bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A163: A diverse array of mutations in MTOR are hyperactivating and correlate with rapamycin sensitivity.
Authors: Grabiner Brian , Sabatini David 
Published: August 2014

Abstract
Components of the PI3K-Akt-mTOR signaling axis are frequently mutated in cancer but relatively few mutations have been observed in the MTOR gene itself, which encodes the mTOR kinase. We used cancer genome sequencing data to generate a catalogue of over 450 MTOR point mutations found in cancer and from these identified a set of over 25 that cause mTOR pathway hyperactivation in cells. Mutations occur in multiple cancer types and cluster in several distinct regions in the C-terminal half of mTOR. The distribution and diversity of hyperactivating mutations is distinct from those found in kinases such as AKT1 or BRAF but similar to the pattern seen in PIK3CA. The mutations do not affect the sub-cellular localization of mTOR or its capacity to nucleate the mTORC1 and mTORC2 complexes, but the mutants do bind less DEPTOR, an mTOR inhibitor. In kinetic analyses, several of the most frequently recurrent mutations demonstrate increased K-cat over wild-type mTOR, suggesting that these mutations alter the mTOR kinase itself. Lastly, cancer cell lines with naturally arising mTOR mutations that fall within the clusters exhibited hypersensitivity to mTOR inhibitors. Thus, a diverse set of mutations in mTOR can activate the mTOR pathway and may predict which patients are most likely to respond to rapamycin-based therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A163.
Citation Format: Brian Grabiner, David Sabatini. A diverse array of mutations in MTOR are hyperactivating and correlate with rapamycin sensitivity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A163.
Abstract A166: A Phase I pharmacokinetic/pharmacodynamic (PK/PD) study of the sachet formulation of the oral dual PI3K-mTOR inhibitor BEZ235 given twice daily (BID) in patients (pts) with advanced solid tumors.
Authors: Bendell Johanna C. , Kurkjian Carla , Infante Jeffrey R. , Bauer Todd , Burris Howard A. , Spigel David R. , Yardley Denise A. , Greco F Anthony , Shih Kent C. , Thompson Dana S. , Jones Suzanne F. 
Published: August 2014

Abstract
Background: The PI3 kinase pathway is the most dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective PI3K inhibitor that also binds to the catalytic site of mTOR, inhibiting mTORC1/2.
Methods: Pts were enrolled in a 3+3 dose escalation design to determine the maximum tolerated dose, toxicities, PK, and PD of BEZ235 when administered BID as an oral sachet formulation. For intrapatient PK comparison, pts received the total dose in a QD schedule for the first 8 days of the initial 28 day cycle. The QD lead-in was later eliminated. PK and PD assessments (PET scans, skin biopsies, and blood-based biomarkers) were collected and disease assessments were conducted every 2 cycles.
Results: 33 pts (median age 62, range 20-86 yrs; 17 male/16 female) received BEZ235 at the doses described below in the table. Two DLTs of gr 3 mucositis occurred early in the treatment cycle at 600 mg BID, so the lead-in QD dosing was eliminated. However, DLTs of fatigue and mucositis limited dosing at 600 mg BID in subsequent pts. The 400 mg BID dose level was re-explored, but dosing was again limited by DLTs and chronic low grade toxicities. Twelve pts were enrolled at an intermediate dose of 300 mg BID with no QD lead-in, and DLT (gr 3 mucositis) was reported in a single patient. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. PET scan evaluations demonstrate anti-PI3K activity via decreased SUV uptake at various doses, including the lowest dose. 15 pts experienced stable disease as their best response.
Conclusions: The recommended dose of BEZ235 administered twice daily as an oral sachet formulation is 300 mg BID. The toxicity profile for BID dosing is similar to that reported for other PI3K and mTOR inhibitors.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A166.
Citation Format: Johanna C. Bendell, Carla Kurkjian, Jeffrey R. Infante, Todd Bauer, Howard A. Burris, David R. Spigel, Denise A. Yardley, F Anthony Greco, Kent C. Shih, Dana S. Thompson, Suzanne F. Jones. A Phase I pharmacokinetic/pharmacodynamic (PK/PD) study of the sachet formulation of the oral dual PI3K-mTOR inhibitor BEZ235 given twice daily (BID) in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A166.
Abstract A168: Hepatitis B virus pre-S2 mutant stimulates aerobic glycolysis through mammalian target of rapamycin signaling in tumorigenesis.
Authors: Teng Chiao-Fang , Wu Han-Chieh , Hsieh Wen-Chuan , Tsai Hung-Wen , Su Ih-Jen 
Published: August 2014

