bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C158: IKKβ inhibition modulates NF-κB signaling and decreases aggressiveness of ovarian cancer
Authors: Hernandez Lidia , Hsu Sarah , Davidson Ben , Birrer Michael J. , Kohn Elise C. , Annunziata Christina M. 
Published: June 2012

Abstract
The NF-κB family of transcription factors has been implicated in the propagation of ovarian cancer, but the significance of constitutive NF-κB signaling in ovarian cancer is unknown. We hypothesized that constitutive NF-κB signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. To this end, we investigated the biological relevance of NF-κB in ovarian cancer cell lines using a small molecule inhibitor of IKKβ, and confirmed with RNA interference using stably expressed short hairpin RNA molecules towards IKKβ. We demonstrate here that the expression of IKKβ protein itself and the ovarian cancer-specific signature of IKKβ-regulated genes are related to poor outcome in independently collected sets of primary ovarian cancers. IKKβ signaling in ovarian cancer regulates the transcription of genes involved in a wide range of cellular effects known to increase the aggressive nature of the cells. We functionally validated the effect of IKKβ signaling on proliferation, invasion and adhesion in ovarian cancer cell lines. IKKβ was involved in all of these cellular functions, reflecting its modulation of the target genes identified. The diversity of functions controlled by IKKβ in ovarian cancer suggest that therapy targeted to this pathway could be efficacious if specific IKKβ inhibitor therapy is focused to patients whose tumors express a molecular profile suggestive of dependence on IKKβ activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C158.
Abstract C16: Prospective real-time analysis of p-cadherin expression to select patients into a phase I oncology trial
Authors: Davis Darren W. , Liu Wen , Jilani Iman , Zhang Yujian , Barlow John W. , Miller Louise M. , Winstanley Reba , Desai Jayesh , Alpaugh Kathy R. , Cooper Harry , Cohen Roger B. , Bang Yung-Jue , Oh Do-Youn , Kim Mi-Yeong , Bae Yoon-Ju , Countouriotis Athena , Shalinsky David R. , Kim Woo Ho 
Published: June 2012

Abstract
Effectively personalizing medicine depends upon selecting patients (pts) amenable to targeted therapies. We report the development of a custom immunohistochemistry (IHC) assay to identify P-cadherin positive expression in the archival biopsy of pts with solid malignancies. Validated reagents including a mAB to P-cadherin were incorporated into a custom IHC kit standardized across three Phase I sites (Seoul National University, Royal Melbourne Hospital, and Fox Chase Cancer Center).
Pts with a P-cadherin positive archival biopsy are being enrolled into an ongoing trial. Clinical results will be reported separately. P-cadherin positivity is defined by a scoring index (SI) [product of the Tumor Area Positive for P-cad x Staining Intensity]. Based on the literature, a SI ≥ 4 is associated with poor clinical outcome and was therefore required for pt entry into the trial. The IHC protocol was standardized across sites using positive and negative controls run in a masked fashion at each site and cross-examined and repeated by a central lab that had final decision-making authority (ApoCell, Inc., Houston, TX). Each site ran independent IHC assays and analyses by board-certified pathologists, and provided stained and unstained archival biopsy slides for independent, masked analysis by ApoCell. The turn-around time for central IHC analysis was ≤ 48 h.
Forty-four of 67 pts (65.7%) were found to be P-cadherin positive and eligible for entry into the trial. The distribution of enrolled patients by site is as follows: Australia (SI ≥ 4, n = 20), Korea (SI ≥ 4, n = 15), and USA (SI ≥ 4, n = 9). Median and mean SI values for the P-cadherin SI were 6 and 5.3 ± 2.9 (SD), respectively, with a range of 0 – 9. Clinical sites produced a SI equal to ApoCell in 56 of 67 pts (85.6% concordance rate). Among solid malignancies tested, a majority of gastric, colon and rectal cancers have demonstrated P-cadherin SI values ≥ 4. Successful execution of this IHC study demonstrates the feasibility of prospectively selecting pts based on IHC expression of P-cadherin using a custom standardized scoring index analysis across multiple clinical sites.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C16.
Abstract C160: Hepatocyte growth factor-MET receptor axis as a potential target for blocking cervical carcinoma metastasis into bones and bone marrow
Authors: Miekus Katarzyna , Kijowski Jacek , Drabik Grazyna , Majka Marcin 
Published: June 2012

