bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B217: Annexin A2 is a novel molecular target for TM601, a peptide with specific tumor targeting and antiangiogenic properties
Authors: Kesavan Kamala , Ratliff Judson , Johnson Eric , Dahlberg William , Jacoby Douglas B. 
Published: June 2012

Abstract
In this study we sought to identify the cell surface target for TM601, a peptide with tumor-targeting and anti-angiogenic effects. The 131I-radiolabeled form of TM601 is currently in clinical trials for having been shown to specifically bind several human tumor types including malignant glioblastoma, colorectal, pancreatic, prostate and non-small cell lung carcinomas. We used a biochemical approach of surface cross-linking followed by affinity-binding assays in conjunction with mass spectrometry and siRNA knock-down to identify and validate the target for TM601 on tumor and vascular endothelial cell. We identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and HUVEC vascular endothelial cells. We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line, Panc-1 is dependent on the expression of annexin A2. Annexin A2 is over-expressed in several human cancers and has functions in angiogenesis by binding to tissue plasminogen activator (tPA) and regulating plasminogen activation on vascular endothelial cells. In HUVEC cells, TM601 inhibits both VEGF and bFGF induced tPA activation which is in turn required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits PDGF-CC induced trans-well migration of both HUVEC vascular endothelial and U373-MG glioma cells. In conclusion, we have identified annexin A2 as a novel cell surface target for TM601 that might mediate both the tumor-targeting and anti-angiogenic effects of the peptide. Importantly, our results also support a role annexin A2 as a molecular target in cancer therapeutics.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B217.
Abstract B221: Expression of EGFR ligands in non-small cell lung carcinoma xenografts as potential biomarkers for classical or targeted therapies
Authors: Fichtner Iduna , Rivera Maria , Rolff Jana , Merk Johannes 
Published: June 2012

Abstract
Increased levels of the epidermal growth factor receptor (EGFR) and its cognate ligands are common in non-small cell lung cancer (NSCLC) and correlate with a poor prognosis. In the last years targeted therapies against the EGFR were developed, but results of clinical trials were rather disappointing. The identification of biomarkers in NSCLC as predictive factors for an individualized therapy is urgently needed.
Twenty six xenografts were established from fresh surgical material from NSCLC patients and characterized with regard to their sensitivity to four cytostatics (Carboplatin, Etoposide, Paclitaxel, Gemcitabine) and two EGFR-inhibitors (Cetuximab, Erlotinib). The expression of EGFR and its ligands epidermal growth factor (EGF), transforming growth factor alpha (TGFα), epiregulin and amphiregulin were examined at mRNA and protein level. Three ligands, which bind exclusively to EGFR (EGF, TGFα and amphiregulin) showed correlations to the mRNA expression of the receptor. Also the mRNA-levels of amphiregulin and epiregulin correlated with each other. The responsiveness towards Etoposide correlated negatively with the EGF-protein (r=-0.479, P&lt;0.05) and with the EGFR-mRNA (r=-0.663, P&lt;0.01) expression. This could mean that the expression of the EGFR-pathway related molecules is able to protect tumor cells from the induction of apoptosis through a cytostatic drug. The response rate to Gemcitabine showed a negative correlation with the TGFα-mRNA level (r=-0.525, P&lt;0.01). Controversially, the amphiregulin-mRNA level correlated positively with the responsiveness to Gemcitabine (r=0.553, P&lt;0.01). A high level of TGFα-mRNA correlated with the resistance to Erlotinib (r=-0.456, P&lt;0.05). The epiregulin-mRNA level showed a positive correlation concerning the sensitivity towards Cetuximab (r=0.476, P&lt;0.05). High EGFR levels seem to be indicative for the resistance to Erlotinib (r=0.636, P&lt;0.05) in squamous cell carcinomas and for the sensitivity to Cetuximab (r=-0.888, P&lt;0.05) in adenocarcinomas.
The results of the present study showed the role of the EGFR activated pathways in the dynamics of tumor progression in NSCLC on the one hand and reflect the high level of redundancy and interrelationships of the EGFR signalling pathway on the other hand. The patient-derived NSCLC models are suitable tools for the identification of biomarkers and their regulation mechanisms in a clinically related and standardized way.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B221.
Abstract B225: Use of RNAi to identify targets for further improving the antitumor activity of gemcitabine and nab-paclitaxel combination therapy in patients with advanced pancreatic cancer
Authors: Xie Lifang , Zhao Yu , Von Hoff Daniel , Han Haiyong 
Published: June 2012

