bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A49: Inhibition of mTOR induces chemoresistance in B-cell acute lymphoblastic leukemia
Authors: Vo Thanh-Trang , Nguyen Duc , Lui Brandon , Lu Mengrou , Mallya Sharmila , Fruman David 
Published: October 2015

Abstract
B-ALL is the most prominent cancer in pediatric patients. Most patients are responsive to the current chemotherapy, but B-ALLs with activated oncogenic kinases including BCR-ABL, PDGFR and JAK have a high risk of relapse. Currently, patients with the BCR-ABL translocation are successfully treated when the BCL-ABL inhibitor dasatinib is added to their chemotherapy regimen. In accord, we found that dasatinib sensitizes B-ALL cell lines to drugs used during induction and consolidation phase of chemotherapy. However, dasatinib protects BCR-ABL leukemia cell lines from killing by maintenance phase drugs methotrexate and 6-mercaptopurine. This protection only occurs in cells where dasatinib reduces downstream mTOR activity. To directly test if reduced mTOR activity can account for the protection, we assessed the effects of the allosteric mTOR inhibitor rapamycin and active-site mTOR inhibitor MLN0128. Indeed, both mTOR inhibitors consistently protect B-ALL cells from killing by methotrexate and 6-mercaptopurine. Inhibitors of AKT and PI3K also result in varying degrees of chemoprotection, which correlates strongly with the degree to which they downregulate mTOR activity. The chemoprotective effect of mTOR inhibition correlates with cell cycle arrest but other mechanisms may also be involved. These data suggest that mTOR inhibition is detrimental in some chemotherapeutic combinations, whether by inhibitors directly targeting mTOR or indirectly targeting upstream effectors. The identification of such drug combination effects is an important consideration for the current use of dasatinib and future use of PI3K/AKT/mTOR inhibitors.
Citation Format: Thanh-Trang Vo, Duc Nguyen, Brandon Lui, Mengrou Lu, Sharmila Mallya, David Fruman. Inhibition of mTOR induces chemoresistance in B-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A49.
Abstract A52: Extracellular matrix regulation of ErbB3 in a subset of wild-type BRAF/NRAS melanoma
Authors: Rosenbaum Sheera , Capparelli Claudia , Berman-Booty Lisa D. , Gaborit Nadège , Zhan Tingting , Davies Michael A. , Setiady Yulius Y. , Yarden Yosef , Aplin Andrew E. 
Published: October 2015

Abstract
While the incidence of melanoma increases each year, treatment options for melanoma patients wild-type for both BRAF and NRAS (WT-WT) remain limited. The tumor microenvironment has been highly implicated in the promotion of tumor growth and proliferation; however, its precise role in melanoma is not well understood. Extracellular matrix (ECM) proteins within the tumor microenvironment have been shown to regulate many cellular pathways, including the activation of several growth factor receptors. The receptor ErbB3 is involved in the regulation of melanocyte homeostasis, and elevated ErbB3 expression in malignant melanomas correlates with reduced patient survival. In our study we demonstrate that, in a subgroup of WT-WT cells, an interaction between melanoma cells and ECM proteins within the tumor microenvironment promotes the activation of the NRG1/ErbB3 pathway, leading to phosphorylation of the downstream target AKT and increased cell growth. Furthermore, knockdown of NRG1 reduced cell viability, which was associated with decreased phosphorylation of ErbB3, its co-receptor ErbB2 and AKT. Analogous effects were obtained targeting ErbB3 with either small interfering RNAs or the neutralizing ErbB3 monoclonal antibodies, huHER-8 and NG33. Additionally, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro and xenograft growth in vivo. These findings are supportive of the crucial role of the ECM in regulating tumor growth through the activation of ErbB3 signaling, and establish a basis for targeting the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of malignant cutaneous melanoma.
Citation Format: Sheera Rosenbaum, Claudia Capparelli, Lisa D. Berman-Booty, Nadège Gaborit, Tingting Zhan, Michael A. Davies, Yulius Y. Setiady, Yosef Yarden, Andrew E. Aplin. Extracellular matrix regulation of ErbB3 in a subset of wild-type BRAF/NRAS melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A52.
Abstract B05: PI3K/mTOR pathway-dependent regulation of oxygen metabolism via pyruvate dehydrogenase (PDH)-E1alpha phosphorylation
Authors: Cerniglia George , Dey Souvik , Gallagher-Colombo Shannon M. , Daurio Natalie , Tuttle Stephen , Busch Theresa M. , Lin Alexander , Esipova Tatiana V. , Vinogradov Sergei , Koumenis Constantinos , Maity Amit 
Published: October 2015