Abstract
Introduction: Cervical carcinoma (CC) is one of the major causes of death among women suffering from tumor. The highest mortality is observed in the group of patients with late diagnosis and a metastatic disease. HGF/MET axis has been shown to be an important modulator of tumor cells motility and invasion. Recently we have shown that HGF/MET axis synergizes with SDF-1/CXCR4 axis in stimulating CC cell chemotaxis and activation of various intracellular pathways.
Objectives: In this study we focused on the role of MET receptor in CC.
Materials and Methods: CC cell lines (HeLa, HTB34 and HTB35) were transduced with MET shRNA and LacZ shRNA expressing virus and subsequently selected with blasticidin. To check receptors expression real-time PCR and flow cytometry was used. Migration was checked by chemotaxis and invasion assays. The level of various protein phosphorylation was estimated by western blot. NOD-SCID mice were used in in vivo experiments.
Results: Morphological assessment of MET negative cell lines revealed that one of them, HTB 35, has changed the morphology and cells became on average 2 times smaller than their control counterparts. The cells were also characterized by different proliferation rate when cultured under stressed conditions. Low oxygen (2%) or low serum condition caused strong &gt; 50% inhibition of growth rate. Moreover, the migration and transmigration (through extracellular matrix proteins) toward HGF of all three cell lines with downregulated of MET was strongly inhibited. CC cells with downregulation of MET receptor showed inhibition of activation of several intracellular signaling pathways including RAS-MAPK, JAK-STAT and PI3K-AKT. We also performed in vivo study using NOD-SCID mice. All three cell lines were able to growth in these mice, however to different degree. HeLa and HTB 35 formed large tumors whereas HTB 34 formed small tumors. Growth of HeLa and HTB 34 cells was not inhibited by blocking MET receptor expression. However, HTB 35 tumor cells that lacked MET expression formed only very small tumors or no tumors at all. Cells present in these tumors were much more differentiated and matured. Moreover they formed structures similar to osteocytes and chondrocytes.
Summary: For the first time we shown here that HGF-MET axis activation significantly influences metastatic behavior of cervical carcinoma in vitro and in vivo and inhibition of this axis could be used as the new therapeutic strategy to block cervical carcinoma metastasis into bones and bone marrow.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C160.
Abstract C162: MET oncogen inhibition as a potentitial target for therapy of uveal melanoma
Authors: Abdel-Rahman Mohamed H. , Boru Getachew , Massengill James B. , Davidorf Frederick H. 
Published: June 2012

Abstract
Purpose: Uveal melanomas (UM), including choroidal, iris and ciliary body melanomas, are the most common intraocular malignancy in adult. The tumor spreads through a hematogenous route mostly to the liver in about 50% of the patients. Once metastatic, UMs are highly fatal and currently there is no available therapy for these tumors. Identifying novel therapy is crucial to improve the survival of these patients. The aim of this study is to investigate the utility of MET inhibition as a potential therapy for UM.
Methods: The frequency of MET activation (phospho-MET expression) in UM was studied using immunohistochemistry in 46 tumors. The half maximum inhibitory concentration (IC50) of selective MET inhibitor SU11274 was assessed on the five UM cell lines using cell proliferation assay. Inhibition of MET activation in UM cells treated with the SU11274 was confirmed using Western blot analysis. Effect of MET inhibition on cell migration was also studied.
Results: Our results showed that the majority (82.5%) of the 46 UM studied showed strong to moderate expression of phospho-MET. Selective MET blocking showed inhibition of tumor cell proliferation at an IC50 ranging from 2∼ 10 µM. In addition significant inhibition UM cell line migration was observed.
Conclusions: Our results indicate that MET is activated in a significant number of uveal melanomas. Our results also indicate the potential utility of MET inhibition as a target for therapy of UM.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C162.
Abstract C166: Cancer cells expressing TMPRSS4 colocalized with carbonic anhydrase IX (CAIX)-positive cells in lung and pancreatic carcinomas
Authors: Nguyen Tri-Hung , Havari Evis , Connors Timothy , Bagley Rebecca G. , McLaren Rajashree , Weber William , Nambiar Prashant R. , Madden Stephen L. , Teicher Beverly A. , Roberts Bruce , Shankara Srinivas 
Published: June 2012

