bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4497: NVP-BEZ235, a dual PI3K/ mTOR inhibitor, may be effective for ovarian clear cell carcinoma cells
Authors: Oishi Tetsuro , Itamochi Hiroaki , Nonaka Michiko , Sato Seiya , Naniwa Jun , Uegaki Kazunori , Sato Shinya , Shimada Muneaki , Terakawa Naoki , Kigawa Junzo , Harada Tasuku 
Published: June 2012

Abstract
[Background] NVP-BEZ235 (BEZ235) is a novel, orally bioavailable imidazoquinoline that potently and reversibly inhibits class 1 PI3K activity by binding to its ATP-binding domain. BEZ235 also binds directly to the mTOR ATP-binding domain and directly inhibits its catalytic activity, thereby inhibiting both TORC1 and TORC2. BEZ235 is currently in phase I testing in patients with solid tumors. There are few reports on the activity of BEZ235 against ovarian carcinoma cells. Ovarian clear cell carcinoma (CCC) has shown the resistance to the standard chemotherapy for epithelial ovarian cancer (EOC). Therefore, patients with CCC have a worse prognosis than those with ovarian serous adenocarcinoma (SAC), which is a dominant subtype in EOC. However, little has been known about genetic alterations in each histologic subtype of EOC. Recently, it has shown that CCC has a high frequency of activating PIK3CA mutations. The purpose of the current study was to determine whether the drug targeting the PI3K-Akt-mTOR pathway suppresses cell proliferation of CCC.
[Material& Methods] We used eight CCC cell lines (KK, OVISE, SMOV-2, KOC-7c, TUOC-1, OVTOKO, OVMANA, and RMG-I) and four SAC cell lines (SHIN-3, TUOS-4, KOC-2s, SK-OV-3) in this study. IC50 to BEZ235 was determined on the basis of the dose-effect curves, using WST-8 assay. Protein expressions of Akt, phospho(p)-Akt(Ser473), mTOR, pmTOR(Ser2448), p70S6K, pp70S6K(Thr389), 4E-BP1, and p4E-BP1(Ser37/46) were examined by western blotting.
[Results] IC50 to BEZ235 for CCC cell lines ranged from 44 to 777 nM and those for SAC cell lines ranged from 989 to 25400 nM. All 8 CCC cell lines showed Akt, mTOR, pmTOR, and p70S6K expressions. Six cell lines showed pAkt expression, and 2 of the 6 cell lines showed both pAkt and p4E-BP1 expressions. Remaining 2 cell lines showed pp70S6K expression. pAkt, p-p70S6K and p4E-BP1 expression in CCC cells were suppressed after exposure to BEZ235 in a dose-dependent manner.
[Conclusion] These results suggest that the PI3K/Akt/mTOR pathway is a potential therapeutic target for CCC and that NVP-BEZ235 is worth exploring as therapeutic agents for CCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4497. doi:10.1158/1538-7445.AM2011-4497
Abstract 4498: HS-104, a novel potent phosphatidylinositol 3-kinase inhibitor, with anticancer activity in human hepatocellular carcinoma
Authors: Hong Soon-Sun , Zheng Hong-Mei , Jung Kyung Hee , Lee Hyunseung , Hong Sang-Won , Li Guang-Yong , Park Byung-Hee , Son Mi-Kwon 
Published: June 2012