Abstract
Pancreatic cancer remains the fourth leading cause of cancer-related deaths in the United States. Gemcitabine has been used as a standard first-line therapy for more than a decade for this deadly disease. However, the benefit of single-agent gemcitabine in advanced pancreatic cancer is small. Combination regimens including gemcitabine have provided only modest improvement. In a Phase I/II clinical trial gemcitabine plus nab-paclitaxel had significant clinical activity (Von Hoff, et al. 2009, J. Clin. Oncol. 27 (15s): Abstract #4525). To further improve the response of gemcitabine plus nab-paclitaxel therapy, we performed a high throughput RNAi (HT-RNAi) screen with a kinase-focused siRNA library consisting of siRNA oligos against 588 genes (2 siRNAs/gene) in the MIA PaCa-2 pancreatic cancer cell line. Eighty eight siRNAs targeting 82 genes were identified as positive hits (≥2 fold decrease in IC50 values). Several commercially available small molecule inhibitors of the positive hits were obtained and tested in combination with gemcitabine and nab-paclitaxel, both alone or in combination. Among the small molecule inhibitors tested, the CHK1 inhibitor, SB 218078, showed the most significant synergistic effect with gemcitabine and nab-paclitaxel, gemcitabine alone, or nab-paclitaxel alone in two pancreatic cancer cell lines, MIA PaCa-2 and PANC-1. The mechanism of SB 218078 induced sensitivity of pancreatic cancer cells to the gemcitabine and nab-paclitaxel are currently under investigation. In summary, using an HT-RNAi screen we have identified a list of gene targets that, when down-regulated by siRNA oligos, sensitize pancreatic cancer cells to the gemcitabine plus nab-paclitaxel combination therapy. Inhibitors of these targets may potentially enhance the anticancer activity of gemcitabine and nab-paclitaxel. (This work was supported by NIH/NCI Program Project grant CA109552).
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B225.
Abstract B23: Notch-induced Hrb suppresses apoptosis in bone marrow stem cells
Authors: Khwaja Shariq S. , van Deursen Jan , Bram Richard J. 
Published: June 2012

Abstract
Notch is activated by somatic mutation in more than 50% of cases of T-cell acute lymphoblastic lymphoma/leukemia (T-ALL). Exuberant notch signaling drives several oncogenic phenotypes, including enhanced proliferation, improved survival, and impaired differentiation. Inhibition of Notch is likely to yield improved treatment strategies for this disease and certain other malignancies, as well. However, because global inhibition of Notch may have intolerable toxicities, efforts are underway to identify the key downstream mediators of its neoplastic effects. We find that the clathrin-mediated receptor uptake adapter Hrb (HIV-rev binding protein) is a downstream target of Notch1. Hrb protein was induced to high levels by retroviral-mediated expression of constitutively active Notch (ICN1) in bone marrow stem cells and T cell precursors in vitro. To explore a potential role for Hrb downstream of Notch, we have examined the effects of ICN1 on bone marrow progenitor cells (BMPCs) from Hrb-deficient mice. Wild type BMPCs transduced with ICN1 grew to higher density in culture than did Hrbdeficient cells. There was no difference in distribution in cell cycle phases, and proliferative rates appeared to be the same. However, we found a significant increase in apoptosis in Hrb-deficient BMPCs in comparison to cells from littermate control mice. This increase in apoptosis could be reversed by reexpression of Hrb in the mutant cells, thus verifying that Hrb provides an enhanced survival signal to ICN1-expressing bone marrow cells. Potential downstream mediators of this survival signaling cascade are currently being identified. Because resistance to apoptosis is a key feature of leukemic cells, we hypothesize that the pro-survival effect of Hrb provides a portion of the oncogenic properties of Notch. Thus, because Hrb-knockout mice have no evident phenotype, other than male sterility, Hrb may be a useful molecular target for therapy of Notch-dependent malignancies, such as T-ALL.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B23.
Abstract B233: c-Met antagonist Avimer™ polypeptide that exhibits potent in vivo and in vitro inhibitor activity
Authors: Cho Song , Smith Richard , Duguay Amy , Li Peng , Bakker Alice , Alba Ben , Thomas Melissa , To Wayne , Silverman Josh , Swimmer Candace , Moore Kevin , Strout Patrick , Bobofchak Kevin , McCarthy Mike , Pemmaraju Kalyani , Lacourciere Gerard , Zhou Qin , Damschroder Melissa , Wu Herren , Coats Steve , Kamal Adeela 
Published: June 2012