Abstract
TMPRSS4, a cell surface transmembrane serine protease, is over expressed at the transcriptional level in pancreatic, colorectal and thyroid cancers compared with normal tissues. Recent studies have indicated a role for TMPRSS4 in tumor cell migration and tumor metastasis. We examined TMPRSS4 expression in dissected non-small cell lung cancer (NSCLC) tissues by quantitative RT-PCR and immunohistochemisty. At the transcriptional level, TMPRSS4 expression was elevated in adeno and squamous cell (SC) carcinomas when compared to the matching normal tissues (p=0.0035). At the protein level, over 100 tumor and normal specimens were examined with rabbit polyclonal anti-TMPRSS4 antibodies via immunohistochemistry. Adeno and SC carcinomas were positive for TMPRSS4 (p&lt;0.05), while little or no staining observed on the normal tissue sections. TMPRSS4 protein expression in tumor samples correlated with mRNA qRT-PCR results. When similar experiments were performed on lung cancer cell lines, six out of 16 lines expressed TMPRSS4 mRNA, particularly NCI-H358 and NCI-H596 cells which exhibited high TMPRSS4 message with an average of 6000 and 5000 copies, respectively, relative to the 18S rRNA; however, no TMPRSS4 protein was detected either by Western blot or flow cytometry. When NCI-H358 cells were implanted into nude mice, TMPRSS4 was detected in the xenograft tumors via immunohistochemistry. When lung SC carcinoma and pancreatic adenocarcinoma were stained for TMPRSS4 and for the hypoxia marker, CAIX, TMPRSS4 positive cells were found to be adjacent to CAIX positive cells; however, no co-staining in the same cell was observed, suggesting that TMPRSS4 has a significant function with the adjacent hypoxic cancer cells in tumor tissues, and hypoxia may induce TMPRSS4 expression in xenograft tumors of NCI-H358 in which protein is not detectable under normal cell culture environment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C166.
Abstract C172: Efficacy of AMG 479, alone and in combination with cisplatin, in ovarian carcinoma xenograft models
Authors: Beltran Pedro J. , Mitchell Petia , Cajulis Elaina , Moody Gordon , Chung Young-Ah , Wang Jon , Belmontes Brian , Radinsky Robert , Calzone Frank J. 
Published: June 2012

Abstract
AMG 479, a fully human monoclonal antibody raised to the type I insulin-like growth factor receptor (IGF1R), is currently being studied in the treatment of patients with ovarian carcinoma. We have previously shown that AMG 479 inhibits the growth of pancreatic and sarcoma tumor models by inhibiting IGF1R signaling through ligand blockade and receptor internalization and degradation. In the present study, we tested the ability of AMG 479 to inhibit the growth of four human ovarian carcinoma xenografts (OV-90, SK-OV3, TOV-21G, and OV-CAR3) in nude mice. Recent evidence has shown that multiple players in the IGF-axis are differentially regulated in human ovarian serous carcinomas, suggesting that the IGF1R pathway may play an important role in the growth of these tumors. The OV-90 model showed exquisite sensitivity to single-agent AMG 479, reaching significant (p&lt;0.0001) tumor growth inhibition (TGI) of more than 90% with 100 or 300 g AMG 479/dose administered twice per week for the duration of the experiment. The OV-CAR3 model was also sensitive to single-agent AMG 479 and showed significant (p&lt;0.0001) TGI of about 50% with 300 g AMG 479/dose, twice per week. The TOV-21G and SK-OV3 models showed resistance to AMG 479 with no significant TGI achieved at any dose. The OV-90 (sensitive) and TOV-21G (resistant) models were used to further characterize the AMG 479 response in a sensitive and a resistant model. AMG 479 effectively inhibited both IGF1R and Akt activity in the OV-90 model but not in the TOV-21G model in vitro. Furthermore, analysis of tumor xenografts collected at the end of the experiment revealed that TGI in the OV-90 model correlated with 50% receptor downregulation (total IGF1R), 90% inhibition of receptor activation (phospho IGF1R), and 50% inhibition of Akt activity, while no measurable inhibition in these analytes were detected in the TOV-21G xenografts. The potential benefit of combining AMG 479 with platinum-based therapy was assessed by combination with cisplatin in the moderately sensitive OVCAR-3 model. Treatment with AMG 479 (300 g/dose, twice per week) in combination with cisplatin (2.5 mg/kg, twice per week) resulted in significant (p=0.0001 vs. AMG 479, p=0.0005 vs. cisplatin) TGI compared with either therapy alone, suggesting that the two agents can be combined clinically for the treatment of ovarian carcinoma patients. Together, the data suggest that AMG 479 has therapeutic potential in treating ovarian carcinoma patients both as monotherapy and in combination with standard of care agents.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C172.
Abstract C174: Therapeutic reactivation of p53 through dual targeting of HDM2 and HDMX with a stapled p53 peptide
Authors: Bernal Federico , Wade Mark , Wahl Geoffrey M. , Walensky Loren D. 
Published: June 2012