Abstract
Phosphatidylinositol 3-kinase (PI3K) has been implicated in cell growth, proliferation, and survival in a variety of diseases including cancer. It is activated by mutational activation of PI3Kα, loss of function of PTEN or activation of receptor tyrosine kinases. A number of PI3K inhibitors have recently been developed for use in cancer therapy. However, there has been no report performed in human hepatocellular carcinoma (HCC), even if the mutation of PI3Ka in HCC have been reported as 6.0∼35.6%. In this study we investigated the effect of HS-104, a novel phosphatidylinositol 3-kinase inhibitor on the proliferation, apoptosis, angiogenesis of HCC cells as well as in vivo mouse xenograft model bearing Huh-7 HCC cells. HS-104 inhibited PI3Ka activity more than LY294002 (a traditional PI3K inhibitor), and it suppressed the phosphorylation of Akt and mTOR in downstream of PI3K in a dose dependent manner. The growth of HCC cells (Huh-7, HepG2, Hep3B) was inhibited by HS-104 treatment in a dose-dependent manner as sorafenib did. Interestingly HS-104 didn't affect the normal liver cell line (HL-7702), while sorafenib showed cytotoxicity at high concentrations. Also, its induction of apoptosis was found by the increase in the proportion of sub-G1 apoptotic cells of 20% at a dose of 10 uM, and the increase in the expressions of cleaved PARP and caspase-3 as well as the decrease in that of bcl-2 in Huh-7 cells. Its induction of apoptosis was confirmed by DNA fragmentation as well as DAPI and TUNEL staining. In addition, we found that HS-104 decreased the expression of hypoxia-inducible factor (HIF-1α), vascular endothelial growth factor (VEGF), and the tube formation and migration of human umbilical vein endothelial cells (HUVECs) in a dose dependent manner, which were confirmed by Matrigel plug assay performed in BALB/c nude mouse. In addition, HS-104 administration (10 mg/kg) for two weeks significantly suppressed the growth of liver cancer in mouse xenograft model using Huh-7 cells, where its induction of apoptosis and anti-angiogenesis was confirmed by immunohistochemistry assay for tumor tissues. Taken together, these results suggest that HS-104 could be used as a drug for the treatment of human hepatoma cells by the mechanism of apoptosis and anti-angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2011-4498
Abstract 4518: Effects of a novel small molecule inhibitor of Wnt signal pathway, CWP232291, on primary tumor cells from patients with malignant hematologic diseases
Authors: Kim Sung-Doo , Byun Young-Hee , Hur Eun-Hye , Oh Se-Woong , Lee Jong Heun , Goo Bon-Kwan , Lee Sung-Sook , Jung Kyung-Yun , Lee Kyoo-Hyung , Lee Jung-Hee , Kim Dae-Young , Choi Yunsuk , Lee Je-Hwan 
Published: June 2012

Abstract
Background: Aberrant activation of Wnt signaling has been implicated in the pathogenesis of hematologic malignancies. CWP232291 is a novel small molecule that inhibits Wnt signaling through promotion of beta-catenin degradation. In vitro and in vivo anti-tumor activities of CWP232291 were demonstrated in previous studies using hematologic cancer cell lines (J.Y.C. 2010 AACR, LB-176). Here we report the effects of CWP232291 on primary tumor cells from patients with malignant hematologic diseases.
Materials and methods: We performed cell viability assay using luminescent-based CellTiter Glo system to determine in vitro growth inhibitory activities in bone marrow mononuclear cells of healthy volunteers and in primary tumor cells collected from bone marrow of the patients with acute myeloid leukemia (AML) and B-cell neoplasms (B-cell non-Hodgkin lymphoma [B-NHL] and multiple myeloma [MM]). Western blot assay was done for changes of intracellular beta-catenin levels after the treatment of CWP232291.
Summary of results: CWP232291 showed little effects on normal bone marrow cells, whereas it exerted potent cytotoxicities in a significant proportion of the patients’ samples (8 of 13 AML patients, 2 of 3 B-NHL patients, and 2 of 4 MM patients). The cytotoxic effects of CWP232291 at sub-micromolar levels were more potent than those of anti-leukemic cytotoxic agents such as cytarabine, daunorubicin, or doxorubicin. All of the tumor samples from the AML patients with t(8;21) (n=3), trisomy 8 (n=3), or MLL translocations (n=1) were sensitive to CWP232291. Baseline intracellular beta-catenin levels were elevated in both B-NHL patients’ samples that were sensitive to CWP232291 and the beta-catenin levels decreased after the treatment with CWP232291.
Conclusion: Our data from primary patients’ samples provide a rationale for exploring the clinical activities of CWP232291 in the treatment of patients with hematologic malignancies, especially AML and B-cell neoplasms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4518. doi:10.1158/1538-7445.AM2011-4518
Abstract 4540: Follicle-stimulating hormone (FSH) enhances the proliferation of epithelial ovarian cancer cells by activating transient receptor potential channel C3 (TRPC3)
Authors: Tao Xiang , Jin Hongyan , Bast Robert C. , Liu Yingtao , Yu Yinhua , Feng Youji 
Published: June 2012