Abstract
The PI3K/mTOR pathway plays a central role in coupling metabolic processes to the cellular proliferative state. In the current study we show that pharmacological inhibition of this pathway leads to a decrease in hypoxia within SQ20B human head and neck cancer xenografts. The mechanism underlying the effect appears in part to be due to reduced tumor cell oxygen consumption induced by the drug. Pharmacologic inhibitors of the PI3K/mTOR pathway or genetic inhibition of Akt/PI3K decreased the oxygen consumption rate (OCR) in transformed cell lines in vitro by 30-40%. Pharmacologic inhibition of this pathway increased phosphorylation of the E1alpha subunit of the pyruvate dehydrogenase (PDH) complex on Ser293, an inhibitory modification of this critical gatekeeper of mitochondrial respiration. Expressing wild type PTEN in a doxycycline-inducible manner in a glioblastoma cell line with mutant PTEN led to an increase in PDH-E1alpha phosphorylation and a decrease in OCR. The decrease in OCR with PI3K/Akt/mTOR inhibition was recapitulated by knocking down PDH-E1alpha expression using siRNA. Pre-treatment with dichloroacetate (DCA), a known inhibitor of the pyruvate dehydrogenase kinases (PDKs) that phosphorylate PDH-E1alpha prevented the upregulation in PDH-E1alpha phosphorylation, induced by inhibition of the pathway and also blunted the decrease in OCR. Our findings highlight an association between the PI3K/mTOR pathway and tumor cell oxygen consumption and reveal a novel link between this pathway and PDH phosphorylation. These results have important implications for understanding the effects PI3K pathway activation in tumor metabolism and also in the use of inhibitors of this pathway in cancer therapy
Citation Format: George Cerniglia, Souvik Dey, Shannon M. Gallagher-Colombo, Natalie Daurio, Stephen Tuttle, Theresa M. Busch, Alexander Lin, Tatiana V. Esipova, Sergei Vinogradov, Constantinos Koumenis, Amit Maity. PI3K/mTOR pathway-dependent regulation of oxygen metabolism via pyruvate dehydrogenase (PDH)-E1alpha phosphorylation. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B05.
Abstract B48: Exploiting aberrant mTOR signaling in hematological malignancies to preferentially enlarge cells for physicochemical destruction
Authors: Trendowski Matthew , Krawiec Gabriela , Fondy Thomas P. 
Published: October 2015

Abstract
The mammalian target of rapamycin (mTOR) pathway has received considerable attention as a potential target for cancer chemotherapy, as aberrant mTOR regulation has been found in a tremendous diversity of malignancies. Such targeted therapies are designed to inhibit mTOR, thereby decreasing oncogenic potential within the cell. However, overexpression of mTOR may also be exploited to further increase the size differential between malignant and normal cells, a hallmark that is the basis of physicochemical therapeutic approaches. Therefore, this study sought to compare the physiological responses of malignant and normal blood cells after exposure to rapamycin, a known inhibitor of mTOR. U937 human promyelocytic leukemia cells were compared with human hematopoietic stem cells (hHSCs) at varying rapamycin concentrations to assess which cell type was more sensitive to mTOR inhibition. Subsequent results indicated that while both cell lines exhibited a marked reduction in cell volume, only U937 cells were able to readily proliferate in the presence of rapamycin. These effects were readily observed in as little as 2nM rapamycin, demonstrating the profound affinity the inhibitor has for mTOR. Further, size reduction could be rescued in U937 cells using vincristine, creating a substantial size differential between malignant and normal blood cell populations. This ultimately suggests that mTOR can be exploited to preferentially enlarge malignant cells for physicochemical destruction, providing a novel therapeutic approach for leukemia and other hematological malignancies.
Citation Format: Matthew Trendowski, Gabriela Krawiec, Thomas P. Fondy. Exploiting aberrant mTOR signaling in hematological malignancies to preferentially enlarge cells for physicochemical destruction. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B48.
Abstract B49: mTORC2 directs breast morphogenesis through Rictor-dependent PKCα/Rac1 signaling independent of Akt
Authors: Morrison Meghan M. , Young Christian D. , Wang Shan , Sanchez Violeta M. , Rebecca Cook S. , Hicks Donna J. , Brantley-Sieders Dana M. 
Published: October 2015

Abstract
Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor knock-out. Surprisingly, Akt re-activation was insufficient to rescue survival, branching, or motility of mTORC2-impaired mammary epithelial cells (MECs). However, activation of the mTORC2 substrate protein kinase C (PKC)-α fully rescued branching, invasion, and survival of MECs after genetic or pharmacological mTORC2 inhibition. PKCα-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary morphogenesis, revealing a novel role for Rictor/mTORC2 in survival and motility of untransformed MECs through an Akt-independent, PKCα/Rac1-dependent mechanism.
Citation Format: Meghan M. Morrison, Christian D. Young, Shan Wang, Violeta M. Sanchez, Cook S. Rebecca, Donna J. Hicks, Dana M. Brantley-Sieders. mTORC2 directs breast morphogenesis through Rictor-dependent PKCα/Rac1 signaling independent of Akt. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B49.
Abstract B50: Targeting KRASG12D colorectal cancer with combined inhibition of PI3K/mTOR and MAPK signaling
Authors: Burgenske Danielle , Monsma David , Dylewski Dawna , Scott Stephanie , Sayfie Aaron , Kim Donald , Luchtefeld Martin , Martin Katie , Stephenson Paul , Hostetter Galen , Dujovny Nadav , MacKeigan Jeffrey 
Published: October 2015