Abstract
p53 is a transcription factor that induces cell cycle arrest or apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase HDM2 controls p53 levels through a direct binding interaction that neutralizes the transactivation activity of p53 and targets it for degradation via the ubiquitylation-proteasomal pathway. Whereas the HDM2-homologue HDMX lacks ubiquitin ligase function, it participates in regulating the p53 axis by heterodimerizing with HDM2 to form an active E3 ligase and/or by binding to p53 to prevent it from functioning as a transcriptional regulator. Loss of p53 activity, either by deletion, mutation, or HDM2/HDMX overexpression, is the most common defect in human cancer. Tumors expressing wild type p53 are rendered vulnerable by pharmacologic approaches that stabilize and upregulate p53. In this context, HDM2 and HDMX have emerged as independent therapeutic targets for restoring p53 activity and resensitizing cancer cells to apoptosis in vitro and in vivo. The small molecule nutlin-3 is an effective antagonist of the p53-HDM2 interaction. However, several studies have demonstrated the inability of nutlin-3 to disrupt the p53-HDMX complex, rendering tumor cells that overexpress HDMX nutlin-3-resistant. We have previously described the synthesis and characterization of a hydrocarbon-stapled α-helical p53 peptide (SAH-p53-8) that binds HDM2 with low nanomolar affinity, targets HDM2 in situ, and reactivates the p53 tumor suppressor pathway in HDM2overexpressing osteosarcoma cells. We now report that SAH-p53-8 binds HDMX with even greater affinity, co-immunoprecipitates with endogenous HDMX, and induces p53-dependent apoptosis in nutlin-resistant cancer cells that overexpress HDMX. Thus, by inserting a chemical staple into a peptide fragment of the p53 transactivation domain, we have generated the first bifunctional HDM2/HDMX inhibitor to investigate and modulate both targets in cancer cells. We further report a novel mechanism to maximize pharmacological activity through combined use of HDM2-specific and bifunctional HDM2-HDMX antagonists.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C174.
Abstract C18: Assessment of Gli1 expression during skin regeneration in mouse models and normal healthy volunteers
Authors: Wang Xi-De , Rowley Bruce , Li Hewei , Lang Lixin , Zhan Ping , Lewin Anne , Hawken Donald , Ho Ching-Ping , Huang Fei , Fargnoli Joseph , Alhers Christoph , Alland Leila , Van Tornout Jan M. , Bennett Kelly 
Published: June 2012

