bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B223: Protein kinase C iota as a target for glioblastoma therapy
Authors: Lorimer Ian A. J. , Gray Douglas A. , Baldwin Mitchell 
Published: June 2012

Abstract
In spite of advances in surgery, radiation and chemotherapy, glioblastoma is still one of the deadliest forms of cancer. Two key features of the malignant nature of glioblastoma are its abnormal proliferation and its ability to invade both locally and to distant sites within the central nervous system. The phosphoinositide 3-kinase pathway is frequently activated by oncogenic mutations in glioblastoma, leading to activation of multiple downstream signaling molecules including protein kinase C iota (PKCι). Stable suppression of PKCι in glioblastoma cells with a short hairpin RNA caused a significant decrease in the proliferation of glioblastoma cells along with increased actin stress fiber formation and decreased cell motility and invasion. Live cell imaging was used to further assess the role of PKCι in glioblastoma cell motility and proliferation. While control glioblastoma cells form a coordinated leading edge lamellipodia and migrate substantial distances, cells stably depleted of PKCι show a loss of the ability to coordinate the formation of a functional leading edge lamellipodia and instead generate projections from all sides of the cell. These cells are therefore unable to move in a coordinated fashion. In addition live cell imaging showed that while glioblastoma cells round up and initiate mitosis, they are significantly impaired in their ability to complete mitosis. These effects on motility and mitosis were also seen when PKCι activity was inhibited with a myristoylated pseudosubstrate peptide. PKCι is therefore a promising new therapeutic target for glioblastoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B223.
Abstract B232: Preclinical evaluation of AMG479 a fully human insulin-like growth factor receptor-1 (IGFR1) antibody in ovarian cancer cells
Authors: Konecny Gottfried E. , Manivong Kanthinh , Guorong Ellen , Glas Ruth , Dering Judy , Anderson Lee , Ginther Charles , Velculescu Victor , Calzone Frank , Slamon Dennis J. 
Published: June 2012

Abstract
Background: Dysregulation of the insulin-like growth factor receptor-1 (IGFR1) signaling pathway has been implicated in the development and progression of ovarian cancer. Here we explore the therapeutic potential of AMG479 a fully human monoclonal antibody that targets the IGFR1 for the treatment of ovarian cancer.
Methods: We examined the effects of AMG479 on tumor cell growth in a panel of 40 characterized human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling, multiplexed phospho-protein ELISA, array comparative genomic hybridization, and mutational analyses. Associations between biomarkers and growth inhibition were analyzed using Spearman's rho correlation, and absolute levels were compared using the Mann-Whitney U test.
Results: Concentration-dependent antiproliferative effects of AMG479 were seen in nearly all ovarian cancer cell lines tested but varied significantly between individual cell lines. In vitro sensitive cell lines demonstrated significantly higher expression levels of IGFR1 (r = 0.36, p = 0.024), IGFBP5 (r =0.45, p =0.005), but lower levels of insulin receptor (r = -0.28, p =0.096). Eighteen of the 40 (45%) ovarian cancer cell lines demonstrated PI3K, KRAS, BRAF, or PTEN mutations. Cell lines without these mutations in the downstream signaling pathway of IGFR1 were significantly more sensitive to AMG479 when compared to those cell lines with downstream mutations (p = 0.026). Response to AMG479 was significantly correlated with its ability to inhibit (pre- versus post-treatment) phospho-p70S6K (r = 0.35, p = 0.028), and phospho-GSK-3 (r = 0.43, p = 0.005), but not with its ability to inhibit phospho-IGFR1 (r = 0.21, p = 0.183). Gene copy number gains or LOH of PTEN or PI3K, although common, were not associated with in vitro response to AMG479.
Conclusions: AMG 479 is a promising candidate for therapeutic use in IGFR1 dependent ovarian cancers. The present correlative study will help to identify biomarkers that may predict sensitivity to IGFR1 inhibition in ovarian cancer. PTEN, PI3K, or KRAS mutations may inversely correlate with sensitivity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B232.
Abstract B238: A phase 1 study of belinostat (PXD101) in combination with bortezomib in patients with advanced solid tumors or lymphoma
Authors: Nallapareddy Sujatha , Leong Stephen , Camidge Ross , Gore Lia , Diab Sami , Messersmith Wells , Lewis Karl , Weekes Colin , Gustafson Daniel , Jimeno Antonio , Zwiebel James , Espinoza-Delgado Igor , Eckhardt Gail , O'Bryant Cindy 
Published: June 2012