Abstract
Hepatitis B virus (HBV) pre-S2 mutant identified in ground glass hepatocytes (GGHs) in patients with chronic HBV infection has been proposed as viral oncoprotein and can induce hepatocellular carcinoma (HCC). Previously, we observed the activation of mammalian target of rapamycin (mTOR) by HBV pre-S2 mutant in GGHs and HCCs. The frequent association of metabolic syndrome with HCC raises the possibility that pre-S2 mutant-induced mTOR activation plays a driving role in the development of metabolic disorders in HBV-related HCC patients. To address this issue, we developed transgenic mice harboring pre-S2 mutant and analyzed gene expression profiles of the transgenic livers. In support of our hypothesis, the pre-S2 mutant transgenic mice showed glycogen depletion and glycolysis elevation in HCCs, a phenotype that has been implicated in highly proliferative malignancy. We identified that pre-S2 mutant could initiate an mTOR-dependent glycolytic pathway, involving Yin Yang 1, c-Myc, and glucose transporter 1 to upregulate aerobic glycolysis. This mTOR-mediated signaling pathway was significantly activated in the pre-S2 mutant transgenic livers and HCCs and contributed to aberrant glucose uptake and lactate production in vitro. Furthermore, we demonstrated that pre-S2 mutant could promote proliferation and invasion of HCC cells by sustaining the aerobic glycolysis. Activation of this glycolysis-associated mTOR signaling cascade was also observed in human HBV-related HCCs. Collectively, our results support the role of mTOR activation in the metabolic reprogramming of hepatocytes in chronic HBV infection and tumorigenesis, which should be valuable for chemoprevention design for HCC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A168.
Citation Format: Chiao-Fang Teng, Han-Chieh Wu, Wen-Chuan Hsieh, Hung-Wen Tsai, Ih-Jen Su. Hepatitis B virus pre-S2 mutant stimulates aerobic glycolysis through mammalian target of rapamycin signaling in tumorigenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A168.
Abstract A19: Andrographolide analogue induces crosstalk between apoptosis and autophagy via inhibition of PI3K/Akt/mTOR pathway in human leukemic cells.
Authors: Kumar Deepak , Roy Rajneeta , Chowdhury Chinmay , Chatterjee Mitali , Das Padma 
Published: August 2014

