bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4516: Evaluation of p70S6K/Akt inhibitor MSC2363318A in patient derived xenograft (PDX) models of breast cancer
Authors: Huck Bayard R. , Tian H , Syed Sakeena , Lin Jing , Ma Jianguo , Clark Anderson , Kaleta Remiguisz , Machl Andreas , Wilker Erik , Lecomte Marc 
Published: May 2015

Abstract
The PI3K pathway is involved in the regulation of cell growth, proliferation, metabolism and other functions. Aberrant signaling (PTEN loss of function, PIK3CA mutation, Akt amplification, etc.) from the PI3K pathway is observed in &gt;50% of all tumors. Clinical evidence suggests that inhibiting the PI3K pathway is beneficial for the treatment of solid tumors and tumors of the hematopoietic system. Inhibition of mTOR via rapalogs has been shown to block a negative feedback loop, thereby leading to the activation of Akt. The activation of this Akt feedback loop has been suggested to potentially compromise the clinical efficacy of selective mTORC1 inhibitors such as temsirolimus and everolimus. Dual p70S6K/Akt inhibition may promote improved pathway inhibition and also block the negative consequences of Akt activation through the negative feedback loop.
MSC2363318A is a highly selective, potent, adenosine triphosphate (ATP) competitive inhibitor of p70S6K, Akt1, and Akt3. In a cellular context, inhibition of p70S6K leads to potent inhibition of ribosomal protein S6 phosphorylation, while inhibition of Akt activity blocks the negative effects of a compensatory feedback loop. In addition, MSC2363318A exhibits potent anti-proliferative activity against many solid tumor cell lines in vitro, especially those with PI3K pathway genomic alterations. Further, MSC2363318A can also cross the blood-brain barrier (via pre-clinical studies in mice, rat, and dog), a unique characteristic that would allow for treating not only malignancies that are driven by PI3K pathway genomic alterations, but also indications with a high incidence of CNS metastases and primary malignancies of the central nervous system.
Patient Derived Xenograft (PDX) models from breast cancers with a high prevalence of PI3K pathway genomic alterations; including, triple negative breast cancer and Her2+ breast cancer were evaluated. In addition, combinations with standard of care agents were then evaluated in these breast cancer PDX models. Results from these studies were correlated with PI3K pathway genomic modifications, and will be used to guide subsequent clinical studies.
Citation Format: Bayard R. Huck, H Tian, Sakeena Syed, Jing Lin, Jianguo Ma, Anderson Clark, Remiguisz Kaleta, Andreas Machl, Erik Wilker, Marc Lecomte. Evaluation of p70S6K/Akt inhibitor MSC2363318A in patient derived xenograft (PDX) models of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2014-4516
Abstract 4517: Evaluation of the TOR kinase inhibitor CC214-2 in a mouse model of hormone-refractory prostate cancer
Authors: Yang Wenqing , Jiu Jing , Narla Rama Krishna , Raymon Heather K. 
Published: May 2015

Abstract
Prostate cancer is one of the most common malignancy diagnosed in men. Although androgen deprivation therapy is effective at the beginning of treatment, the majority of patients eventually progress to hormone refractory prostate cancer (HRPC), which leads to a poor outcome. HRPC mouse models have been developed to study transition from hormone dependent (HD) to hormone refractory (HR) disease; however, the exact mechanism behind this phenotypic conversion remains unclear. By using serial in vivo transplantation of LNCap xenograft tumors in castrated male SCID mice, we developed, validated and characterized a mouse model of HRPC, HR-LNCap. In vivo passaged tumor fragments form solid tumors in castrated male SCID mice. By comparison, HR-LNCap tumors grow more aggressively than parental LNCap tumors in SCID mice. A tumor cell line established from HR-LNCap xenograft tumors was able to grow in charcoal stripped serum containing medium, indicating it is androgen independent. HR-LNCap tumors lost sensitivity to androgen receptor antagonist bicalutamide, but remained sensitive to MDV-3100, a second generation AR antagonist approved for treating HRPC. Characterization of this model revealed that HR-LNCap tumors had unique AR signaling pathway profiles, including elevated AR expression and decreased expression of the AR-regulated genes, prostate specific antigen (PSA) and FKBP5, when compared with parental LNCap tumors. RNA sequencing was performed on HR-LNCap tumors to determine expression signature of the model. Interestingly, additional pathway analysis showed that HR-LNCap tumors have significantly higher levels of pAKT in comparison with parental LNCap tumors, indicating activation of AKT/mTOR pathway. Treatment of HR-LNCap tumor bearing mice with a small molecule TOR kinase inhibitor CC214-2 showed significant tumor growth inhibition. Further analysis demonstrated that treatment with CC214-2 inhibited TORC1 and TORC2 pathway markers, pAKT, pS6 and p4EBP1, in HR-LNCap tumors. Taken together, this study describes a mouse model of HRPC with a unique molecular profile, which can be used to evaluate novel therapeutics against HRPC.
