen levels and mechanistic readout for viability
Authors: Yan Michelle , O’Grady Michael , April Anderson , Clarke Scott , Low Quentin , DeMarco Carolyn , Calderon Veronica , Kihn Kathy , Montoya Leticia , Finnessy Carmen , Wickett Marcy 
Published: July 2016

Abstract
Oxygen levels in typical cell culture conditions do not accurately reflect the oxygen levels cells are exposed to within the body. Furthermore, oxygen levels can vary within the tumor microenvironment. These variances can affect how cells respond to a variety of drugs and small molecules often used during cancer treatment. Previous studies have shown altered drug sensitivities in MCF7 cells depending on the oxygen levels the cells are grown in. To further understand how oxygen levels affect drug sensitivity, the response of tumorigenic MCF7 cells were compared to non-malignant MCF10A cells, cultured under low and high oxygen.
The goal of this study was to examine the differences in the sensitivity of MCF7 and MCF10A cells to drugs from the Tocriscreen Total compound library when cultured under low and high oxygen levels and for different drug exposure time periods. Cells were grown using standard cell culture conditions (19% oxygen) or low oxygen (5%). Using high-content imaging and high-throughput analysis methods, viability was assessed using two different mechanistic readouts; cellular metabolic activity and membrane permeability. Post-screening analysis was performed to confirm positive hits by performing dose-responses and determining IC50 concentrations using the same reagents as in the screen, and reagents to assess oxidative stress and cellular proliferation.
Results showed that viability differed depending on mechanistic readout and platform method used to determine hits as well as duration of exposure to compound. In addition, the response of MCF10A cells was not always identical to that of the MCF7 cells. Post-screening analysis of “hits” indicated different potencies of compounds tested depending on oxygen level and cell type. These data suggest that some drugs may affect MCF7 and MCF10A cells differently depending on environmental oxygen levels and mechanistic readout used to determine cellular health.
Citation Format: Michelle Yan, Michael O’Grady, Anderson April, Scott Clarke, Quentin Low, Carolyn DeMarco, Veronica Calderon, Kathy Kihn, Leticia Montoya, Carmen Finnessy, Marcy Wickett. High content screening in MCF7 and MCF10A cells show differential responses depending on oxygen levels and mechanistic readout for viability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2169.
Abstract 2180: Drug-like inhibitors of SGK1: Discovery and optimization of low molecular weight fragment leads
Authors: Zapf James , Meyer Todd , Wade Warren , Lingardo Laura , Batova Ayse , Alton Gordon , Pallai Peter 
Published: July 2016

Abstract
Triple negative (ER, PR and HER2/neu negative) breast cancers (TNBC) constitute 15-24% of breast cancers, but account for a disproportionate share of mortality. TNBC tumors are more aggressive, lack a targeted therapy, and are prone to relapse and metastasis after cytotoxic drug treatments, the only drug therapy currently available. Serum and glucocorticoid-regulated kinase 1 (SGK1) promotes the growth, invasiveness and chemo-resistance of cancer cells and is overexpressed in 48% of breast cancers, yet is not detected in normal breast tissue. In particular, SGK1 is overexpressed in TNBC cells and knockdown of SGK1 blocks the proliferation and invasiveness of TNBC cells. Thus, SGK1 is an attractive targeted therapy for TNBC. In the SGK1 inhibitors that have been reported previously, poor physicochemical properties have prevented these inhibitors from being active in vivo and advancing to the clinic. To discover drug-like inhibitors of SGK1, we used our technology platform (Leap-To-Lead™) and a fragment-based screening approach to find SGK1 inhibitor scaffolds. Low molecular weight inhibitors like ours are more readily optimized for potency while retaining drug-like properties. From this screen, we identified 11 scaffolds as novel inhibitors of SGK1. Four scaffold series had clear structure activity relationships (SAR). To illustrate the potential of these scaffolds, we carried out a limited synthetic expansion around one scaffold and improved potency more than 600-fold (SGK1 IC50 = 1 μM; LE = 0.4). Several compounds dose-dependently inhibited the proliferation of a TNBC cell line (MDA-MB-231) and inhibited the phosphorylation of the biomarker protein N-Myc downstream regulated 1 (NDRG-1). Unlike previously reported SGK1 inhibitors, our fragment lead compounds show excellent cellular penetration in Caco-2 assays.
In summary, a fragment-based screening approach was used to identify four novel scaffolds with clear SAR trends. A single scaffold series was further optimized and shows anti-proliferative activity and biomarker modulation in a TNBC cell line. These SGK1 inhibitor series represent excellent starting points for further SAR studies and development of a novel preclinical candidate.
Citation Format: James Zapf, Todd Meyer, Warren Wade, Laura Lingardo, Ayse Batova, Gordon Alton, Peter Pallai. Drug-like inhibitors of SGK1: Discovery and optimization of low molecular weight fragment leads. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2180.
Abstract 2190: Isolated cannabidiol from Cannabis sativa plant extracts inhibit growth and induce apoptosis in cervical cancer cells
Authors: Motadi Lesetja Raymond , lukhelo. sindiswa 
Published: July 2016

Abstract
Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, however, over a quarter of a million women die of cervical cancer, annually. Therefore, it is important to search for new drugs through effective screening of medicinal plant extracts to identify lead anti-cervical cancer drugs. The aim of this study was to evaluate for the anti-growth effects of Cannabis sativa extracts and its isolate, cannabidiol on cervical cancer cell lines HeLa, SiHa, and ME-180. To determine for the presence of important constituents and evaluate for the anti-growth effects, phytochemical screening, MTT assay, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 assay, and ATP measurement assay were conducted were conducted. Results obtained indicate that both plant extracts induced cell death at an IC50 of 50 - 100μg/ml and the Inhibition of cell growth was cell line dependent. Flow cytometry confirmed that, with or without cell cycle arrest, the type of induced cell death was apoptosis. Cannabis sativa extracts led to the up-regulation of apoptosis proteins (p53, Bax, caspase-3, and caspase-9) and the down regulation of anti-apoptosis proteins (Bcl-2 and RBBP6), signalling the execution of apoptosis. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels. In conclusion, this data implies Cannabis sativa crude extracts has the potential to inhibit growth and induce apoptosis in cervical cancer cell lines, which may be due to the presence of cannabidiol.
Citation Format: Lesetja Raymond Motadi, sindiswa lukhelo. Isolated cannabidiol from Cannabis sativa plant extracts inhibit growth and induce apoptosis in cervical cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2190.