bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4467: Role of 12-lipoxygenase in regulation of ovarian cancer growth
Authors: Guo Austin M. , Al-Wahab Zaid , Liu Xiuli , Maddippadi Krishna Rao , Ali Rouba , Scicli A. Guillermo , Munkarah Adnan 
Published: June 2012

Abstract
Eicosanoid-related enzymes may be implicated in the pathogenesis of ovarian cancer. We found that high grade serous ovarian carcinoma had a significantly higher level of 12-LOX expression than normal ovarian epithelium. These data led us to hypothesize that the lipoxygenase pathway is important in the regulation of ovarian cancer growth. In the present study, we examined the role of 12-lipoxygenase (12-LOX), the main human 12-HETE generating enzyme, in the regulation of proliferation and survival in epithelial ovarian cancer in vitro and ovarian cancer development and angiogenesis in vivo. Down-regulation of the 12-LOX expression using 12-LOX siRNA also resulted in markedly reduction in the epithelial ovarian cancer (EOC) OVCAR-3 growth as we have previously observed with BMD-122, a selective 12-LOX inhibitor. In addition, BMD-122 significant inhibited the VEGF expression whereas purified 12-HETE increase VEGF expression in OVCAR-3 cells. Furthermore, we found that BMD-122 markedly decreases angiogenesis induced by OVCAR-3 in a Matrigel plug angiogenesis assay. Systemic administration of BMD-122 to nude mice bearing experimentally-induced ovarian cancer resulted in a 60 % decrease in tumor size. These data suggest that 12-LOX may be involved in regulation of ovarian cancer growth, survival and cancer-induced angiogenesis. Thus inhibition of 12-LOX could be useful as adjuvant therapy 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 4467. doi:10.1158/1538-7445.AM2011-4467
Abstract 4481: Topical application of the dual PDPK1/AKT inhibitor PHT-427 inhibits signaling and growth of human breast cancer cutaneous metastases in mice
Authors: Kirkpatrick D. Lynn , Johnson Jenny L.H. , Lemos Robert , Abdelemelek Mena , Ihle Nathan , Powis Garth 
Published: June 2012

Abstract
Despite advances in the treatment of breast cancer between 10 to 15% of patients develop cutaneous metastatic disease (CMD) most frequently on the face, neck and chest wall, usually in later stages of the disease as a harbinger of metastasis that will occur in other organs 1 to 3 years later. CMD is not life threatening but can significantly impact patients’ quality of life and is a cause of anxiety, pain, discomfort, and a portal for infection. CMD could also be a seed for metastases at other sites. Surgery or radiotherapy is used for single or localized CMD. Topical (epicutaneous) therapy with molecularly targeted agents provides an attractive modality for treatment of more widespread breast CMD. PHT-427 is a dual pleckstrin homology (PH) domain inhibitor of PDPK and AKT, two key enzymes of PI3K signaling that is frequently activated in breast cancer. We report here PHT-427's topical activity in CMD. MCF-7 human breast cancer (mutant PIK3CA) 106 cells in 20 μI were injected intradermaly in the flank of estradiol pelleted female nu/nu mice. When tumors reached 40-200 mm3 groups of 5 mice were treated twice a day with 0.1 ml vehicle or vehicle with 50 mg/ml PH-427, applied to a 1 cm patch of skin over the tumor. Mice were housed individually with collars to prevent them ingesting applied drug. After 10 days mice were euthanized 4 hr after the last application and blood, tumor and overlying skin were removed for analyses. Topical PHT-427 gave 89 % inhibition of tumor growth (p = 0.017, 3/5 no measurable tumor). There was no change in body weight and no apparent skin toxicity. Western blotting showed that PHT-427 inhibited p-AKT Thr308/Ser473 in skin and tumor, and decreased total AKT in skin but not tumor. p-PDPK1 Ser241 was inhibited in tumor but not skin, as was the downstream target pPKC Thr410 and pMAPK Thr202/Tyr204. Measurement of PHT-427 by HPL-MS showed very high levels in the skin at the site of application, levels of ∼50 μg/g in tumor and 5.5 μg/ml in plasma. In vitro levels of PHT-427 of 5 μg/ml are required for killing of sensitive cell lines. Thus, topical application of PHT-427 can deliver active drug levels to skin and tumor, inhibiting PDPK1 and AKT, and significantly inhibiting tumor growth without adverse effects on normal skin. Topical PHT-427 could have use in skin conditions driven by PDPK/AKT such as prevention of sun damage and skin cancer, and in the personalized therapy of breast CMD.
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 4481. doi:10.1158/1538-7445.AM2011-4481
Abstract 4485: Preclinical characterization of PWT33597, a dual inhibitor of PI3-kinase alpha and mTOR
Authors: Matthews David J. , O'Farrell Marie , James Joyce , Giddens Anna C. , Rewcastle Gordon W. , Denny William A. 
Published: June 2012

