bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3688: Akt pathway genes classify GBM into 6 prognostic subgroups with different clinical and molecular features
Authors: Joy Anna M. , Ramesh Archana , Smirnov Ivan , Misra Anjan , Shapiro William , Phillips Heidi , Aldape Ken , Mills Gordon , Kim Seungchan , Feuerstein Burt 
Published: August 2012

Abstract
The Akt pathway is a therapeutic target in Glioblastoma Multiforme (GBM) and an important determinant of patient outcome. However, it is not known if akt pathway variations exist in GBM tumors. To investigate we developed a list of Akt pathway genes and investigated expression subgroups in a set of human GBM. Akt classification divides GBM into 6 subgroups with differing survivals and clinical/molecular features. Median survival of patients in the longest surviving subgroup (subgroup 5) was 3.9 yr vs 0.75 yr for patients in the shortest surviving subgroup (p &lt; 0.01 Bonferroni corrected log rank). Patients in the long surviving subgroup were younger than the rest (median age = 38 vs 49 respectively; p = 0.05 corrected for multiple comparisons), but survival differences were independent of age (p = 0.027; subgroup 5 vs the rest). Tumors in short surviving subgroups were characterized by chr7 gain, chr10 loss and high ser473 phosphorylated-akt (p-akt) staining. The long surviving subgroup tumors were enriched for chr19q loss, low p-akt staining, elevated Notch staining and had no DNA copy number alterations in chr7 or chr10. Previously described subgroups (Phillips et.al.) were enriched in akt subgroups (all with p&lt;0.001). These results suggest that tumors with a pathological diagnosis of GBM are a collection of molecular subgroups with fundamental differences in biology and clinical behavior. We hypothesize that Akt subgroups will enhance drug discovery and help personalize treatment for GBM therapeutics. Supported by Barrow Neurological Foundation (BGF and AMJ), Halle Family Foundation (BGF), and NIH 1 K01 NS064952-01A1 (AMJ).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3688. doi:1538-7445.AM2012-3688
Abstract 370: Tetrazine trans-cyclooctene ligation: An efficient 18F labeling method for cysteine containing peptides and proteins
Authors: Li Zibo , Liu Shuanglong , Hassink Matt , Selvaraj Ramajeyam , Yap Li-peng , Chen Xiaoyuan , Fox Joseph M. , Conti Peter S. 
Published: August 2012

Abstract
18F PET has a number of attributes that make it clinically attractive, including almost 100% positron efficiency, very high specific radioactivity, and short half-life of ∼110 min. However, the short half-life of 18F and the poor nucleophilicity of fluoride make it difficult to incorporate 18F in complex molecules. Recently, the tetrazine-trans-cyclooctene ligation has been introduced as a novel 18F labeling method that proceeds with fast reaction rates without any catalysis. To further explore the scope of this reaction, herein we reported an efficient method for 18F-lableing of free cysteine-containing bioligands based on the tetrazine-trans-cyclooctene ligation. The newly developed method was tested for site specific labeling of both c(RGDyC) and VEGF-SH protein. Starting with 4 mCi of 18F-trans-cyclooctene and only 10 μg of tetrazine-RGD (80-100 µM) or 15 μg of tetrazine-VEGF (6.0 µM), the 18F labeled RGD peptide or VEGF protein could be obtained in 95% yield and 75% yield within five minutes. The obtained tracers were then evaluated in small animals. In conclusion, a highly efficient method has been developed for site-specific 18F labeling of cysteine containing peptides and proteins. The special characteristics of the tetrazine-trans-cyclooctene ligation provide unprecedented opportunities to synthesize 18F-labeled probes with high specific activity for PET applications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 370. doi:1538-7445.AM2012-370
Abstract 3701: Phase II study of BIBF1120 in recurrent glioblastoma multiforme
Authors: Lassen Ulrik , Mau-Soerensen Morten , Muhic Aida , Ehrnrooth Eva , Poulsen Hans S. 
Published: August 2012