Citation Format: Wenqing Yang, Jing Jiu, Rama Krishna Narla, Heather K. Raymon. Evaluation of the TOR kinase inhibitor CC214-2 in a mouse model of hormone-refractory prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4517. doi:10.1158/1538-7445.AM2014-4517
Abstract 454: TET2 alterations facilitate progression of metastatic prostate cancer
Authors: Nickerson Michael L. , Das Sudipto , Lou Hong , Li Hongchuan , Turan Sevilay , Im Kate , Anderson Stephen , Andresson Thorkell , Dean Michael 
Published: May 2015

Abstract
Metastatic prostate cancer (mPCa) is a highly lethal disease and molecular markers identifying disease subtypes and/or therapeutic targets are needed. We sequenced the exomes of five metastatic tumors and healthy kidney tissue from an index patient with castration resistant mPCa to identify lesions associated with disease progression and metastasis. A somatic missense TET2 alteration predicted to be deleterious to the protein was observed at the metastatic stage of disease. We sequenced TET2 in additional mPCa tumors and PCa cell lines and detected somatic missense alterations, frequent LOH, and a frameshift truncation in PCa cell line, DU-145, derived from a mPCa brain tumor. We also observed complex combinations of frequent and rare germline missense SNPs, which may contribute to a previously described association of TET2 with PCa risk by GWAS. In this study, we confirm transcription factor binding to TET2 alleles associated with disease by GWAS. We examine TET2 binding partners in prostate cells by affinity purification, mass spectrometry, and forward and reverse immunoprecipitation. We confirmed a protein complex containing TET2, OGT, and two transcriptional co-activators/splicing factors implicated in receptor-mediated gene expression. Functional analysis shows TET2 loss alters expression of a unique set of genes, increases cell proliferation, and therefore is a driver of PCa. TET2 loss may facilitate progression to castration resistant mPCa and appears to define a subset of cases with metastatic disease.
Citation Format: Michael L. Nickerson, Sudipto Das, Hong Lou, Hongchuan Li, Sevilay Turan, Kate Im, Stephen Anderson, Thorkell Andresson, Michael Dean. TET2 alterations facilitate progression of metastatic prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 454. doi:10.1158/1538-7445.AM2014-454
Abstract 4547: Enhanced anti-tumor effect of WNT pathway antagonists in combination with taxanes
Authors: Yen Wan-Ching , Fischer Marcus M. , Lewicki John , Gurney Austin , Hoey Timothy 
Published: May 2015

Abstract
The Wnt/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and several co-receptors, has long been implicated in cancer. We have previously demonstrated that inhibition of WNT/beta-catenin signaling by vantictumab (anti-FZD) or OMP-54F28 (FZD8-Fc) inhibits tumor growth, decreases tumorigenicity and induces differentiation in solid tumors. The anti-tumor effect of our Wnt antagonists is most evident in combination with chemotherapeutic agents. We sought to determine if the anti-tumor effect of Wnt pathway inhibitors varied with different chemotherapeutic agents. We compared the growth inhibitory effect of vantictumab and OMP-54F28 with either taxanes (paclitaxel and nab-paclitaxel) or with DNA synthesis inhibitors (gemcitabine and carboplatin) in patient-derived tumor xenografts. In a model for pancreatic ductal carcinoma, vantictumab with nab-paclitaxel was more efficacious than vantictumab with gemcitabine in inhibiting tumor growth and Wnt target gene expression (at doses of nab-paclitaxel and gemcitabine that were equivalent in their single-agent growth-inhibitory effects). Histologic analysis indicated that nab-paclitaxel increased mitotic cells and beta-catenin levels. Importantly, the addition of vantictumab to nab-paclitaxel reversed the nab-paclitaxel-induced increase in mitotic cells and beta-catenin expression. An independent experiment in a serous ovarian cancer xenograft model also showed enhanced anti-tumor activity when combining OMP-54F28 with either paclitaxel or nab-paclitaxel compared to the combination with carboplatin. A potential mechanism to account for these results involves on the observation that Wnt/beta-catenin signaling is under cell cycle control and peaks at the G2/M phase. Taxanes inhibit microtubule function and block the cell cycle at G2/M. In contrast, other chemotherapeutic agents, such as platinum compounds and nucleoside analogs, inhibit DNA synthesis and block cell proliferation at S phase. We hypothesize that combination of Wnt blockade with chemotherapeutic agents, such as taxanes, that induce G2/M arrest may result in optimal anti-tumor activity.