Abstract
At present, epithelial ovarian cancer is the leading killer among all gynecological malignancies. Despite much research, development of this neoplasm is still not fully understood. The five-year survival rate for this disease still remains about 30%. Recent studies suggest that follicle-stimulating hormone (FSH) may play a major role in ovarian epithelial carcinogenesis. Our group has demonstrated that FSH stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis, and facilitates neovascularization by increasing vascular endothelial growth factor (VEGF) expression. To understand the mechanisms by which FSH stimulates ovarian cancer growth, we have performed gene expression arrays and confirmed changes in protein expression by Western blots. Interestingly, we found that FSH stimulation enhances expression of transient receptor potential channel C3 (TRPC3) at both mRNA and protein levels. Silencing TRPC3 expression by siRNA inhibited the ability of FSH to stimulate proliferation of ovarian cancer cell lines and to block apoptosis. TRPC channels are nonselective cation channels with permeability to Ca2+. Increases in cytosolic free Ca2+ can promote different physiological changes including cell growth, differentiation and death. TRPC3 is one of 7 TRPC family members. Our previous work has shown that TRPC3 contributes to the progression of human ovarian cancer. TRPC3 protein levels in human ovarian cancer specimens were greatly increased relative to those in normal ovarian specimens. Downregulating TRPC3 expression led to reduced proliferation, suppression of epidermal growth factor-induced Ca2+ influx, and decreased growth of xenografts. In this study, we further explored the interaction of FSH-TRPC3. FSH stimulation was associated with upregulation of TRPC3 levels and translocation of TRPC3 from the cytoplasm to cell membrane, facilitating the influx of Ca2+ after treatment with a TRPC3 specific agonist. Knocking down TRPC3 abrogated Akt/PKB phosphorylation by FSH stimulation, leading to decreased expression of down-stream effectors including survivin, HIF1α and VEGF. Our findings indicate that TRPC3 plays a significant role in the tumor-stimulating activity of FSH and could be a potential therapeutic target of ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4540. doi:10.1158/1538-7445.AM2011-4540
Abstract 4552: Naturally occurring osmolyte, trehalose induces a functionally active conformation in an intrinsically disordered transactivation function domain (AF1) of the Glucocorticoid Receptor
Authors: Khan Shagufta H. , Arnott John A. , Atamna Hani , Ahmad Nihal , Kumar Raj 
Published: June 2012

Abstract
Due to the ability of glucocorticoids to prevent the growth and to cause apoptotic death of malignant cells, they are a mainstay of therapy for many lymphomas and leukemias. Glucocorticoid receptor (GR) mediates the biological effects of glucocorticoids at the level of gene regulation. To initiate transcription of target gene(s), GR interacts with its response element DNA, and/or with various coregulatory proteins. However, specific interaction surfaces of GR with its coregulators are not well understood. Consequently, precisely how transcription is regulated by GR is largely unknown. This is due, in part, to the lack of information about GR's major transactivation function region, AF1 located in the N-terminal domain. The major obstacle in determining the structure of AF1 has been due to its intrinsically disordered (ID) conformation, frequently found in the activation domains of many transcription factors, and it is believed that ID nature of these activation domains promote molecular recognition by creating large interaction surfaces suitable for interactions with their specific protein binding partners, which is a critical component of gene regulation by transcription factors. It has been hypothesized that conditional folding of these activation domains may be a prerequisite for their efficient interaction with specific coregulatory proteins, and subsequent transcriptional activity leading to the regulation of target gene(s). In this study, we tested whether a naturally occurring osmolyte, trehalose can promote functionally ordered conformation in the GR's major activation function domain, AF1, which is found to exist as an ID protein, and requires an efficient interaction with coregulatory proteins for optimal activity. Our data show that trehalose induces an ordered conformation in AF1 such that its interaction with steroid receptor coactivator-1 (SRC-1), a critical coregulator of glucocorticoid receptor's activity, is greatly enhanced. Our results may provide a mechanism for cell-type specificity of the effects of GR in gene regulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4552. doi:10.1158/1538-7445.AM2011-4552
Abstract 4562: Superior targeting of the human epidermal growth factor receptor 2 (HER-2) with recombinant monoclonal antibody mixtures
Authors: Pedersen Mikkel W. , Jacobsen Helle J. , Poulsen Thomas T. , Meijer Per J. , Kragh Michael 
Published: June 2012