Abstract
Background: BIBF 1120, a potent, orally available triple angiokinase inhibitor targeting VEGFR 1-3, PDGFR- α/-α, and FGFR 1-3, has shown promising clinical activity with a good safety profile in patients with advanced non-small cell lung cancer or ovarian cancer. The specific and simultaneous abrogation of these three pathways results in effective growth inhibition of both endothelial and perivascular cells. This may be more effective than inhibition of endothelial cell growth via the VEGF pathway alone. In addition, signalling via FGF-receptors has been identified as a possible escape mechanism for tumour angiogenesis when the VEGF pathway is disrupted. Recurrent glioblastomas (GBM) have an extremely poor prognosis and consequently new and innovative therapies are still needed. Accordingly, the purpose of this study was to assess the efficacy and safety of BIBF 1120 in two parallel groups of patients with recurrent GBM after radiotherapy and temozolomide (STD) or the same regimen and subsequent bevacizumab based therapy (BEV). Methods: Patients were included in one of two parallel groups depending of prior exposure to bevacizumab (STD or BEV). Inclusion critieria included recurrent GBM, PS 0-1, normal organ function, available archival tissue blocks, and measurable disease according to RANO guidelines. A total of 32 patients were to be enrolled in each group in a two-stage design including a stopping rule if less than 4/16 patient responded. BIBF-1120 was administered orally 200 mg bid, with weekly plasma sampling for the first 4 weeks and MRI assessement every 8 weeks. Primary endpoint was objective response rate. Secondary endpoints were safety, PFS and plasma and tissue biomarkers. Results: The study was prematurely stopped for after inclusion of 13 patients in the STD arm and 12 patients in the BEV arm. No objective responses were seen in either arm. One patient in the BEV arm has had stable disease for 8 months while the remainder of the patients in both arms progressed within the first 4 cycles. BIBF-1120 was very well tolerated with no observed grade III or IV adverse events. Most frequent adverse events were grade I-II hypertension, diarrhoea and fatigue, with a frequency of &lt; 10%. Conclusion: BIBF-1120 was well tolerated, but did not show anti-tumor activity in recurrent GBM at the dose of 200 mg bid in this patient population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3701. doi:1538-7445.AM2012-3701
Abstract 3707: Captopril inhibits colorectal cancer liver metastases following 70% partial hepatectomy in a mouse model
Authors: Koh Shir Lin , Ager E. I. , Malcontenti-Wilson C. , Costa P L. , Muralidharan V. , Christophi C. 
Published: August 2012

Abstract
Background: Blockade of the renin-angiotensin system (RAS) with the angiotensin-converting enzyme inhibitor, Captopril, has been shown to inhibit CRCLM. Partial hepatectomy (PH) for colorectal cancer liver metastases (CRCLM) can stimulate tumour recurrence. Aim: This study investigated the effects of Captopril on liver regeneration (LR), as well as on CRCLM in the regenerating liver. Methods: Male CBA mice were used for 70% PH as well as 70% PH following CRCLM induction. Mice were randomly assigned to control or Captopril-treated groups. Liver and tumour samples were collected on days 1, 2, 4, 6 and 8, 16 and 21 post-surgery. The rate of LR was measured by liver-to-body weight (LBW) ratio. The percentage of liver metastases was quantified using quantitative stereology and immunohistochemistry was performed to quantify hepatocyte and tumour cell proliferation (anti-Ki67) and apoptosis (anti-caspase-3). Results: Captopril increased LBW (0.57 ± 0.02 Captopril, 0.49 ± 0.02 control, p = 0.027) compared to controls on day 2 following 70% PH. At day 6, Captopril had decreased LBW (0.5 ± 0.03, 0.73 ± 0.06, p = 0.006). However, by day 8, LBW was not different between the control and Captopril groups. At day 21, Captopril decreased the percentage of liver metastases compared to controls (24.4 ± 6.2%; 48.7 ± 4.7%, p = 0.008) in the regenerating liver. Tumour volume (388.3 ± 150.4; 1046.2 ± 200.2mm3, p = 0.02) and tumour nodule count per image field (68 ± 17.6; 181.1 ± 28.5, p = 0.005) were also decreased by Captopril. In contrary, Captopril did not significantly alter liver volume compared to controls (886.1 ± 65.2; 1044.1 ± 115.8, p = 0.254). Furthermore, LBW during LR in the presence of CRCLM at day 2 (0.53 ± 0.01; 0.51 ± 0.02, p = 0.449) and day 6 (0.71 ± 0.01; 0.73 ± 0.03, p = 0.51) were not different between Captopril and control groups. Conclusion: Captopril enhanced the early stage of LR following 70% PH. Captopril inhibits CRCLM in the regenerating liver without inhibiting LR. Understanding the mechanisms of actions of Captopril is required to improve CRCLM patient outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3707. doi:1538-7445.AM2012-3707
Abstract 3711: Discovery of new therapeutic strategies for rare cancers with defined genetic lesions
Authors: Kerr Lauren T. , Young Sophie , Williams Elizabeth D. , Thomas David , Johns Terrance G. 
Published: August 2012