Abstract
Compounds validated in preclinical models frequently exhibit limited efficacy when transitioned into human trials. As a result, many patients are stratified into treatment regimens that have little impact on their disease. With the goal of establishing preclinical models that can more accurately predict tumor responses, there has been a recent emphasis to develop patient-derived xenograft (PDX) models. We strove to develop new PDX models of colorectal cancer (CRC) to test the feasibility of targeted therapy using small molecule inhibitors. Following transplantation of patient tumor specimens into athymic nude mice, sixteen PDX models were successfully established. Common somatic mutations were determined using custom gene panels and targeted with appropriate inhibitors against PI3K/AKT, mTOR and/or MAPK signaling. In four independent models, single agent therapies against PI3K and mTOR had little impact on tumor growth. Conversely, robust declines in tumor burden were universally observed in all models with MEK inhibition with the exception of one, a KRAS G12D mutant model. Within this model, tumor response was achieved only with dual inhibition of mTOR and MAPK signaling. Given the unmet clinical need to treat tumors with aberrant KRAS signaling, these results encourage further investigation into combination treatment strategies with these small molecule inhibitors.
Citation Format: Danielle Burgenske, David Monsma, Dawna Dylewski, Stephanie Scott, Aaron Sayfie, Donald Kim, Martin Luchtefeld, Katie Martin, Paul Stephenson, Galen Hostetter, Nadav Dujovny, Jeffrey MacKeigan. Targeting KRASG12D colorectal cancer with combined inhibition of PI3K/mTOR and MAPK signaling. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B50.
Abstract B51: The tyrphostin, NT157, suppresses insulin receptor substrates and augments therapeutic response of prostate cancer
Authors: Ibuki Naokazu , Ghaffari Mazyar , Reuveni Hadas , Pandey Mitali , Fazli Ladan , Azuma Haruhito , Gleave Martin E. , Levitzki Alexander , Cox Michael E. 
Published: October 2015

Abstract
Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate cancer (CRPC) progression. Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and anti-apoptotic signaling from IGF-1 receptor (IGF-1R), insulin receptor and other oncoproteins. This study demonstrates that IRS1/2 expression is increased in PCa and, persists in CRPC. Furthermore, this study assesses the anti-cancer activity of NT157, a small-molecule tyrphostin targeting IRS proteins, using androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. NT157 treatment resulted in dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF-1-induced AKT activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing apoptosis of LNCaP cells and increasing G2M arrest in PC3 cells. NT157 also suppressed androgen-responsive growth, delayed CRPC progression of LNCaP xenografts and suppressed PC3 tumor growth alone and in combination with docetaxel. This study reports the first preclinical proof-of-principle data that this novel small-molecule tyrosine kinase inhibitor targeting human IRS suppresses IRS1/2 expression, delays CRPC progression, and suppresses growth of CRPC tumors in vitro and in vivo. Demonstration that IRS expression can be increased in response to a variety of stressors that may lead to resistance or reduced effect of the therapies indicate that NT157-mediated IRS1/2 down-regulation is a novel therapeutic approach for management of advanced prostate cancer.
Citation Format: Naokazu Ibuki, Mazyar Ghaffari, Hadas Reuveni, Mitali Pandey, Ladan Fazli, Haruhito Azuma, Martin E. Gleave, Alexander Levitzki, Michael E. Cox. The tyrphostin, NT157, suppresses insulin receptor substrates and augments therapeutic response of prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B51.
Abstract B53: Targeting PI3K signaling pathway for therapeutic enhancement of verteporfin-mediated photodynamic therapy
Authors: Kraus Daniel , Chen Bin 
Published: October 2015