Abstract
Current chemotherapeutic agents solely based on apoptosis induction have limited efficacy. Therefore, new therapeutic strategies and drugs still need to be explored. Various forms of programmed cell death are being increasingly implicated in anticancer therapy and the complex interplay among them is critical to the overall fate of cells. We elucidated the underlying mechanism of the most potent Andrographolide analogue (AG-4) mediated action that involved crosstalk between apoptosis and autophagy in human leukemic U937 cells. AG-4 induced cytotoxicity was associated with redox imbalance and apoptosis which involved mitochondrial depolarisation, altered apoptotic protein expressions, activation of the caspase cascade leading to cell cycle arrest. Incubation with caspase inhibitor Z-VAD-fmk or Bax siRNA decreased cytotoxic efficacy of AG-4 emphasising critical roles of caspase and Bax. In addition, AG-4 induced autophagy as evident from LC3-II accumulation, increased Atg protein expressions and autophagosome formation. Pre-treatment with 3-MA or Atg 5 siRNA suppressed the cytotoxic effect of AG-4 implying the pro-death role of autophagy. Furthermore, incubation with Z-VAD-fmk or Bax siRNA subdued AG-4 induced autophagy and pre-treatment with 3-MA or Atg 5 siRNA curbed AG-4 induced apoptosis - implying that apoptosis and autophagy act as partners in the context of AG-4 mediated action. AG-4 also inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR (by rapamycin or mTOR siRNA) or Akt (by LY294002 or Akt siRNA) augmented AG-4 induced apoptosis and autophagy signifying its role in apoptosis-autophagy crosstalk. Thus, these findings provide new perspective of AG-4 as potential molecule targeting programmed cell death for future cancer therapeutics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A19.
Citation Format: Deepak Kumar, Rajneeta Roy, Chinmay Chowdhury, Mitali Chatterjee, Padma Das. Andrographolide analogue induces crosstalk between apoptosis and autophagy via inhibition of PI3K/Akt/mTOR pathway in human leukemic cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A19.
Abstract A195: The role of P2X7 receptor in glioma cells.
Authors: Tamajusuku Alessandra S. K , Kipper Franciele C. , Filippi-Chiela Eduardo C. , Flores Débora G. , Reder Gleice M. , Meurer Luise , Battastini Ana M.O. , Roesler Rafael , Lenz Guido , Wink Marcia R. 
Published: August 2014

Abstract
P2X7 is an ionotropic receptor, whose activation by extracellular ATP can cause pro- or anti-apoptotic responses, depending on the concentration of the ligand. This receptor is expressed in almost all the cell types of the central nervous system and has been linked to cell death in several cells. Gliomas are primary tumors that arise in the CNS, and glioblastoma is the most deadly brain tumor due to their high proliferation, migration and infiltrative nature. Here, we show that survival of patients with gliomas directly correlate with the expression of P2X7 purinergic receptor analyzed with immunohistochemistry of a local group of patients or microarray in a set of patients from “REMBRANDT” and “The Cancer Genome Atlas” databases. A sub-population of cells more sensitive to ATP expressed more P2X7 when compared to a less sensitive subpopulation. Accordingly, RNA interference of the P2X7 receptor drastically reduced ATP-induced cell death, decreased cell adhesion and promoted migration, suggesting that this receptor is necessary for this effect. Since these are features of more aggressive cancers, this could be part of the explanation for the correlation observed in the patients’ outcome. These data support the importance of the purinergic system in general and the P2X7 receptor particularly in the pathobiology of gliomas.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A195.
Citation Format: Alessandra S. K Tamajusuku, Franciele C. Kipper, Eduardo C. Filippi-Chiela, Débora G. Flores, Gleice M. Reder, Luise Meurer, Ana M.O. Battastini, Rafael Roesler, Guido Lenz, Marcia R. Wink. The role of P2X7 receptor in glioma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A195.
Abstract A196: Downregulation of kynurenine 3-monooxygenase (KMO) function prohibits canine mammary gland tumor (cMGT) cells from going wild.
Authors: Liao Albert T. , Lin Chen-Si , Chang Mei-Hsien 
Published: August 2014