Abstract
Rare cancers are defined as those with an incidence of less than 0.05% in a given population, yet collectively make up ∼20% of all cancers. A proportion of these are characterized by a primary, driving genetic lesion which disrupts normal cell regulation, resulting in malignancy. Patients of rare cancer could potentially benefit from clinically approved targeted therapies developed for other cancers; however their rarity makes recruitment for clinical trials extremely difficult. Cell lines derived from these patients often maintain the genetic lesions present in the parent tumor, and therefore can serve as a platform to evaluate the efficacy of novel therapeutic strategies. Here we describe in vitro strategies for identifying novel treatment regimens for the rare, simple karyotype cancer Myxoid Liposarcoma (MLS). MLS is characterized by a single genetic event, the chromosomal translocation t(12;16)(q13;p11), which occurs in &gt;95% of cases. The gene product of this translocation is the constitutively active fusion protein FUS-CHOP, which alters the expression of transcription factors responsible for regulating adipocytic differentiation. This drives the cells into a perpetual state of proliferation in the absence of differentiation, thus leading to malignancy. This study uses the cell lines MLS 402 and MLS 1765, which are derived from MLS patients, and express FUS-CHOP. Cells were screened with a panel of anti-cancer treatments, including antibodies, small molecule inhibitors and chemotherapies. Axitinib was identified as an efficacious treatment both alone and in combination with other therapies. Axitinib caused cell cycle arrest and induced apoptosis as verified by Annexin V flow cytometry assay. This multi-kinase inhibitor targets the membrane-bound receptors c-Kit, PDGFRα/β and VEGFR1/2/3. Western blot and bioplex assays were utilised to determine the downstream target molecules inhibited by axitinib treatment. Axitinib significantly reduced signalling activity through the AKT/mTOR and MEK/ERK1/2 pathways. Axitinib also displayed additive and synergistic anti-tumor activity with other targeted therapies. The establishment of cell lines that retain the key genetic mutation found in rare cancers is a useful approach for identifying novel therapeutic options.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3711. doi:1538-7445.AM2012-3711
Abstract 3715: EP-100 syndergizes with paclitaxel in ovarian, breast and prostate cancer cell lines
Authors: Leuschner Carola , Giardina Cody , Alila Hector W. 
Published: August 2012

