bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A225: The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG
Authors: Keen Heather , Ricketts Sally-Ann , Bales Juliana , Shannon Aoife , Logie Armelle , Odedra Rajesh , Wedge Steve , Guichard Sylvie 
Published: June 2012

Abstract
Introduction: mTOR is a a sensor of mitogen, energy and nutrient levels and a central controller of cell growth. mTOR is present in two multi-protein complexes: mTORC1, rapamycin sensitive and containing raptor, and mTORC2, rapamycin-insensitive. AZD8055 is a small molecule ATP competitive inhibitor of mTOR kinase, thus inhibiting both mTORC1 and mTORC2. This results in a greater reduction of mTORC1 substrates pS6 on Ser235/236 and p4EBP1 on T37/46 compared to rapamycin. AZD8055 also reduces the mTORC2 substrate pAKT on Ser473. The PI3K-AKT-mTOR pathway is involved in glucose uptake/metabolism. 18F-Flurodeoxyglucose (18F-FDG) is a biomarker for glucose metabolism detectable by positron emission tomography (PET). It is used in clinical oncology for tumor diagnosis and is currently under evaluation for therapy monitoring. The aim of this study was to assess the impact of a single and 4 daily dosing of AZD8055 on 18F-FDG uptake in U87-MG human glioma xenografts implanted subcutaneously in nude mice.
Methods: AZD8055 was administered orally at a dose of 20 mg/kg qd for 1 or 4 days. Animals received either vehicle or AZD8055 1 hour prior to imaging. Mice were anaesthetised and then injected with approximately 15 MBq 18F-FDG i.v. via the tail vein. Forty-five minutes later, mice underwent PET scanning (20 minute scan, 3D histogramming and OSEM2D reconstruction) followed by biodistribution analysis. Image analysis was carried out using Inveon Research Workplace (IRW) software. Biodistribution data were derived from gamma counting.
Results: Plasma drug concentrations were not modified significantly by anesthesia and the imaging procedure. In the vehicle and AZD8055-treated groups, tumor volumes were comparable after single dose, but differed significantly following 4 days of treatment due to drug effect. Image analysis of 18F-FDG uptake after single and multiple doses showed that there was a significant difference (p&lt;0.05) in meanSUV, maxSUV and the percentage of injected dose per gram of tissue (%ID/g) between vehicle and drug treated tumors. Biodistribution analysis showed that the average 18F-FDG %ID/g in vehicle-treated tumors was significantly higher than in AZD8055-treated tumors (p&lt;0.05).
The changes in glucose uptake after 1 and 4 administrations were consistent with the pharmacodynamic effects of AZD8055 on pS6 and pAKT biomarkers in U87-MG tumors collected at the same time-points.
Conclusions: AZD8055 reduces significantly 18F-FDG uptake in U87-MG human glioma xenografts, as early as 1 hour after a single dose. This data suggests that 18F-FDG uptake could be used as an early sign of metabolic response to AZD8055.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A225.
Abstract A241: Searching for extracellular signal-regulated kinase (ERK)-independent molecular targets of sorafenib in hepatocellular carcinoma (HCC)
Authors: Fan Hsiang-Hsuan , Yu Sung-Liang , Ou Da-Liang , Shen Ying-Chun , Huang Yi-Ting , Hsu Chiun , Cheng Ann-Lii 
Published: June 2012

Abstract
We have recently identified Bim, a pro-apoptotic factor regulated by ERK signaling pathway, is an important mediator of sorafenib-induced apoptosis in HCC cells.. In this study we further explored other possible mediators of sorafenib activity in HCC cells that is independent of mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK)/ERK signaling. Huh7 cells were treated with sorafenib or the MEK inhibitor CI-1040, alone or in combination, for 24 hours. The gene expression profiles were analyzed by Affymetrix oligonucleotide microarray analysis using HG_U133A chip, and the candidate genes were selected if (1) they had &gt; 1.2 fold or &lt; 0.8 fold change than control after treatment with sorafenib 10 M and (2) they had been reported to be involved in important carcinogenesis-related cellular signaling pathways, such as apoptosis regulation, cell proliferation/survival, cell cycle control, and angiogenesis. The gene expression was considered MEK/ERK-dependent if the direction of changes was similar after treatment with sorafenib 10 M or CI-1040 1 M; otherwise it was considered MEK/ERK-independent. Thirty candidate genes of interest were identified and the expression patterns were validated by real-time PCR (see table). The 14 genes whose expressions were considered ERK-independent involved apoptosis regulation (GADD45b, BAX, JUN), cell proliferation (PCNA, RPS6KA3, SMAD7, BMP2, DUSP1, DUSP8, IL1RAP, RHEB), cell cycle control (CCNE1, CDC25A), and angiogenesis (VEGF). Validation of the biological significance of these markers is ongoing. The preliminary data revealed that induction of GADD45b and JUN gene expression after sorafenib treatment was correlated with intrinsic or acquired resistance of HCC cells to sorafenib. Our data indicated that MEK/ERK-independent signaling pathways may also contribute to sorafenib-induced apoptosis and growth regulation in HCC cells. The signaling molecules identified in this study can serve as novel therapeutic targets for HCC. (Supported by grants NSC97-3112-B-002-012, NSC98-3112-B-002-007, NSC98-3112-B-002-037)
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A241.
Abstract B121: Phase I study of MK-0646, a humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine + erlotinib (E) for advanced previously untreated pancreatic cancer
Authors: Javle Milind , Varadhachary Gauri , Bhosale Priya , Shroff Rachna , Ukegbu Lerma , Overman Michael , Wolff Robert , Abbruzzese James 
Published: June 2012