Abstract
Phosphoinositide-3-kinase (PI3K) is an important mediator of tumor cell growth, survival and proliferation. In particular, PI3K alpha is important for signaling downstream of receptor tyrosine kinases and is also frequently amplified or mutationally activated in tumors, suggesting that selective inhibitors of this isoform may have therapeutic utility in the treatment of cancer. Downstream of PI3K, the mTOR kinase also plays a critical role in cellular growth and metabolism, and inhibitors of mTOR have demonstrated clinical benefit in several tumor types. We report here the discovery and characterization of PWT33597, a dual inhibitor of PI3K alpha and mTOR. PWT33597 inhibits PI3K alpha and mTOR in biochemical assays with IC50 values of 19 and 14 nM respectively, and is approximately 10-fold selective with respect to PI3K gamma and PI3K delta. Profiling of PWT33597 against 442 protein kinases (Ambit Kinomescan) revealed little or no cross-reactivity with either serine/threonine or tyrosine kinases, and there was little cross-reactivity with an additional panel of 64 pharmacologically relevant targets. In NCI-H460 and HCT116 tumor cells with mutationally activated PI3K alpha, PWT33597 inhibits phosphorylation of PI3K and mTOR pathway proteins with cellular IC50 values similar to its biochemical IC50 values. PWT33597 has good pharmacokinetic properties in multiple preclinical species, is not extensively metabolized in vivo and shows little potential for interaction with cytochrome P450 enzymes. Following a single oral dose in vivo, PWT33597 shows durable inhibition of PI3K and mTOR pathway signaling in xenograft tumors. High compound distribution into tumors and potent anti-tumor activity has been observed in multiple tumor xenograft models with activated PI3K/mTOR pathways. Also, administration of PWT33597 in mice is associated with transient increases in plasma insulin, consistent with an effect on PI3K/AKT signaling. A robust PK/PD relationship has been defined, which will guide interpretation of the planned phase I clinical study. IND-enabling studies with PWT33597 are currently in progress.
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 4485. doi:10.1158/1538-7445.AM2011-4485
Abstract 4495: Treatment effects of the novel mTOR kinase inhibitor AZD8055 in prostate cancer cell models
Authors: Dai Yao , Siemann Dietmar 
Published: June 2012