Abstract
EP-100 is a targeted anti-cancer drug comprised of Luteinizing Hormone Releasing Hormone (LHRH) fused to a lytic peptide. EP-100 is currently being investigated in human clinical trials. EP-100 seeks and destroys LHRH receptor positive cancer cells via a novel mechanism of action involving direct membrane disruption. Studies were conducted to determine the cytotoxic effects of combining EP-100 with paclitaxel using multi-drug resistant LHRH receptor positive ovarian (OVCAR-3), breast (MDA-MB-231), uterine sarcoma (MES-SA-Dx5), prostate (PC-3) and LHRH receptor negative ovarian (SKOV-3) cancer cells. Cells were cultured in the presence of EP-100 (0.005 nM-50µM, N=8) or paclitaxel (0.0025-500 nM, N=8) alone or in combination for 48 to 72 hours in non-constant and constant ratio formats (N=6). Cell viability was measured by luminometric assays. Data for IC50 values were obtained using the GraphPad Prism and GraphPad Software for the Hill Equation. The synergistic effects of EP-100 and paclitaxel were expressed as Combination Index (CI) using the CompuSyn Software analysis program. EP-100 alone killed LHRH receptor positive OVCAR-3, MDA-MB-231, MES-SA-Dx5 and PC-3 cells at low micromolar concentrations after 48 to 72 h incubation(IC50 values 2.189 ± 0.027 µM, 2.092 ± 0.114 µM, 1.419 ± 0.133 µM and 1.9 ± 0.071 µM respectively). As expected, SKOV-3 cells did not respond well to EP-100 (IC50= 10.3 ±0.36 µM) because they lack LHRH receptors on their surfaces. OVCAR-3, MDA-MB-231, MES-SA-Dx5 and SKOV-3 cells were resistant to paclitaxel (IC50 values = 13.6 ± 0.7 nM 86.2 ± 5.9 nM, 94.1 ± 0.3 nM and 48.52 ± 4.5 nM, for OVCAR-3, MDA-MB-231, MES-SA-Dx5 and SKOV-3, respectively) and PC-3 cells were very sensitive to paclitaxel with IC50 of 5.2 ± 1.1 nM. The combination of EP-100 at 50 nM and paclitaxel at 500 nM resulted in 3620 and 6720- fold increased sensitivity when compared to paclitaxel alone. The median CI values were 0.18, 0.05, 0.25, and 0.6 for for MES-SA-Dx5, OVCAR-3, MDA-MB-231 and PC-3, respectively indicating synergistic responses in the cell lines. No synergy was observed in the LHRH receptor negative SKOV-3 cell line (CI=8.4). These results indicate that a combination of EP-100 and paclitaxel results synergistic responses in LHRH-receptor positive and multi-drug resistant cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3715. doi:1538-7445.AM2012-3715
Abstract 3721: Combination of temozolomide and O6- benzylguanine inhibits breast cancer growth
Authors: Jeudy Sheila , Srivenugopal Kalkunte S. , Konduri Santhi D. 
Published: August 2012

Abstract
O6 methylguanine DNA methyltransferease (MGMT) is over expressed in breast cancer cells. A number of cytotoxic agents utilized in the treatment of cancer directly or indirectly damage DNA, thus initiating a cascade of events which finalizes in cell death. MGMT has received significant focus for its role in the repair of DNA damage caused by a number of chemotherapeutics including alkylating agents, chlorethylating and methylating agents. In the present study, we tested the administration of the MGMT inhibitor [O6-benzylguanine (BG)] at non-toxic doses in combination with MGMT alkylator (temozolomide) on breast cancer cells in cell culture and xenograft models. Here, we report that temozolomide in combination with BG effectively inhibits breast cancer cell growth in vitro and in vivo. Here, we also report that BG either alone or in combination with temozolomide inhibits gene expressions which are involved in breast tumorigenesis and cell division process (CDC20, TOP2A, AURKB, BIRC5) and induces the expression of p21cip1 cell cycle inhibitor. The combination also enhanced PARP cleavage, indicative of apoptosis. In breast cancer xenograft models, BG alone or in combination with temozolomide caused marked delay in tumor growth. These findings suggest that MGMT inhibition may provide a novel and effective approach for breast cancer growth inhibition. Furthermore, the combination of MGMT inhibitors and MGMT alkylators can provide alternative therapeutic approaches to treat breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3721. doi:1538-7445.AM2012-3721
Abstract 3734: Paclitaxel disrupts polarized entry of membrane permeable C6 ceramide into ovarian cancer cells resulting in synchronous induction of cell death
Authors: Best Charles , Calianese David , Szulak Kevin , Brum Gabriella , Higgins Katelyn , Carbone Thomas , McCauley Michael , Di Wen , Wanebo Harold , Wan Yinsheng 
Published: August 2012