Abstract
c-Met is a receptor tyrosine kinase (RTK) that is activated upon binding to its only known ligand, hepatocyte growth factor (HGF). Although essential in development, aberrant c-Met signaling can lead to oncogenesis by promoting proliferation, survival, metastasis, and angiogenesis. Deregulated expression/activation of cMet is found in many neoplasms, and the linkage to disease severity and poor prognosis make this RTK an attractive candidate for targeted anticancer therapy. Challenges of inhibiting c-Met/HGF signaling with a classic antibody therapeutic approach have included: (1) the inhibition of receptor activation required more than one antibody, and (2) bivalent antibodies caused receptor activation. Using a novel non-antibody protein technology platform, we have identified potent polypeptide inhibitors of HGF-mediated c-Met activation. This non-antibody class of proteins, termed Avimer (avidity multimer) polypeptides, are based on naturally occurring domain (e.g., A-domain) containing proteins and can be generated using a phage display library and expressed in E. coli. c-Met antagonist Avimer polypeptides potently inhibit HGF-mediated receptor activation, migration, and proliferation in in vitro assays. Improvement in pharmacokinetic profile gained through attaching polyethylene glycol molecules to avimers enabled in vivo studies. In multiple preclinical tumor models (U87MG glioblastoma, KP-4 pancreatic, U118 glioblastoma), Avimer-treated animals exhibited reduced cMet activation in xenografts and significantly decreased tumor growth. These data indicate that the c-Met antagonist Avimer polypeptides are potent c-Met inhibitors and offer an alternative to small molecules or antibodies in targeting cMet/HGF pathway for anticancer therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B233.
Abstract B25: Apoptotic signaling in AML cells after therapy with the monoclonal antibody-therapeutic gemtuzumab ozogamicin
Authors: Haag Petra , Lindberg Marita Lagergren , Kanter Lena , Lewensohn Rolf , Stenke Leif , Viktorsson Kristina 
Published: June 2012

Abstract
The aim of this study was to identify essential signaling molecules involved in apoptotic cell death in acute myeloid leukemia (AML) cells after treatment with the targeted drug gemtuzumab ozogamicin (GO).
New effective therapeutic drugs are highly desirable in the treatment of AML. Although a majority of treated patients initially respond to conventional treatment, most patients will relapse within 1–2 years. Also, the treatment is associated with severe off-target effects. GO is a novel therapeutic approach, consisting of a monoclonal CD33 antibody coupled to a DNA damaging toxin, calicheamicin. GO enters the cell after binding to the CD33 antigen, preferentially expressed on myeloid cells, and cause DNA double strand breaks (DSB). We have previously demonstrated that activation of Bak and Bax is critical for GO-induced apoptotic signaling, followed by downstream mitochondrial depolarization and caspase-3 activation. As a continuation, we have now examined potential proapoptotic signaling events induced by GO upstream of mitochondria in HL60 AML cells in vitro. We identified caspase-2 and the pro-apoptotic BH3-only protein Bid as two candidates. By analyzing caspase-2 by western blotting after GO treatment we found that GO caused cleavage of caspase-2 after 24h, which was prior to mitochondria-mediated signaling. At the same time, full-length Bid was cleaved to its truncated, active form tBid. The importance of caspase-2 activation in the signaling cascade after GO treatment was demonstrated using z-VDVAD-fmk, a caspase 2 inhibitor. Preincubation with this inhibitor reduced caspase-3 activation with around 50%, suggesting that caspase-2 is an important molecule, located upstream of caspase-3, in the signaling between DNA double stranded breaks and apoptosis signaling in AML cells. In conclusion, we demonstrate that GO, at clinically applicable concentrations (100–1000ng/ml), induce pro-apoptotic signaling which involve activation of caspase-2, and cleavage of the BH3-only protein Bid to the truncated, active protein tBid. Blocking caspase-2 activity reduced caspase-3 activation to only half. This suggests multiple signaling pathways capable of activating caspase-3. The caspase-2 pathway appears central for downstream caspase-3 activity, after GO treatment in AML. Our findings may highlight possible resistance mechanisms in AML, which might have profound therapeutic implications.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B25.
Abstract B29: SMAC-mimetic induced apoptosis of SKOV3 cells requires NIK and activation of canonical NFκB signaling
Authors: Sullivan John F. , Stegmeier Frank , Porter Dale , Zawel Leigh 
Published: June 2012