Abstract
Photodynamic therapy (PDT) induces cell injury and death through generation of reactive oxygen species (ROS) after light activation. Verteporfin is a photosensitizer that has been approved for the treatment of age-related macular degeneration and is under investigation for targeting tumor vasculature for therapy. Being primarily localized in mitochondria, verteporfin-mediated PDT induced a rapid apoptotic cell death in SVEC mouse endothelial cells by activating mitochondria-initiated cell death pathways. However, activation of phosphatidylinositol 3-kinase (PI3K) signaling pathway was also observed after verteporfin-PDT, especially at a sub-lethal dose. Furthermore, activation of PI3K signaling was correlated with cell growth after PDT. Thus, the goal of this study is to test the hypothesis that therapeutic outcome of verteporfin-PDT can be enhanced by targeting PDT-induced pro-survival PI3K signaling pathway.
We found that PI3K-mTOR pathway inhibitor NVP-BEZ235 (BEZ235) significantly inhibited PDT-induced PI3K signaling activation and combination of BEZ235 and verteporfin-PDT resulted in more cell apoptosis and greater inhibition in cell proliferation in SVEC cells. The combination therapy led to significantly more tumor growth inhibition than each individual treatment in the PC-3 prostate tumor model. Examination of tumor samples for PI3K signaling activity and functional vasculature revealed that the combination treatment caused more inhibition in PI3K signaling and reduction in functional blood vessels than verteporfin-PDT or BEZ235 treatment alone. These results indicate that targeting pro-survival PI3K signaling pathway is an effective approach for enhancing tumor response to verteporfin-PDT.
Citation Format: Daniel Kraus, Bin Chen. Targeting PI3K signaling pathway for therapeutic enhancement of verteporfin-mediated photodynamic therapy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B53.
Abstract IA05: The role of glucose and lipid metabolism in growth and survival of cancer cells
Authors: Peck Barrie , Lewis Caroline A. , Schulze Almut 
Published: October 2015

Abstract
Aberrant metabolism has been found to be central to oncogenic transformation. Shifting metabolic pathways to favor macromolecule biosynthesis, for example de novo lipogenesis, while maintain energy production is integral to cell growth and proliferation. Alterations in metabolic activity have emerged as one of the features of cancer cells and many oncogenic signaling pathways directly regulate the activity of metabolic processes.
We have investigated the involvement of metabolic processes in the proliferation and survival of cancer cells using gene expression analysis and functional genomics. These strategies have identified metabolic alterations in cancer and highlighted selective dependencies within the glucose and lipid metabolism that support growth and survival of cancer cells. Our results demonstrate that regulation of SREBP-dependent lipid synthesis by the Akt/mTORC1 signaling axis is required for the growth and survival of cancer cells. Disruption of SREBP resulted in altered lipid composition, mitochondrial dysfunction and oxidative stress leading to the engagement of the unfolded protein response pathway (UPR), induction of apoptosis and reduced tumor growth. Importantly, activation of fatty acid desaturation through enhanced expression of stearoyl-CoA desaturase (SCD) was identified as an essential function of SREBP downstream of the Akt/mTORC1 pathway. We also found evidence that some SREBP target genes are deregulated in cancer and that SREBP and SCD are essential to support cancer cell survival under metabolically compromised conditions.
Citation Format: Barrie Peck, Caroline A. Lewis, Almut Schulze. The role of glucose and lipid metabolism in growth and survival of cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA05.
Abstract IA14: Targeting the PTEN/PI3K pathway: From mouse model to human cancer
Authors: Wu Hong 
Published: October 2015

Abstract
Disease relapse represents a significant problem in treating T cell acute lymphoblastic leukemia (T-ALL), particularly in the context of PTEN alterations. It is hypothesized that leukemia-initiating cells (LICs) are responsible for both T-ALL development and treatment relapse. Here, we use the Pten null T-ALL model with functionally defined blast and LIC-enriched populations to test whether T-ALL LICs are responsible for therapeutic resistance. In this model, disease is initiated by the conditional deletion of Pten in the fetal liver hematopoietic stem cells and animals develop T-ALL with 100% penetrance in the absence of activating Notch1 mutations. Besides Pten deletion, at least two subsequent key events associated with human leukemogenesis have been identified, namely β-catenin activation and a T cell receptor α-c-Myc (Tcrα/δ-c-Myc) translocation, which lead to the transformation of T progenitor cells to self-renewable LICs enriched in the CD3+c-kitmidLin- subpopulation. In contrast to LICs in acute and chronic myelogenous leukemia, in vivo labeling revealed that T-ALL LICs are actively cycling. Furthermore, we demonstrate that T-ALL LICs are biologically distinct and respond differently to Rapamycin in comparison to their differentiated blast cell progeny. Importantly, we found that co-targeting deregulated phosphoinositide 3-kinase (PI3K) and Myc pathways, two common alterations found in human T-ALL that are associated with LIC formation in vivo, provides a potent therapeutic approach to eliminate T-ALL LICs. Our study suggests that LICs are addicted to molecular events critical for their formation and can be effectively eliminated by targeting these alterations, and that T-ALL may be stratified and treated according to such molecular defects.
Citation Format: Hong Wu. Targeting the PTEN/PI3K pathway: From mouse model to human cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA14.