Citation Format: Wan-Ching Yen, Marcus M. Fischer, John Lewicki, Austin Gurney, Timothy Hoey. Enhanced anti-tumor effect of WNT pathway antagonists in combination with taxanes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4547. doi:10.1158/1538-7445.AM2014-4547
Abstract 4566A: Effect of the anti-histaminic cyproheptadine on cell cycle of hepatocellular carcinoma cells and its mechanisms
Authors: Hsu Cheng-Da , Feng Yu-Min , Chen Syue-Yi , Feng Jing-Wen 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer deaths worldwide; however, current chemotherapeutic drugs for hepatocellular carcinoma (HCC) are either poorly effective or expensive. The majority of patients can't have good outcomes by taking these drugs. Currently, we had a breakthrough finding in a case report of two patients with advanced HCC. We found one had complete remission of liver tumors, one had decrease of their alpha-fetoprotein levels and that both their lung metastasis had complete remission after the concomitant use of thalidomide and cyproheptadine. In light of a previous study that cyproheptadine affects the cell cycle and impedes leukemia cell growth by suppressing the action of transcription factor of cyclin D, we assume that cyproheptadine is the key factor in this treatment. Therefore, the purpose of this study was to investigate whether cyproheptadine inhibits HCC cell growth by impeding cancer cell cycle and to explore the molecular mechanisms of cyproheptadine-induced cell cycle arrest. First, we confirmed that cyproheptadine had inhibition effect on two HCC cell lines, HepG2 and Huh-7, by cell viability assay. Besides, to explore how cyproheptadine affects HCC cell cycle we analyzed DNA content by flow cytometry and found cell cycle arrest at the G1 to S transition in HepG2 cells and at the S to G2 transition in Huh-7 cells. Finally, we investigated the mechanism of cyproheptadine-induced cell cycle arrest using western blot analysis. Interestingly, our results showed that cyproheptadine promoted P38 activation by phosphorylation than subsequently stabilized P16 and caucused hypophosphorylation of Rb in HepG2 cells. On the other hand, cyproheptadine not only promoted P38 activation but also activated ATM/Chk2 pathway to stabilize P21 in Huh-7 cells. These novel results demonstrated that cyproheptadine suppressed HCC cells through the Non-classical P38 MAP Kinase Functions: Cell Cycle Checkpoints and ATM/Chk2 pathway, and provided a potential treatment option in HCC.