Abstract
By stimulating the autoubiquitination and proteosome mediated degradation of CIAP1, Smac mimetics hypersensitize tumor cells to TNFα mediated apoptosis. Indeed, Smac mimetics induce the production of TNFα in sensitive but not insensitive tumor cell lines. The precise mechanism of NFκB activation and subsequent TNFα induction is not well understood, and identifying the mechanism by which LBW242 induces TNFα may provide potential biomarkers for patient stratification. Paradoxically, these agents have been reported to both activate and inhibit the canonical NFκB pathway and to activate the non-canonical pathway.
To elucidate this mechanism, we knocked down nodes of the canonical and non-canonical NFκB pathways and assessed activation of an NFκB/p65-reporter, induction of TNFα expression and cell death after treatment with the Smac mimetic compound LBW242. In the canonical pathway, knockdown of IKKB and p65 ablated TNF induction and rescued SKOV cells from LBW242-mediated cell death, suggesting that activation of the canonical pathway is required for LBW242-mediated cell death. In the noncanonical pathway, knockdown of NIK, but surprisingly not RelB, rescued SKOV cells from LBW242-mediated cell death. This data suggests a role for NIK in LBW242-mediated activation of the canonical but not the non-canonical NFκB pathway. Consistent with this model, we find overexpression of NIK is sufficient to activate the p65 reporter. Moreover, activation of the non-canonical NFκB pathway was robustly observed in both sensitive and insensitive tumor cell lines, further invalidating the contribution of the non-canonical arm to Smac mimetic induced TNF production. We propose NIK-mediated activation of the canonical NFκB signaling is responsible for Smac mimetic induced TNFα production.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B29.
Abstract B60: Combination of tivozanib (AV-951) and temsirolimus in patients with renal cell carcinoma (RCC): Preliminary results from a phase 1 trial
Authors: Fishman Mayer N. , Srinivas Sandy , Hauke Ralph J. , Amato Robert J. , Esteves Brooke , Dhillon Reena , Cotreau Monette , Al-Adhami Mohammed , Bhargava Pankaj , Kabbinavar Fairooz F. 
Published: June 2012

Abstract
Background: Based on preclinical data, a combination of VEGF and mTOR inhibitors (mTORi) may be active in RCC and other tumors. However, it has been difficult to combine VEGF tyrosine kinase inhibitors (TKIs) and mTORi due to toxicity. Clinical trials have demonstrated that VEGF TKI and mTORi can only be combined after reducing the doses of both agents, which may also result in reduced anti-tumor activity of this drug combination. Tivozanib, a potent VEGF receptor 1, 2 and 3 TKI, has demonstrated antitumor activity in a phase 2 study in RCC and may be easier to combine with mTORi due to its selective adverse event profile (Proceedings of ASCO 2009, Abstract no. 5032). The combination of tivozanib and temsirolimus was tested in a phase 1 study.
Methods: Patients (pts) with advanced RCC (with clear cell component) who had failed up to one prior VEGF-targeted therapy received oral tivozanib (3 wks on, 1 wk off) and intravenous temsirolimus (once weekly). Dose levels tested (tivozanib/temsirolimus) were: 0.5mg/15mg, 1.0mg/15mg, 1.5mg/15mg, 1.5mg/25mg. The goals of the study were to determine the maximum tolerated dose (MTD), safety, dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical activity of this drug combination.
Results: As of September 1, 2009, 15 pts had been enrolled: 15 males/ 0 females, median age 63 yrs (range 43–70), KPS 100% (11 pts) or 90% (4 pts). Nine (60%) pts had received prior VEGF targeted therapy. The median duration of treatment was 8 wks (range 0–40 wks). Based on preliminary data, treatment-related AEs seen in ≥20% pts (No. of pts with all grades/grade 3 toxicity) were thrombocytopenia (5/2), fatigue (5/1), mucositis (4/0), rash (3/0) and stomatitis (3/0). There were no DLTs and no grade 4 toxicities. The MTD of this combination was: tivozanib 1.5 mg and temsirolimus 25 mg. Available data suggest lack of PK interaction between the two agents. One pt had a confirmed PR, and 7 pts had stable disease for ≥ 8 wks.
Conclusions: The combination of tivozanib with temsirolimus is well tolerated in patients with advanced RCC. Tivozanib is the first VEGF TKI that can be combined with temsirolimus at full doses of both agents. Additional patients are being enrolled in the MTD cohort for an expanded safety assessment, and updated results will be available for presentation. An all oral combination of tivozanib and the mTORi everolimus is also being developed for the treatment of RCC and other tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B60.
Abstract B61: Multicenter phase I clinical trial of an insulin like growth factor (IGF-R) inhibitor (IMC-A12) in combination with a mammalian target of rapamycin (mTOR) inhibitor (CCI-779) to overcome resistance to mTOR inhibition
Authors: Naing Aung , Kurzrock Razelle , Chen Helen , Hong David S. , Falchook Gerald , Doyle Laurence , Iawhorn Kristie , Burger Angelika M. , Ng Chann , Amin Hesham , LoRusso Patricia M. 
Published: June 2012