Abstract
The mTOR pathway is frequently hyperactivated in prostate cancer due to PTEN loss of function, hence rendering prostate cancer cells sensitive to mTOR inhibitors. Although the classic allosteric mTOR inhibitor rapamycin has shown considerable preclinical efficacy, clinical results suggest that rapamycin alone is insufficient to inhibit tumor growth in prostate cancer patients. AZD8055 is an ATP-competitive mTOR kinase inhibitor that efficiently blocks activation of both mTOR complex (mTORC) 1 and 2. In this study we evaluated the effects of AZD8055 in prostate cancer cell models. Cell proliferation after drug treatment was determined by MTT assay and cell cycle was analyzed using propidium iodide staining followed by flow cytometry. Protein expression was detected by Western blot. In both PC-3 (PTEN null) and DU145 (PTEN wildtype) cells, AZD8055 suppressed cell proliferation at the nanomolar level in a dose dependent manner. At the same concentration (100 nM), AZD8055 induced greater G1 phase arrest than rapamycin and the expression of proteins related to G1 progression (cyclin D1, c-Myc) was significantly decreased by AZD8055 while only slightly reduced by rapamycin. Mechanistically, although both drugs blocked phosphorylation of mTORC1 downstream targets S6K and S6, only AZD8055 inhibited phosphorylation of 4E-BP1, another mTORC1 downstream molecule, and Akt, a typical target of mTORC2. Importantly, cells that were able to survive and proliferate under rapamycin (100 nM) selective pressure remained responsive to AZD8055, even at the lowest dose (10 nM). Furthermore in a PC-3 cell line established to be highly resistant to rapamycin (PC-3RR), AZD8055 could still potently decrease cell proliferation, with an IC50 of 0.5 nM. Taken together, these findings indicate that a) AZD8055 is superior to rapamycin in growth inhibition of prostate cancer cells irrespective of PTEN status, b) AZD8055 is able to deactivate rapamycin-insensitive complexes involved in the mTOR signaling, and c) AZD8055 treatment can overcome rapamycin treatment-associated resistance. In summary, the novel mTOR kinase inhibitor AZD8055 may have significant therapeutic potential in prostate cancer treatment.
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 4495. doi:10.1158/1538-7445.AM2011-4495
Abstract 4522: Identification of small molecule agonists/activators of BMP-2, 4, 7 signaling
Authors: Vrijens Karen , Lin Wenwei , Cui Jimmy , Shelat Anang , Taylor Michael , Guy Kip R. , Chen Taosheng , Roussel Martine F. 
Published: June 2012

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is a cancer of the cerebellum that occurs in children between the ages of 3 and 7. Human MBs have been classified into four subgroups, two of which harbor mutations in pathways that regulate normal development of the brain: Sonic Hedgehog/Patched (Shh/Ptch) (25%) and Wnt (15%). Our laboratory found that the bone morphogenetic proteins (BMP-2, 4, 7) antagonize Shh signaling by inducing the irreversible differentiation of MB cells into neurons leaving normal post-mitotic neurons intact. We designed a cell-based luciferase assay in which a human carcinoma cell line, C33A, expressed a multimerized BMP-responsive element from the Id1 promoter linked to luciferase. We then screened 3,488 compounds with known bioactivity and 31,441 compounds from the St. Jude diversity library for small molecule agonists of the BMP-2, 4, 7 signaling cascade. To date, 14 candidate compounds induced luciferase activity in a dose-dependent manner. Secondary screens showed that these small molecules induce P-Smad1/5/8 and Id2 expression in a dose-dependent manner in C33A cells by western blotting analysis, and alkaline phosphatase (ALP) activity which is a quantitative measure for the differentiation of C2C12 mouse myoblasts into osteoblasts. One of the compounds ventralized zebrafish embryos. Ongoing efforts are focused on understanding the mechanism of activation of BMP-4 signaling by these small molecule agonists.
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 4522. doi:10.1158/1538-7445.AM2011-4522
Abstract 4527: Pharmacodynamic and pathway analysis of three presumed inhibitors of poly (ADP-ribose) polymerase: ABT-888, AZD2281, and BSI201
Authors: Ji Jiuping , Lee Maxwell P. , Kadota Mitsutaka , Zhang Yiping , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H. 
Published: June 2012