Abstract
Kynurenine 3-monooxygenase (KMO), mainly found on the outer membrane of the mitochondria, is one of the enzymes in the kynurenine pathway of tryptophan metabolism. KMO catalyzes L-kynurenine (KYN) to form 3-hydroxy kynurenine (3-HK) and further generates the downstream metabolite quinolinic acid (QA) which is an N-methyl-D-aspartate (NMDA) agonist. In the past, KMO was considered to be associated with neurodegenerative diseases because the downstream metabolites demonstrate excitotoxicity to CNS and act as factors in neurodegenerative diseases. In our previous study has shown that overexpression of KMO is related to tumor malignancy and survival time of cMGT-suffering dogs (in progress). In this study, we investigated function of KMO in cMGT cells. First of all, KMO expression of cMGT cells (CMT-1, MPG and CF41.mg) was identified in mRNA and protein level. Second, the application of KMO inhibitor reduced proliferation and migration of cMGT cells. The reduced proliferation, not migration, could be restored by NMDA or QA. Third, the application of KMO inhibitor also decreased the activity of Erk, Akt and STAT3 in cMGT cells. However, the decreased activity of Erk and STAT3 in cMGT cells could be restored through the application of NMDA of QA. Our data suggest that KMO is involved in the proliferation and migration of cMGT cells. Furthermore, the inhibition of proliferation by KMO inhibitor is mainly through Erk and STAT3 signaling cascades and the signaling pathway may be activated through the NMDA receptor. The inhibition of migration by KMO inhibitor is mainly through Akt signaling cascades. In conclusions, KMO might be a new therapeutic target of cMGT due to the downregulation of KMO reduces proliferation and migration of cMGT cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A196.
Citation Format: Albert T. Liao, Chen-Si Lin, Mei-Hsien Chang. Downregulation of kynurenine 3-monooxygenase (KMO) function prohibits canine mammary gland tumor (cMGT) cells from going wild. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A196.
Abstract A201: Development of new assay systems for screening inhibitory molecules of c-Myb.
Authors: Uttarkar Sagar R. , Goblirsch Michael , Jose Joachim , Klempnauer Karl-Heinz 
Published: August 2014

Abstract
c-myb is a proto-oncogene encoding a transcription factor which is highly expressed in hematopoietic progenitor cells. It is primarily involved in regulation of the expression of genes important for differentiation, cell proliferation and lineage determination. The c-Myb protein is an interesting therapeutic target because emerging evidence suggests that deregulated c-Myb expression is involved in several types of leukemia and development of human tumors such as breast and colon cancer, adenoid cystic carcinoma and subtypes of glioblastoma. So far therapeutic low molecular weight inhibitors for c-Myb have not been reported. Based on the fact that the ability of c-Myb to act as a transcription factor is highly dependent upon its interaction with the coactivator CBP/p300, we have developed novel in vivo and in vitro assays which allow screening of chemical inhibitors of Myb. The in vivo assay consists of the N- and C-terminal halves of firefly luciferase which are expressed as fusion proteins with either the KIX domain of p300 or the p300 binding region of c-Myb. KIX and c-Myb interaction leads to complementation of the luciferase molecule rendering it active, which can be monitored by a standard luciferase assay. The in vitro system employs a bacterial auto-display system. The KIX domain of p300 is expressed in E coli in such a way that it is displayed on the surface of the bacterial cells. Myb is expressed as a soluble GFP fusion protein which is added to the bacterial cells. The interaction between both binding partners renders the bacterial cells fluorescent which can be quantified by flow-cytometry. These assays should be useful to screen large libraries of compounds as they both allow high throughput techniques.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A201.
Citation Format: Sagar R. Uttarkar, Michael Goblirsch, Joachim Jose, Karl-Heinz Klempnauer. Development of new assay systems for screening inhibitory molecules of c-Myb. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A201.
Abstract A224: Autophagy and SQSTM1 on the RHOA(d) again.
Authors: Belaid Amine , Diogop N'diaye Papa , Cerezo Michaël , Brest Patrick , J. Klionsky Daniel , Carle Georges F , Hofman Paul , Mograbi Baharia 
Published: August 2014