Abstract
Background: Belinostat (B) is a low molecular weight, synthetic hydroxamic acid derivative that inhibits class I and II histone deacetylases. Bortezomib (Bz) is a potent, selective inhibitor of the 26S proteasome. In preclinical studies, synergistic antiproliferative and pro-apoptotic effects were observed with the combination, providing the rationale for this study.
Methods: This phase 1 study is designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) behavior of the combination of B and Bz. Each 21-day treatment cycle consists of B (600–1000 mg/m2) IV daily over 30 minutes on days 1–5 and Bz (0.7–1.5 mg/m2) IVP over 3–5 seconds on days 1, 4, 8, and 11 (days 2, 5, 8 and 11, cycle 1 only).
Results: To date, 26 patients have been enrolled (median age 59 [range 27–72]; median PS 1 [range 0–1]). Twenty-two patients were evaluable for toxicity and received a total of 58 treatment cycles (median 2 [range 1–6]). Four patients, 2 at dose level (DL) 3 (B: 600 mg/m2)/Bz: 1.3 mg/m2) and 2 at DL 5 (B: 1000 mg/m2)/Bz: 1.5 mg/m2) experienced a dose limiting toxicity (DLT). At DL 3, the DLTs were grade (gr) 3 dehydration and gr 4 thrombocytopenia. The exact relationship of the gr 3 dehydration and study combination is unclear as the patient had uncontrolled constipation and decreased oral intake as a result of a change in pain medications on cycle 1 day 1. This cohort was expanded to 9 pts to further determine tolerability of the study combination. No other DLTs were identified and dose escalation continued. At DL 5, DLTs included gr 4 thrombocytopenia and gr 4 fatigue. Most adverse events (AEs) have been mild to moderate. Gr 1–2 AEs (number of cycles) include anorexia (8), acute infusion reaction (5), fatigue (14), nausea (19), neutropenia (1), pain (12), phlebitis (6), thrombocyctopenia (11), and vomiting (12). Gr 3 AEs (occurring after course 1) include anorexia, dehydration, fatigue, nausea, vomiting, hypoalbuminemia, and elevation of alkaline phosphatase. Analysis of B PK demonstrates no statistical differences in the parameters between days 1 (B only) and 2 (B + Bz) for AUC, Cmax, clearance, or t1/2. Likewise, increasing Bz doses have no effect on B PK, whereas doses of B from 600 to 1000 mg/m2 result in dose-proportional increases in drug exposure. Four patients have maintained stable disease for 4–6 cycles of therapy.
Conclusions: Belinostat and bortezomib is a reasonable combination with a tolerable toxicity profile and no evidence of pharmacological interactions. Accrual is ongoing at the MTD, DL 4 (B: 1000 mg/m2)/Bz: 1.3 mg/m2). Additional biological assessments are planned in an expanded cohort of patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B238.
Abstract B240: Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON variant containing the complete sema sequences
Authors: Qi Ma , Zhang Kun , Wang Ming-hai 
Published: June 2012

Abstract
The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON-MSP pathway in various cancer cells. The variant was an 85 kDa soluble protein from a mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop code leading to a RON variant composed of a full 35kDa α-chain and a 45 kDa partial extracellular β-chain. The protein was featured by a sema domain, a hinge and a portion of the first IPT unit (designated as RON 85). RON 85 directly bound to the MSP, formed the MSP-RON 85 complex, and inhibited RON phosphorylation. RON 85 disrupted RON or RON 160 dimerization, prevented their phosphorylation, and attenuated their downstream signaling events. The action of RON 85 was specific to RON and had no effect on MET and EGFR. In colon and pancreatic cancer cells, RON 85 inhibited spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RON 85 also inhibited spontaneous or MSP-induced cell migration. We concluded that RON 85 is an antagonist to the MSP-RON pathway with therapeutic potentials for controlling tumorigenic phenotypes of cancer cells.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B240.
Abstract B241: Extended follow-up from a phase I study of AS1409, a novel antibody-cytokine fusion protein, suggests efficacy in malignant melanoma (MM)
Authors: Rudman Sarah M. , Jameson Michael B. , Savage Philip , Jodrell Duncan , Erlandsson Fredrik , Jones David , McKeage Mark , Spicer James F. 
Published: June 2012