Abstract
Background: Inhibition of the Hedgehog pathway using Smoothened antagonists is emerging as a promising targeted therapy for cancers with pathway activating mutations or dysregulated expression. In support of the clinical development of BMS-833923 (XL139), an orally available, potent Smoothened antagonist, a pharmacodynamic assay was developed to measure Gli1 protein expression during the wound healing process.
Results: Gli1 protein and mRNA expression were first examined by immunohistochemistry or RT-PCR in mouse skin at baseline and in regenerating skin at various time points following the initial punch biopsy. The effects of BMS-833923 treatment on pathway expression profiles were then determined. The results showed that in control mice, Gli1 protein levels were elevated at as early as 3h and sustained for up to 72h. The intensities of Gli1 staining in both hair follicles and epidermis were greatly enhanced. However, in the mice treated with BMS-833923 at the time of initial biopsy, the magnitude and duration of Gli1 up-regulation were greatly reduced. While the Gli1 protein level was elevated within 6h, it returned to nearbaseline levels at 24h and remained low thereafter. Gli1 mRNA expression data support these observations. To better define the timing of potential Hedgehog pathway activation in human skin, an experimental medicine study was conducted to examine the expression of Gli1 after skin wounding and during regeneration in eighteen normal healthy volunteers. The baseline skin was sampled at the nape of the neck and the regenerating skin sample completely encompassed the initial wound. The intensities of both nuclear and cytoplasmic staining, as well as the percent cell staining positivity were scored. The data indicated that Gli1 protein was significantly up-regulated at 6h and 24h following wounding.
Conclusion: Gli1 protein level at 24h post-skin wounding assessed by immunohistochemistry is currently being used as a surrogate tissue pharmacodynamic measurement in a first-in-human multiple ascending dose trial in subjects with advanced or metastatic solid tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C18.
Abstract C189: Active compound isolated from human urine induced differentiation and apoptosis in K562 chronic myelogenous leukemia cells and enhanced the effects of imatinib
Authors: Lai Gi-Ming , Yao Chih-Jung , Yeh Chi-Tai , Chen Suz-Wen , Yan Jiann-Long , Li Chi-Han , Chuang Shuang-En 
Published: June 2012

Abstract
Leukemia is a serious disease that affects both children and adults. Although all-trans retinoic acid (ATRA) and targeted drug such as imatinib could effectively treat acute promyelocytic (APL) and chronic myelogenous leukemia (CML), respectively, rare therapeutics is available when drug resistance or recurrence occurred. Searching for alternative agent for refractory patient is urgently needed. Our previous studies had found that a human urine extract CDA-2 could induce differentiation of HL60 APL cells as well as potentiate the effects of ATRA and imatinib on HL60 and K562 CML cells, respectively. Purification of active compound possessing these anti-leukemic effects from CDA-2 was thus performed. Recently, an active compound named as P18.9 was isolated. It induced differentiation of K562 CML cells as evidenced by the nitroblue-tetrazolium (NBT) reduction test. At higher dose, flow cytometry analysis showed that P18.9 induced sub-G1 apoptotic fraction of K562 cells and enhanced the sub-G1 fraction induced by imatinib at a scale of about two folds. Although P18.9 did not induce differentiation of HL60 APL cells, it substantially enhanced the ATRA-induced differentiation. This is the first study to isolate an active compound from human urine, which exerts anti-leukemic effects alone or cooperatively with clinical used drugs. The chemical structure of P18.9 had been identified and further subsequent structure modification is ongoing. Continuing the effort to develop P18.9 and its derivatives as novel therapeutics for refractory APL or CML patients is warranted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C189.
Abstract C190: BMS-777607, a potent small molecule c-MET inhibitor, inhibits prostate cancer progression in vitro
Authors: Dai Yao , Siemann Dietmar 
Published: June 2012

Abstract
Overexpression of c-MET is highly associated with prostate cancer progression and therapy resistance. BMS-777607 is a selective and potent c-MET inhibitor that was advanced to clinical evaluation. Herein we report the effects of BMS-777607 in androgen-independent prostate cancer cells (PC-3, DU145). When assessed using an MTT assay, BMS-777607 treatment was found to inhibit cell growth in the absence of hepatocyte growth factor (HGF), with an IC50 &gt;5.0 uM for both cell lines. In a wound-healing assay, BMS-777607 suppressed PC-3 and HGF-induced DU145 cell motility in a dose-dependent fashion (IC50 values of 3.0 and 0.5 uM, respectively). Moreover, BMS-777607 efficiently blocked HGF-triggered DU145 cell scattering in a cell scatter assay; with 40% inhibition at 0.2 uM. Using a Matrigel-based Transwell assay, BMS-777607 also inhibited PC-3 cell invasion in a dose-dependent manner, with 60% inhibition occurring at 1 uM. Western blot analysis demonstrated that BMS-777607 blocked c-MET autophosphorylation, and downregulated multiple downstream kinases involved in c-MET signaling pathway, including Src, Fak and Akt. These data indicate that BMS-777607 inhibited prostate cancer progression in vitro including proliferation, motility, scattering and invasion. Furthermore, the finding of more potent effects on cell migration and invasion than cell proliferation suggests that this small molecule c-MET inhibitor could have utility as an anti-metastatic agent for the treatment of advanced prostate cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C190.