Abstract
Exogenous cell permeable C6 ceramide is demonstrated to act synergistically with chemotherapeutic drugs: paclitaxel, cisplatin, doxorubicin and histone deacetylase inhibitor trichostatin A (TSA) to induce cell death in a variety of cancer cells. We previously showed that C6 ceramide and paclitaxel act synergistically to induce ovarian cancer cell death via modulation of PI3/AKT cell survival pathway. This current study is focused on the process of C6 ceramide into the cell and its behavior during apoptosis. We investigated the entry pattern of C6 ceramide into ovarian cancer cells using fluorescent short chain C6-NBD sphingomyelin (or C6-NBD). As imaged with confocal microscopy, we observed that C6-NBD enters cells in a polarized pattern, characterized by strong signals at one cellular end, a probable mitosis initiation site. Pretreatment of the cells with filipin, an inhibitor of the raft/caveolae endocytosis pathway, decreases C6-NBD entry into cells. Pretreatment of water channel inhibitor CuSO4 also reduces entry of C6-NBD. Interestingly, pretreatment of cells with paclitaxel disrupts the polarized entry of C6-NBD into the cells, resulting in even distribution of C6-NBD in the cytoplasm. Further studies show that pretreatment of the cells with paclitaxel destabilizes cytoskeletal proteins, releasing increased number of short fragments of tubulins. The data suggests that C6 ceramide enters the cells preferably through a predetermined initial site of mitosis. In addition to diffusion, short chain C6 ceramide enters cells also via water channels and caveolae-mediated endocytosis. Paclitaxel disrupts cytoskeletons and induces an even distribution of C6 ceramide in the cytoplasm resulting in synergistic ovarian cancer cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3734. doi:1538-7445.AM2012-3734
Abstract 3735: Increased efficacy with use of combination therapy of API 31510 and gemcitabine in the treatment of pancreatic cancer
Authors: Narain Niven R. , Sarangarajan Rangaprasad , Ouro-Djobo Rakib , Bourdelais Justin J. , Grund Eric , Vishnudas Vivek , Mauro Lucia M. , Lens Assuan , Yunis Adel , Agarwal Shuili , Song Paul Y. , McCook John P. , Jimenez Joaquin J. 
Published: August 2012

Abstract
Pancreatic Carcinoma is one of the deadliest types of cancers and certainly one that is most clinically difficult to manage given that most diagnoses occur in late-stage disease. Gemcitabine is among the few FDA approved drugs used alone and in combination with other antineoplastic agents for pancreatic cancer. API 31510, a novel intravenous formulation of Ubidecarone, induced superior cell death kinetics in pancreatic carcinoma cell line, MiaPaca alone or in combination with gemcitabine. In addition, the study employed an in vivo model of pancreatic cancer to assess the translation of the cell-based data of combination gemcitabine and API 31510. Animals were randomized into 4 groups of 30 rats each; group 1 received no treatment, group 2 received gemcitabine (150 mg/kg weekly for 3 weeks with one week rest), group 3 were injected with API 31510 (50 mg/kg daily), and group 4 received a combination of daily API 31510 (50kg/mg) and gemcitabine at the aforementioned regimen. The untreated group exhibited steep death rates, whereas in API 31510, gemcitabine alone and the combination of API 31510 resulted in prolongation of life. API 31510 alone had significantly greater impact than gemcitabine alone. Animals treated with gemcitabine + API 31510 exhibited prolonged survival and elicited long-term remission that was statistically significant compared to other groups. In addition, palpable tumors were decreased in the groups treated with API 31510, and to a greater degree, in those treated with gemcitabine in combination with API 31510. It is noteworthy that tumor histology demonstrated a hallmark disruption in tumor vasculature with use if API 31510. Taken together, these findings suggest that API 31510 offers a new approach to treatment and management of pancreatic cancer alone and combination with established chemotherapy regimens that include gemcitabine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3735. doi:1538-7445.AM2012-3735