Abstract
Introduction: AS1409 (huBC1-huIL-12) is a fusion protein comprising the humanized antibody, BC1, specific for the ED-B splice variant of fibronectin, and the human cytokine, IL-12. ED-B-fibronectin is expressed in tumor vasculature but has restricted distribution in normal tissue. IL-12 has immunostimulatory, anti-metastatic and anti-angiogenic properties. Responses to IL-12 occur in MM and RCC but with high systemic toxicity. AS1409 is designed to target IL-12 to tumor vasculature. We report extended follow-up from a phase I study to assess the tolerability, safety, pharmacokinetics and activity of AS1409 in patients with MM or renal cell carcinoma (RCC).
Methods: Patients with MM or RCC were treated in a dose-escalating trial of weekly i.v. AS1409 for 6 weeks at a starting dose of 15mcg/kg. Patients without unacceptable toxicity or disease progression could continue therapy. IFN-gamma and IP-10 were measured as markers of immune response.
Results: 13 patients (11 MM, 2 RCC) were treated (7 at 15mcg/kg, 6 at 25mcg/kg). DLTs observed at 25mcg/kg were transaminase elevation, fatigue and hemolytic anemia. Most common drug-related adverse events were Grade 1 or 2 and related to flu-like syndrome. Four patients continued to receive AS1409 beyond 6 weeks and one received 30 cycles of treatment. All patients showed elevation of IFN-gamma and IP-10 following the first dose. Tumor shrinkage was demonstrated in 5/9 evaluable MM patients - a partial response was confirmed in a patient with MM metastatic to lymph nodes and a further four patients achieved stable disease. One MM patient with previously rapidly progressive disease exhibited prolonged tumor shrinkage 12 months after discontinuing treatment. Anti-drug antibody (ADA) responses were seen in all patients. ADAs were shown not to neutralize the effect of AS1409 in vitro.
Conclusions: At 15mcg/kg, AS1409 was associated with manageable toxicity. Biomarker activation and objective radiological evidence of anticancer activity was observed at this dose in patients with MM, including one partial response and one patient with prolonged clinical benefit beyond 12 months from treatment. Further development of AS1409 in MM is warranted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B241.
Abstract B244: Inhibition of metastases by a neutralizing TGFβ-specific antibody involves the activity of cytotoxic T lymphocytes and natural killer cells
Authors: Munroe Kenneth , Manning Charlene , Green Tessa , Tao Jingzang , Simon Kailene , McPherson John , Kaplan Johanne , Pinkas Jan , O'Brien Megan , Gregory Richard , Harper Jay , Lonning Scott 
Published: June 2012

Abstract
TGFβ plays a key role in metastasis by promoting epithelial to mesenchymal transition, up-regulating proteases that degrade extracellular matrix, enhancing tumor cell motility and suppressing antitumor immunity. Preclinical studies were conducted to determine the effect of neutralizing TGFβ on both primary tumor growth and metastases in in vivo models of experimental and spontaneous metastasis. Treatment with the pan-neutralizing TGFβ antibody, 1D11, as a single agent had limited effect on the growth of established, primary, syngeneic tumors (4T1 mammary carcinomas or B16-F10 melanomas) and did not enhance the efficacy of chemotherapeutic agents against these primary tumors. However, TGFβ antagonism was shown to have a significant effect on inhibiting metastasis to the bone following intracardiac injection of 4T1 cells. In addition, it was demonstrated that neutralization of TGFβ in B16-F10 melanoma models inhibited experimental pulmonary metastases following injection of cells into the tail vein, and inhibited spontaneous metastases from a subcutaneous primary tumor to the draining lymph node. Studies aimed at elucidating the mechanism of action of 1D11 in mice lacking specific immune effector cells suggest that the activity of cytotoxic T lymphocytes is important in the inhibition of metastases. The role of natural killer (NK) cells is less clear; NK cell activity is not required for inhibition of experimental metastasis to the lung, but is critical for the ability of 1D11 to inhibit spontaneous metastasis from a primary tumor to the draining lymph node. Investigation into the effects of neutralizing TGFβ on innate immunity and the tumor microenvironment are currently ongoing. Together these data suggest that neutralization of TGFβ significantly inhibits metastasis and anti-TGFβ strategies may be effective at treating metastatic disease in the clinic.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B244.
Abstract B245: The antitumor agent, Dp44mT, perturbs lysosomal function by binding copper and inducing oxidative damage
Authors: Lovejoy David B. , Jansson Patric J. , Brunk Ulf T. , Wong Jacky , Richardson Des R. 
Published: June 2012