Abstract
Poly (ADP-ribose) (PAR) polymerases (PARP1 and PARP2) are activated in response to DNA single-strand breaks and are pivotal to the base excision repair pathway for homologous recombination-defective cells or for the chemotherapy-damaged genome. ABT-888, AZD2281, and BSI201 are three presumed PARP inhibitors currently being evaluated in phase 1-3 clinical trials; each has demonstrated therapeutic activity either as a single agent for patients with BRCA-deficient malignancies or in combination with DNA-damaging chemotherapeutic agents. To compare the pharmacodynamics of these agents, we employed the BRCA1-defective breast cancer cell line MX-1 as a model. By monitoring γH2AX foci formation with a validated slide-based immunofluorescence assay, we found that γH2AX foci increased in a dose- and time-dependent fashion during treatment with each of the three drugs. However, utilizing our validated quantitative chemiluminescence ELISA for PAR (Clin. Cancer Res. 14: 6877, 2008), we unexpectedly found that PARP1/2 inhibition was dose and time dependent only for tumor cells treated with ABT-888 or AZD2281, but not BSI201. This observation was confirmed using ex vivo treatment of PBMCs from human whole blood. To investigate the mechanism of action of these drugs further, we used next-generation sequencing to identify genes that were induced or suppressed by exposure to these drugs. We found that a 4-hour exposure of MX-1 cells to a clinically achievable concentration of either ABT-888 or BSI201 produced expression changes in dramatically different sets of genes. Gene ontology and pathway analyses indicated that BSI201 specifically suppressed genes in the telomere pathway, suggesting PARP5/6 as potential targets and a different mechanism of γH2AX foci formation, whereas ABT-888 induced genes in the chromosome organization network, consistent with PARP1/2 as primary targets. These experiments strongly suggest that the major therapeutic mechanism of action of BSI201, unlike ABT-888 and AZD2281, is not mediated by inhibition of PARP1 or PARP2. Funded, in part, by NCI Contract No. HHSN261200800001E.
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 4527. doi:10.1158/1538-7445.AM2011-4527
Abstract 4561: Preclinical characterization of MT112/BAY 2010112, a novel PSMA/CD3-bispecific BiTE antibody for the treatment of prostate cancer
Authors: Lutterbuese Ralf , Friedrich Matthias , Kischel Roman , Rau Doris , Hoffmann Patrick , Ebert Evelyn , Zopf Dieter , Finnern Ricarda , Mueller Peter , Baeuerle Patrick A. , Wolf Andreas , Rattel Benno , Raum Tobias , Kufer Peter 
Published: June 2012

Abstract
Prostate-specific membrane antigen (PSMA) has been frequently selected as target antigen for antibody-based therapy of prostate cancer. Here, we recombinantly constructed a PSMA/CD3-bispecific BiTE antibody, called MT112/BAY 2010112. The BiTE antibody was produced in Chinese hamster ovary cells as a secreted protein of 55 kDa, showing high serum and thermal stability. MT112/BAY 2010112, purified as homogenous monomeric protein, bound at low nanomolar concentrations to defined epitopes on PSMA and CD3 antigens of human and macaque origin, respectively. In cell culture studies bispecific binding of MT112/BAY 2010112 selectively redirected human T cells against several PSMA-positive human prostate cancer cell lines as well as PSMA cDNA-transfected cell lines and potently induced specific target cell lysis with EC50 values ranging from 1 to 50 pM using non-stimulated human peripheral blood mononuclear cells as effector cells. EC50 values correlated with the number of PSMA molecules on the cell surface ranging from 37,000-500,000 molecules per cell among the cell lines analyzed.
The anti-tumor activity of MT112/BAY 2010112 was assessed in several SCID mouse models bearing subcutaneous xenografts derived from the human prostate cancer cell lines LNCaP, PC3 and 22Rv1. The BiTE antibody completely inhibited growth of tumors at doses as low as 0.005 mg/kg administered daily intravenously when human T cells and tumor cells were co-inoculated. Transient regression of tumors were observed in a model where human T cells were adoptively transferred into the peritoneal space of mice with subcutaneously established tumors.
These data suggest that the PSMA/CD3-bispecific antibody MT112/BAY 2010112 has high therapeutic potential for treatment of prostate cancer. Its cross-reactivity with human and macaque PSMA and CD3 antigens will greatly facilitate assessment of pharmacology, pharmacokinetics and safety during further pre-clinical development.
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 4561. doi:10.1158/1538-7445.AM2011-4561
Abstract 4571: 515H7, a novel anti-CXCR4 antibody: In vitro efficacy on CXCR4-associated signaling pathways and in vivo anti-tumor activity
Authors: Corvaia Nathalie , Berger Sven , Wurch Thierry , Boute Nicolas , Broussas Matthieu , Beau-Larvor Charlotte , Akla Barbara , Robert Alain , Haeuw Jean-François , Goetsch Liliane , Bailly Christian , Klinguer-Hamour Christine 
Published: June 2012