Abstract
Human epidermal growth factor receptor 2 (HER2) is involved in development and maintenance of malignant phenotypes of several human cancers and therefore represent an attractive therapeutic target. Trastuzumab is currently the only anti-HER2 antibody approved for treatment of human cancers and although succesful more efficacious treatments are warranted. Mixtures of recombinant monoclonal antibodies are promising candidates as the next generation of antibody therapeutics due to their multipotent activities.
The aim of the present study was to identify mixtures of anti-HER2 antibodies with superior activity to existing monoclonal antibodies. Anti-HER2 antibodies were raised in mice by immunizations with HER-2 in different antigen presenting formats. A large antibody repertoire consisting of approximately 150 unique anti-HER-2 antibodies was cloned from the mice using the mSymplex™ technology. Based on a thorough sequence and binding analysis, 40 antibodies were selected for functional evaluation. The 40 antibodies were tested as individual antibodies and in mixtures of two and three for the ability to inhibit the growth of four human cancer cell lines using a standard viability assay. In total, more than 1300 mixtures were evaluated for ability to inhibit growth of the four cell lines. The 20 mixtures with the highest levels of growth inhibition were further characterized with regard to potency (IC50) and ability to engage in ADCC and CDC. The results demonstrated that HER2 mixtures were superior to trastuzumab, pertuzumab and the mixture of the two at inhibiting the growth of seven of the 10 cell lines investigated. Interestingly, the mixtures also inhibited the growth of the trastuzumab resistant breast cancer cell line HCC202, reflecting the differentiated mechanisms of anti-HER2 antibody mixtures. In vivo, anti-HER2 mixtures had superior activity compared to the monoclonal anti-HER2 antibody trastuzumab in two models of human gastric cancer. Based on these results, a candidate mixture was selected and referred to as Sym005.
In conclusion, these data demonstrate that the novel antibody mixture Sym005 has a unique set of HER2 inhibitory mechanisms, which translates into superior anti-cancer activity in HER2-positive tumor xenografts. Furthermore, the results provide a clear rationale for evaluation of Sym005 in clinical trials on patients with HER2 positive tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4562. doi:10.1158/1538-7445.AM2011-4562
Abstract 4566: AGS-1C4D4: A fully human anti-PSCA antibody inhibits tumor formation and metastasis in orthotopic models of pancreatic cancer
Authors: Navas Tony , Haubrich Trisha , Llamas Jenny , Avina Hector , Chunying Zhang , Perez Myra , Capo Linnette , Leavitt Monica , Chen Rou-Yu , Verlinsky Alla , An Zili , Secrest James , Ganguly Nandini , Satpayev Daulet , Morrison Karen , Raitano Art , Challita-Eid Pia , Jia Xiao-Chi , Morrison Kendall , Hartford Alan , Stover David 
Published: June 2012

Abstract
Prostate stem cell antigen (PSCA) is a cysteine-rich cell surface glycoprotein expressed in about 50% of pancreatic and prostate cancers. AGS-PSCA is a hybridoma-derived fully human IgG1κ monoclonal antibody (MAb) targeting PSCA previously reported to have anti-tumor efficacy in prostate and pancreatic tumor models. AGS-1C4D4 is a CHO-derived antibody generated from the same gene as AGS-PSCA, with similar specificity and binding affinity to PSCA (Kd = 2.0 × 10-10M). Since hybridoma and CHO-derived MAbs displayed disparate glycosylation patterns by mass spectroscopy, we further evaluated their MAb effector functions. AGS-1C4D4 was found to have more potent ADCC activity in vitro on PSCA-expressing pancreatic cell lines, HPAC and Panc0203, using human PBMCs from multiple normal donors. However, both MAbs were similarly effective in mediating CDC on PSCA-expressing recombinant B300.19 cells. Deglycosylation greatly reduced the relative ADCC and CDC activities of both MAbs compared to their intact versions. Additional studies to elucidate the role of the effector functions of AGS-1C4D4 are currently being conducted in vivo using intact and deglycosylated MAbs and will be presented. While neither intact antibody had any direct cytotoxic activity on HPAC cells in vitro, both MAbs significantly inhibited tumor formation, local invasion and metastases to distant sites in orthotopic HPAC xenograft tumor models in vivo. In addition, AGS-1C4D4 significantly inhibited the growth and metastasis of established orthotopic HPAC tumors in combination with Gemcitabine. AGS-1C4D4 is currently being evaluated in a Phase 2 clinical study for pancreatic cancer in combination with Gemcitabine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4566. doi:10.1158/1538-7445.AM2011-4566
Abstract 4578: Nonclinical safety assessment of VX15/2503: A humanized IgG4 monoclonal antibody to sema4D
Authors: Cornelius Chad A. , Fisher Terrence L. , Winter Laurie A. , Seils Jennifer , Reilly Christine A. , Jonason Alan S. , Smith Ernest , Watkins Raymond , Zauderer Maurice , Leonard John E. 
Published: June 2012