Citation Format: Cheng-Da Hsu, Yu-Min Feng, Syue-Yi Chen, Jing-Wen Feng. Effect of the anti-histaminic cyproheptadine on cell cycle of hepatocellular carcinoma cells and its mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4566A. doi:10.1158/1538-7445.AM2014-4566A
Abstract 4582: CRLX522, a novel dynamic tumor-targeted cabazitaxel nanopharmaceutical
Authors: Lazarus Douglas , Kabir Sujan , Eliasof Scott 
Published: May 2015

Abstract
Cabazitaxel is an approved treatment for castration-refractory prostate cancer. As with other taxanes, the therapeutic benefits of cabazitaxel are often compromised by immunosuppression and neurotoxicity. In order to address the obstacles to using cabazitaxel, we developed the dynamic tumor-targeted cabazitaxel nanopharmaceutical CRLX522. This nanopharmaceutical possesses significantly enhanced efficacy and improved pharmacokinetics compared to the parent drug. CRLX522 showed a superior PK profile, with a &gt;400-fold increase in AUC, a significantly longer half-life and a 32-fold higher drug concentration in tumor tissue 72 hours after a single administration versus cabazitaxel alone. The improved PK and biodistribution of CRLX522 translated into superior antitumor activity in murine syngeneic and human xenograft models. In the murine B16.F10 tumor model, median survival at the MTD exceeded 58 days for CRLX522 compared to 26 days for the parent drug cabazitaxel. CRLX522 demonstrated superior efficacy over cabazitaxel with a cure rate of 100% in a xenograft model representing breast cancer tumors, compared to 50% cures for the parent drug cabazitaxel. In summary, CRLX522 represents a new and potent anticancer therapeutic that has the potential to be a best-in-class taxane.
Citation Format: Douglas Lazarus, Sujan Kabir, Scott Eliasof. CRLX522, a novel dynamic tumor-targeted cabazitaxel nanopharmaceutical. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4582. doi:10.1158/1538-7445.AM2014-4582
Abstract 459: The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation
Authors: Yuan Chengfu , Wang Lei , Zhou Liang , Fu Zheng 
Published: May 2015

Abstract
Polo-like kinase 1 (PLK1) plays crucial roles in multiple stages of cell division. Our previous studies suggest that global transcriptional regulation by PLK1 may contribute to its multiple functions. PLK1 depletion is associated with a decrease in cell viability and the induction of apoptosis; however, the underlying mechanisms are not completely understood. Here, we report that forkhead box protein O1 (FOXO1) is a novel physiological substrate of PLK1. FOXO1 is at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell cycle progression, and oxidative-stress resistance. PLK1 interacts with and phosphorylates FOXO1, mainly at the G2/M phase of the cell cycle. PLK1-mediated phosphorylation leads to the impairment of FOXO1's transcriptional activity in an Akt-independent manner. By immunofluorescence staining and subcellular fractionation, we demonstrate that PLK1-induced FOXO1 phosphorylation causes its nuclear exclusion. Furthermore, PLK1-mediated phosphorylation of FOXO1 negatively regulates its pro-apoptotic function, and abrogates its ability to delay entry into and progression through G2/M transition. Therefore, our results suggest that PLK1 abrogates the inhibitory effects of FOXO1 on cell growth and survival to ensure timely cell cycle progression. This study not only reveals a novel and major regulatory mechanism of FOXO1 at the late phases of the cell cycle, but also provides new insight into the molecular mechanisms by which PLK1 inhibition leads to growth arrest and cell death.
Note: This abstract was not presented at the meeting.
Citation Format: Chengfu Yuan, Lei Wang, Liang Zhou, Zheng Fu. The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 459. doi:10.1158/1538-7445.AM2014-459
Abstract 4594: Reversal of Warburg effect by Apigenin and 5-Fluorouracil loaded dual drug liposomes result in enhanced colorectal chemotherapy
Authors: Sen Kacoli , Banerjee Shubhadeep , Mandal Mahitosh 
Published: May 2015

Abstract
Recent combinatorial approaches have demonstrated multidrug-based chemotherapy which target multiple pathways simultaneously leading to enhanced efficacy and reduced toxicity. Our study reports simultaneous delivery of 5-Fluorouracil (a clinically approved drug) and Apigenin (a naturally occurring isoflavonoid abundantly present in fruit and vegetables) through a single liposome to combat and control colon cancer effectively in-vitro and in-vivo based on synergy studies after screening natural product library. Uniform homogeneous suspension of dual drug-loaded large unilamellar vesicles with substantial entrapment of both drugs was obtained by modified thin film hydration method. The vesicles exhibited excellent hemocompatibility and cytocompatibility against normal fibroblasts. The cytotoxicity and cellular effects of individual and combinatorial free drugs, neat vesicles and single or dual drug-loaded liposomes tested against different human colon cancer cell lines revealed significantly higher cytotoxicity of dual-drug liposomes in comparison to other formulations. The dual drug loaded liposomal formulation was observed to be effectively internalized by endocytosis and demonstrated enhanced inhibition of angiogenesis, better reduction in cell proliferation, increased apoptotic potential and significantly decreased cellular migration and invasion capacity. Cell signaling studies indicating a significant upregulation of AMPK and activity against downstream targets by dual drug liposomes resulted in apoptosis, autophagy and senescence, suggesting its role in the reversal of Warburg effect. Enhanced apoptotic potential of the formulation was traced to its ability to induce greater oxidative stress through the generation of reactive oxygen and nitrogen species. The formulation was tested in a preclinical setting in nude mice tumor xenograft model and was found to have greater anti-neoplastic and anti-tumorigenic effect. The study indicated the potential of the synergistic effect of Apigenin in 5-Fluorouracil treatment of colon cancer which effectively circumvents the problem of drug resistance and 5-Fluorouracil associated toxicity. This dual drug loaded liposomal formulation thus, offers a new attractive alternative to enhance the therapeutic potency of drugs and paves way for potential clinical applications.