Abstract
Chemokines are small, secreted peptides that control the migration of leukocytes along a chemical gradient of ligand, especially during immune and inflammatory reactions. They are divided into two major subfamilies, CC and CXC, based on the position of their NH2-terminal cysteine residues, and bind to G protein coupled receptors, whose two major sub families are designated CCR and CXCR. More than 50 human chemokines and 18 chemokine receptors have been discovered so far. Chemokine receptor CXCR4/[Stromal cell-derived factor (SDF)-1] axis plays a central role in various physiological and pathological processes, including cancer. CXCR4 is over-expressed in a large number of tumors: colon, breast, prostate, lung, ovary, pancreas. CXCR4/SDF-1 axis is directly implicated in migration, invasion leading to metastases, cell proliferation and angiogenesis. Moreover, CXCR4 overexpression correlated with poor prognosis in many types of cancer.
A novel monoclonal antibody (Mab 515H7) was raised against the human CXCR4. It displayed efficacious antagonist properties for all major pathways associated with SDF-1-induced CXCR4 signaling in vitro. It was able to efficiently bind CXCR4 on both transfected cells and human tumor cell lines. It was found to strongly inhibit SDF-1 binding, Gα protein activation and beta-arrestin2 recruitment. It also blocked second messenger release (calcium, cAMP) and constrained by itself the formation of CXCR4 homodimers. It also inhibits SDF-1-induced cell migration in vitro. 515H7 Mab antitumor activities were also investigated in vivo using several human tumor models.
We demonstrated that 515H7 Mab was able to significantly inhibit growth of xenograft tumors in mice. In addition to its effect on tumor growth, 515H7 Mab was also able to significantly improve mice survival in the lethal U937 model.
The herewith data demonstrate that Mab 515H7 behaves as a potent and efficacious antagonist of all major CXCR4-controlled signaling pathways and suggest that targeting CXCR4 is a promising way for the treatment of 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 4571. doi:10.1158/1538-7445.AM2011-4571
Abstract 4577: A tetravalent bispecific TandAb for treating Hodgkin's lymphoma
Authors: Little Melvyn 
Published: June 2012

Abstract
Affimed has developed a tetravalent bispecific antibody (TandAb) for treating Hodgkin's lymphoma. It has a molecular weight of 105kDa and targets CD30 on Reed-Sternberg/Hodgkin cells and the FcγIIIA receptor (CD16A) on NK cells and macrophages. The anti CD16A antibody moiety does not bind the B isoform, which is present in relatively large numbers on granulocytes. Furthermore, in contrast to other therapeutic antibodies such as Rituximab, it binds with equal affinity to the various alleles of the receptor and should thus work equally well for all patients.
The anti CD30 x anti CD16A TandAb has been granted Orphan Drug Status by both the FDA and EMEA. To provide toxicological and clinical material, a robust CMC production process was established with a good yield. The purified TandAb successfully completed an extensive toxicology programme in cynomolgus monkeys. No adverse clinical events occurred and no measurable amounts of antibodies to the drug product were found. The Tandab can probably be stored for a long time in its present lyophilised formulation, since no loss of activity has been observed on storage at 40degC for one year. A clinical Phase 1 trial started on October 5th. So far the treatment has been well tolerated with no adverse events.
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 4577. doi:10.1158/1538-7445.AM2011-4577