Abstract
Degradation of signaling proteins is one of the most powerful tumor suppressive mechanisms by which a cell can control its own growth, its survival, and its motility. Emerging evidence suggests that autophagy limits several signaling pathways by degrading kinases, downstream components, and transcription factors; however, this often occurs under stressful conditions. We show here that the constitutive autophagy is required for fine-tuning the RHOA pathway. Specifically, inhibition of autophagosome degradation induces the accumulation of the GTP-bound form of RHOA. The active RHOA is sequestered via SQSTM1/p62 within autolysosomes, and accordingly fails to localize to the lamella of crawling cells, one region where RHOA inactivation is essential in cell migration. As a result, all autophagy compromises deregulate cell motility. We therefore propose the term “signalphagy” to indicate a dedicated type of macroautophagy that degrades and thereby maintains the appropriate level of active signaling proteins to achieve tumor suppression. In this model, the remarkable dynamics of autophagy together with its integration of extracellular cues might dictate the time and place where RHOA is active to ensure directed cell motility.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A224.
Citation Format: Amine Belaid, Papa Diogop N'diaye, Michaël Cerezo, Patrick Brest, Daniel J. Klionsky, Georges F Carle, Paul Hofman, Baharia Mograbi. Autophagy and SQSTM1 on the RHOA(d) again. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A224.
Abstract A23: Bioinformatic analysis of PTPRK reveals a potential link to STAT3 phosphorylation in HNSCC.
Authors: Pendleton Kelsey P. , Lui Vivian W. , Lu Yiling , Gilbert Breean R. , Levine Kevin , Mills Gordon B. , Grandis Jennifer R. 
Published: August 2014

Abstract
Purpose: The emerging role of various PTPRs (protein tyrosine phosphatase receptors) on signaling regulation prompted us to investigate the genomic alterations of members of the PTPR in HNSCC. PTPRK is a known tumor suppressor, and knockdown or mutation of PTPRK has been found to drive tumorigenesis in breast and colorectal cancer. The role of PTPRK in HNSCC is largely unknown. Recent genomic studies in HNSCC revealed that PTPRK is mutated in HNSCC. Here, we further investigated the genomic aberrations of PTPRK, in primary HNSCC tumors and examined if any of these genomic aberrations are associated with key phosphorylation changes in signaling proteins in HNSCC tumors.
Experimental Design: Data-mining of the HNSCC genomic and protein array data was performed using the cBio portal (http://www.cbioportal.org/public-portal/). A total of 306 HNSCC primary tumors were analyzed in the genomic analysis, while proteomic data were available for a subset of these tumors (total of 200). We analyzed for genomic events, including PTPRK amplification, gain of copy number, and increased in mRNA expression (&gt; 1 SD above the mean). The levels of phosphorylated signaling proteins of 150 proteins were compared between the PTPRK-altered group vs. the PTPRK-unaltered group. Preliminary validation on signaling changes were performed.
Results: Bioinformatic analysis of the cBio data showed that PTPRK is mutated in 1% (2/200 cases), amplified in 0.5% (1/200 cases), with copy gain in 12% (24/200 cases), and increased mRNA expression in 13.5% (27/200 cases). There are no tumors with PTPRK deletion. These results implicate a gain of function of PTPRK in HNSCC. Unexpected proteomic findings revealed that increased phosphorylation of STAT3 (p = 0.005), ERBB2 (p = 0.018), and EGFR (p = 0.031) proteins were found to be associated with tumors with the genomic signature of “PTPRK-mutated/amplified/gain/increased in mRNA expression” vs. the PTPRK-unaltered tumors. Preliminary validation of the proteomic findings indicate that increased expression of PTPRK (by transient transfection into HNSCC cells) did result in increased pSTAT3 expression (34% increase vs. vector control).
Discussion: This study used both bioinformatics and cellular assays to demonstrate PTPRK associated with enhanced pSTAT3. Future studies are required to elucidate the role of PTPRK, likely indirect, on STAT3 regulation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A23.
Citation Format: Kelsey P. Pendleton, Vivian W. Lui, Yiling Lu, Breean R. Gilbert, Kevin Levine, Gordon B. Mills, Jennifer R. Grandis. Bioinformatic analysis of PTPRK reveals a potential link to STAT3 phosphorylation in HNSCC. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A23.