Abstract
Current chemotherapies for solid tumors remain severely limited due to toxicity and the development of drug resistance. Hence, new agents are vital to explore in order to improve patient outcomes.
We have identified the novel chelator Dp44mT as a potent and selective anti-tumor agent that overcomes resistance to standard chemotherapeutics (Whitnall, M., Howard, J., Ponka P. and Richardson, D.R. PNAS USA 2006; 103:14901–6).
To understand its mechanism of action and potential anti-angiogenic activity, we have investigated its ability to interact with cellular copper (Cu). In contrast to its marked ability to potently mobilize cellular 59Fe, Dp44mT caused marked intracellular 64Cu accumulation. Cellular fractionation demonstrated that 64Cu was concentrated in a fraction containing lysosomes and mitochondria. Moreover, the lysosomotropic character of Dp44mT suggested that it may become concentrated in lysosomes. To test this, studies with the lysosomotropic agent, acridine orange, demonstrated that the Cu-Dp44mT complex potentiated loss of lysosomal integrity, indicating that the lysosome was a target of the compound.
This was confirmed using the fluorescent probe, pepstatin A BODIPY FL, which demonstrated relocalisation of the lysosomal enzyme cathepsin D from the lysosome to the cytosol after incubation with the Cu-Dp44mT complex. Further, the altered lysosomal membrane permeability was demonstrated by cleavage of the pro apoptotic Bcl2 family member, Bid. The Cu-Dp44mT complex was markedly more redox active than the Fe complex at lysosomal pH. This indicated that Cu mediated redox events were responsible for the cytotoxicity observed, in particular the induction of apoptosis induced by lysosomal damage. Further, the Cu chelator, tetrathiomolybdate potently attenuated Dp44mT mediated cell death.
Our results indicate the potent anti-tumor and anti-angiogenesis activity of Dp44mT is mediated not only by Fe chelation, but also via its binding of cellular Cu, leading to the generation of a cytotoxic complex.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B245.
Abstract B248: Characterization and preclinical development of LCI-1, a selective and potent Chk1 inhibitor in phase 1 clinical trials
Authors: Marshall Mark , Barda David , Barnard Darlene , Cox Karen , Diaz H. Bruce , King Constance , Nutter Suzanne , Westin Eric 
Published: June 2012

Abstract
Interference of DNA damage checkpoints has been demonstrated to be a highly effective means of increasing the cytotoxicity of a wide number of anti-cancer therapies. Ionizing radiation, DNA cross-linkers, topoisomerase inhibitors and anti-metabolites all cause severe cellular DNA damage and activation of multiple DNA damage checkpoints. Cell cycle arrest at these checkpoints protects injured cells from apoptotic cell death until the DNA damage can be repaired. In the absence of functioning DNA damage checkpoints, cells with damaged DNA proceed into premature mitosis followed by rapid apoptotic death. A key protein kinase involved in activating and maintaining the S and G2/M checkpoints is Chk1. Pharmacological inhibition of Chk1 in the absence of p53 leads to abrogation of the DNA damage checkpoints and has been shown to enhance the preclinical activity of many standard of care chemotherapeutic agents. LCI-1 is a novel small molecule inhibitor of Chk1 (IC50 = 7 nM). In cell-based experiments LCI-1 inhibited doxorubicin-dependent autophosphorylation of Chk1 (IC50 = 52 nM). Treatment of cells with LCI-1 alone caused a phenotype identical to that reported for cells depleted of Chk1, demonstrating the mechanism-dependent activity of the compound. Treated with 100 nM doxorubicin, HeLa cells arrested at the G2M checkpoint. When treated 24 hours later with LCI- 1, the arrested cells traversed the G2M checkpoint, allowing cells to proceed into mitosis with unresolved replicated chromosomes. Consistent with abrogation of the Chk1-dependent G2M checkpoint, HT-29 cells (mutant p53) treated with LCI-1 were more sensitive to killing by gemcitabine then were LCI-1 treated HCT116 cells (wild-type p53). In vivo, LCI-1 effectively inhibited Chk1 autophosphorylation, as well as released the S and G2M block induced by gemcitabine treatment. When used preclinically in combination with DNA damaging agents, LCI-1 increased DNA damage and cell death over gemcitabine alone. These results indicate that LCI-1 may prove to be an effective potentiator of DNA damaging therapies in the clinic. LCI-1 is currently undergoing clinical testing in combination with gemcitabine and pemetrexed.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B248.
Abstract B251: Combined anticancer effects of sphingosine kinase inhibitors and sorafenib
Authors: Beljanski Vladimir , Knaak Christian , Zhuang Yan , Smith Charles 
Published: June 2012