Abstract
Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type I insulin-like growth factor receptor (IGF-1R)-dependent mechanism, resulting in resistance to mTOR inhibition. Combining an mTOR inhibitor with an IGF-1R antibody/inhibitor is expected to enhance mTORtargeted anticancer therapy. This NCI-CTEP sponsored multicenter phase I clinical trial funded by R-21 mechanism was aimed to define the maximum tolerated dose (MTD), biologic effects, and metabolic activity, individually and in combination, of IMC-A12, a fully humanized IgG1 monoclonal antibody directed at the IGF-IR, and temsirolimus, an inhibitor of mTOR.
Methods: A standard “3+3” design used a fixed dose of 25 mg IV weekly of temsirolimus with an escalating weekly dose of IV IMC-A12 at 3, 4 and 6 mg/kg with no intrapatient dose escalation; 32 patients with advanced cancer (13 male, 19 female) were enrolled across 3 dose cohorts with the current dose cohort at 6 mg/kg weekly IV of IMC-A12 and 25 mg weekly IV of temsirolimus. The MTD has not been reached. Two out of three patients with Ewing sarcoma had more than 20% tumor reduction. One patient with adenocortical carcinoma and one patient with Ewing sarcoma had stable disease for more than 6 months and are still receiving treatment.
Conclusions: Preliminary correlatives data show downregulation of pAKT and pS6K and suggest that the combination is well tolerated, warranting further investigation with dose escalation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B61.
Abstract B67: Thapsigargin sensitizes multidrug-resistant human ovarian carcinoma cells to doxorubicin
Authors: Lim Chuan-Bian , Ky Nung , Hamza Mohamed Sabry , Zhao Yan 
Published: June 2012

Abstract
Chemoresistance to anticancer drugs is a common and troublesome occurrence in ovarian cancer patients. Despite advances in surgical and chemotherapeutic modalities, survival rates remain alarmingly low. Hence, it has been suggested that strategies for reversing multidrug resistance (MDR) are top priorities for reducing cancer mortality. Thapsigargin (TG), a sesquiterpene lactone isolated from the roots of Thapsia garganica, has been demonstrated to possess anticancer properties. The impact of TG, however, on chemoresistance has not been fully elucidated. Here, we report the effects of combining TG with doxorubicin (DOX), since DOX forms part of the standard treatment for women with advanced ovarian cancer. Multidrug-resistant A2780/MDR human ovarian carcinoma cells were treated with TG in combination with a clinically relevant concentration of DOX (10 µM) and assessed for cell proliferation using the MTT assay. A2780/MDR cells were 100-fold more resistant to DOX than parental A2780 cells on the basis of MTT assay. The IC50 of DOX decreased from 8.02 µM to 0.07 µM, in the presence of 1 µMTG, after 24 h of continuous drug combination exposure, producing a 115-fold reversal of MDR. Flow cytometric analysis of cells treated for 24 h with 10 µM DOX with and without 5 µMTG demonstrated significantly increased apoptosis in the presence of TG. TG by itself had little effect on the viability of A2780/MDR cells, as evident by less than 5% cell death after 24-h TG treatment. The activation of caspases-3 and -9 and PARP cleavage were enhanced in combination therapy relative to single agent treatments. Combined treatment with TG and DOX also increased JNK phosphorylation in A2780/MDR cells and pretreatment with JNK inhibitor SP600125 partially rescued apoptosis. Our data demonstrated that addition of TG at subtoxic concentration restored the sensitivity to DOX-induced apoptosis in A2780/MDR cells via JNK pathway. Taken together, these data support the concurrent use of DOX and TG in ovarian cancer therapeutics.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B67.