Abstract
VX15/2503 is a humanized IgG4 monoclonal antibody that binds with approximately 3 nM affinity to Semaphorin 4D (SEMA4D, CD100). SEMA4D is an important mediator of axonal growth cone guidance, vascular development, angiogenesis, and T cell and B cell activation. SEMA4D is found predominantly as a 150 kDa transmembrane protein on lymphocytes and as a 240 kDa, homodimeric, soluble form of the protein. VX15/2503 or its murine progenitor (MAb 67-2) suppressed tumor growth and angiogenesis in syngeneic, xenograft and transgenic tumor models. Toxicology and pharmacology studies of VX15/2503 were performed in Sprague-Dawley rats and cynomolgus macaques using single or five weekly intravenous injections. Toxicology profiles were similar for both species in both studies. Single dose studies employed doses of between 0.01 and 100 mg/kg; repeat dose studies evaluated 10, 30 and 100 mg/kg. No adverse histopathologic or clinical effects were noted in either species injected with doses up to 100 mg/kg. Appetence, body weights, serum chemistry and ophthalmologic factors were also unaffected, as were primate ECG results. Thus the NOAEL was established at 100 mg/kg for both species. Partial to complete T cell associated SEMA4D saturation was observed in all animals across the dose ranges evaluated and SEMA4D saturation was dose dependent. Single dose animals that reached a VX15/2503 serum concentration of ≥2 µg/mL exhibited transient complete T cell saturation. Prolonged saturation occurred at the 100 mg/kg dose level. Repeat dose animals in the 100 mg/kg dose group were on average at least 20% saturated for 134 and 169 days in rats and cynomolgus macaques, respectively. Single dose VX15/2503 half-life values increased with dose and varied from 27 to 246 hours in rats; similar results were obtained from the primate single dose study. Repeat dose Cmax and AUC (exposure) values were higher in both species than those from the single dose studies and steady-state was achieved after the fourth dose. Anti-VX15/2503 responses were detected in the sera of most animals in both studies. Human tissue arrays incubated with VX15/2503 showed diverse distribution of SEMA4D on resident or itinerant lymphocytes in lymphoid tissues as well as in sections of brain, lung and endometrium. Based on these results VX15/2503 was selected for clinical development in oncology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4578. doi:10.1158/1538-7445.AM2011-4578
Abstract 4587: Identification of a monoclonal antibody to treat HCC xenografts with EGFRvIII expression
Authors: Li Zonghai , Jiang Hua , Wang Huamao , Shi Bizhi 
Published: June 2012

Abstract
Purposes:To identify monoclonal antibodies targeting Epidermal Growth Factor Receptor Variant III (EGFRvIII) and their anti-tumor effect on Hepatocellular carcinoma (HCC) with EGFRvIII expression. Procedures: Hybridoma technology was used to prepare monoclonal antibody recognizing EGFRvIII. Anti-tumor effects of several hybridoma clones were examined on HCC xenografts with EGFRvIII expression. Monoclonal antibody with highest growth-suppression effect on HCC was selected. Binding specificity of the antibody was tested by FACS assay. The targeting ability of this antibody was tested by injected the cyanin 5.5 labeled antibody into mice carrying EGFRvIII positive and negative xenografts. Findings: Among the tested monoclonal antibodies, mAb 12H23 has the highest tumor-suppression effect on HCC with EGFRvIII expression. mAb 12H23 bind preferentially to HCC cells with EGFRvIII expression. Cy5.5 labeled mAb 12H23 can significantly accumulate into EGFRvIII positive tumors but not the negative tumors. Conclusion: These data indicate mAb 12H23 is a potential biotherapeutic agent for treating HCC with EGFRvIII expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4587. doi:10.1158/1538-7445.AM2011-4587