Abstract
Purpose: The pro-apoptotic lipid sphingosine is phosphorylated by sphingosine kinases 1 and 2 (SK1 and SK2) to generate the pro-survival lipid sphingosine-1-phosphate (S1P). We previously reported that inhibition of SK activity delays tumor growth in a mouse mammary adenocarcinoma tumor model. Because SK inhibitors and the multikinase inhibitor sorafenib both suppress the MAP kinase pathway, we hypothesized that the combination may provide enhanced tumor growth inhibition. Therefore, we evaluated the effects of two SK inhibitors, ABC294640 (a SK2-specific inhibitor) and ABC294735 (a SK1/SK2 inhibitor), alone and in combination with sorafenib on human pancreatic adenocarcinoma (Bxpc-3) and kidney carcinoma (A-498) cells in vitro and in vivo.
Experimental Design: Effects of the compounds as single agents or in combination in cell culture were assessed using the SRB assay, and CalcuSyn software was used to calculate synergistic or additive growth inhibition. Western blotting measured effects of compounds on signaling pathways. SCID mice bearing tumors of either Bxpc-3 or A-498 cells were treated with the agents and tumor growth was monitored.
Results: Exposure of either Bxpc-3 or A-498 cells to ABC29464/sorafenib or ABC294735/sorafenib combinations resulted in synergistic cytotoxicity, associated with increases in caspases 3/7 activation and apoptotic DNA fragmentation. In addition, strong decreases in ERK phosphorylation were observed in Bxpc-3 and A-498 cells exposed to the either sorafenib/ABC29464 or sorafenib/ABC294735 combinations. An increase in the phosphorylation of inhibitory site of c-Raf (S259) was also observed in the drug-treated cells. Oral administration of either ABC294640 or ABC294735 to mice led to a delay in tumor growth in both xenograft models without overt toxicity to the animals. Tumor growth delay was potentiated by co-administration of sorafenib.
Conclusions: These studies show that combination of an SK inhibitor with sorafenib causes synergistic inhibition of cell growth in vitro and potentiates antitumor activity in vivo. Thus, a foundation is established for clinical trials evaluating the efficacy of combining these signaling inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B251.
Abstract B260: Antitumor activity of HM781-36B, an irreversible pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer cells
Authors: Nam Hyun-Jin , Kim Hwang-Phill , Yoon Young-Kwang , Hur Hyung-Seok , Kim Maeng-Sup , Lee Gwan-Sun , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue 
Published: June 2012

Abstract
Background: HM781-36B is a novel quinazoline-based irreversible pan-HER inhibitor. Although the effects of many other pan-HER inhibitors (CI-1033, PF00299804, BMS-599626, BMS-690514 and JNJ-28871063) have been studied in various types of cancer, data regarding the use of pan-HER inhibitors to treat gastric cancers are limited. In this study, we evaluated the therapeutic potential of HM781-36B for the treatment of gastric cancers by testing its in vitro and in vivo efficacy. In addition, we further characterized its activity when administered in combination with chemotherapeutic agents.
Methods: Experiments were conducted in gastric cancer cell lines. Enzyme activity assay was conducted to determine the IC50 values of HM781-36B for kinase inhibition and MTT assay was used for determining growth inhibitory effect. Cell cycle distribution was analyzed by flow cytometry and apoptotic effect was measured by annexin V assay. And N87 xenograft model was used to see tumor regression effect. Western blot analysis was used to verify mechanism of this compound.
Results: We found that HM781-36B suppressed the proliferation of HER2-amplified gastric cancer cell lines (SNU216 and N87) potently when compared to the effects of other HER family tyrosine kinase inhibitors (gefitinib, lapatinib, BIBW-2992 and CI-1033). Furthermore, we found that HM781-36B inhibited the phosphorylation of HER family and their downstream signaling proteins, which resulted in apoptosis through the caspase-mediated mitochondrial pathway and G1 arrest. The apoptotic process requires the induction of the proapoptotic BH3-only BCL2 family member, BIM, and HM781-36B led to a dramatic increase in the BIM level in SNU216 and N87 cells. Consistent with these in vitro findings, HM781-36B showed exceptional anti-tumor activity in a xenograft model of N87 cells. Furthermore, HM781-36B exerted synergistic effects when administered in combination with 5-fluorouracil or cisplatin in both HER2 amplified cells and HER2 non-amplified gastric cancer cells.
Conclusion: Taken together, these data suggest that HM781-36B may be useful as a targeted therapy for the treatment of HER2 amplified gastric cancer as well as a chemosensitizer of cytotoxic chemotherapeutic agents used to treat gastric cancer, even in HER2 non-amplified gastric cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B260.