Note: This abstract was not presented at the meeting.
Citation Format: Kacoli Sen, Shubhadeep Banerjee, Mahitosh Mandal. Reversal of Warburg effect by Apigenin and 5-Fluorouracil loaded dual drug liposomes result in enhanced colorectal chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4594. doi:10.1158/1538-7445.AM2014-4594
Abstract 4595: RPL18A as putative target of rigosertib
Authors: Oussenko Irina , Divakar Saikrishna , Reddy M. V. Ramana , Holland James F. , Reddy E. Premkumar , Ohnuma Takao 
Published: May 2015

Abstract
Rigosertib (ON 01910.Na) is clinical stage anti-mitotic cancer inhibitor that causes spindle abnormalities in neoplastic cells. Rigosertib inhibits PI3K and PLK1 signaling pathways, down regulates cyclin D1 expression and induces apoptosis. Previously we reported rigosertib led to hyperphosphorylation of RanGAP1•SUMO1, regulator of RanGTP/RanGDP cycle, and hypothesized phosphatase inhibition [Cancer Res 2011; 71; 4968-76]. Using biotin-conjugated rigosertib and avidin-conjugated agarose beads, we sought rigosertib molecular target from HeLa cell lysates by pull-down assay. Long-linker 1910-biotin showed an IC50 for cytotoxicity similar to unmodified rigosertib and efficient avidin binding. Asynchronously grown HeLa cell lysates were incubated with designated ligands and avidin beads. Bound lysate proteins were recovered from beads, resolved on SDS-PAGE and stained. Specific protein band of ∼20 kDa was detected only with long-linker 1910-biotin. Identification of proteins from the gel was performed by LC-ESI-MS/MS. Four ribosomal proteins possessed Mascot score above cut-off level with RPL18A, score of 367, and other proteins scored 153 or less. Specific dose-dependent binding of long-linker 1910-biotin to RPL18A was confirmed by Western blot analysis in replicate pull-down experiments using HeLa or MOLT-3 cell lysates. Recombinant RPL18A possessed specific reactivity to 1910-biotin in the pull-down assay. Knock-down of RPL18A with siRNA causes apoptosis in cancer cell lines [Sudo et al, Genomics 2010; 95; 210-6; and our data]. We propose that nucleocytoplasmic transport of RPL18A is impaired when hyperphosphorylated RanGAP1•SUMO1 fails to provide RanGTP/GDP gradient for nuclear pore complex. Importin-9 (IPO-9) is a major nucleocytoplasmic transporter for RPL18A. Among other cargos of IPO-9 are HSP27 (important anti-apoptotic player), scaffold subunit A of PP2A (major mitotic phosphatase), core histones and ribosomal proteins. Considering the essential role of nucleocytoplasmic transport in general and probable consequences of impeded transport of HSP27, PP2A and/or core histones, that actually match those observed with rigosertib, we hypothesize that binding with RPL18A in the presence of hyperphosphorylated RanGAP1•SUMO1 interferes with normal function of IPO-9, resulting in a variety of malfunctions and apoptosis observed in rigosertib treated cancer cells.
Citation Format: Irina Oussenko, Saikrishna Divakar, M. V. Ramana Reddy, James F. Holland, E. Premkumar Reddy, Takao Ohnuma. RPL18A as putative target of rigosertib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2014-4595