Abstract
Background: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/Akt signaling. Collectively, these pathways are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. IGF-1R + EGFR antagonists result in synergistic anti-tumor activity in preclinical pancreatic cancer models.
Methods: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0–1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Arm A: G 1000 mg/m2 over 100 min, weekly × 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly × 4; Arm B: same schedule of G and MK-0646 as Arm A + E 100 mg daily. Cycles were repeated every 4 weeks. Radiologic responses measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival (PFS), response rate, toxicity and overall survival.
Results: 22 pts enrolled, 15 males, 2 priorWhipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1–8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Two dose limiting toxicities observed in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Best radiologic responses: 6 PR (including 1 hepatic CR), 7 PD, 3 SD, 4 too early, 1 not evaluated, 1 not treated. PFS range in weeks for evaluable patients (n=12) was (4, 36+).
Conclusion: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B121.
Abstract B163: Pharmacokinetic analysis and preclinical evaluation of the SMAC mimetic TL32711 in an orthotopic human breast tumor xenograft model
Authors: Moore Mitchell M. , Estrada Vanessa A. , Nieves Francis E. , Burns Jennifer M. , Mitsuuchi Yasuhiro , Chunduru Srinivas K. , Graham Martin A. , McKinlay Mark A. , Tolcher Anthony W. , Wick Michael J. 
Published: June 2012

Abstract
Inhibitor of Apoptosis Proteins (IAPs) are cellular proteins that prevent cell death by apoptosis and are frequently overexpressed in cancer cells resulting in elevated levels leading to cancer survival and progression. Currently we are developing a class of compounds called SMAC mimetics that reverse the effects of IAPs including XIAP, cIAP-1 and cIAP-2 and ML-IAP causing cancer cells to undergo apoptosis in a broad range of tumor types. TL32711 is a SMAC mimetic which has demonstrated potent and selective activity in several human tumor cell lines as well as in vitro inhibition of IAP target proteins. To determine translational effects in vivo, we evaluated PK/PD and single agent antitumor activity of TL32711 in an orthotopic human breast tumor xenograft model. Single agent toxicity as well as tumor growth inhibition, delay and regression were monitored in the study. The designated endpoint for the efficacy experiment was a mean control tumor volume of approximately 1 cm3.
TL32711 administered by intravenous injection on a q3dx5 schedule was well tolerated up to 10 mg/kg alone, the highest dose tested. The minimal effective dose was determined to be 1.25 mg/kg. When tumors were allowed to grow to 260 mm3 prior to initiation of treatment, the treatment effect was not diminished. PK/PD analysis of TL32711 found a longer half-life of TL32711 in tumor compared to normal tissue and a time and dose dependent inhibition of the target protein cIAP-1. The effects on the cIAP-1 target were in good agreement with the tissues levels measured using a LC/MS method. TL32711 was not found to cross the blood brain barrier in this analysis.
Results from these studies confirm translational effects of TL32711 in a preclinical model of human breast cancer. In addition, PK/PD analysis demonstrated dose and time dependent target inhibition in vivo and decreased half life in tumor tissue.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B163.
Abstract B166: Effects of PTX-008, a non-peptidic topomimetic targeting galectin-1 in human epithelial cancer cells
Authors: Astorgues-Xerri Lucile , Serova Maria , Bieche Ivan , Vivier Sabrina , Cvitkovic Esteban , Noel Kay , Raymond Eric , Faivre Sandrine 
Published: June 2012

Abstract
Galectin-1, a lectin implicated in several biological processes, selectively binds neuropilin-1, enhances VEGFR2 signalling, and contributes to membrane anchorage of H-RAS in cancer cells. PTX-008 is a calyx[4]arene analogue designed as a galectin-1 mimetic, showing antiangiogenic properties in vitro and in vivo in tumor models. In this study, we investigated the potential antiproliferative effects of PTX-008 in a panel of colon (HT29, HCT116, COLO205, HCC2998), breast (MCF7, MDA-MB-435, SKBR3, ZR-75-1), ovarian (OVCAR3, IGROV1, SKOV3), lung (HOP62, HOP92), prostate (PC3, DU145), head and neck (SCC61, SQ20B, HEP2), hepatocellular carcinoma (SK-HEP1) and renal (CAKI1) human cancer cell lines. Antiproliferative effects were detected in several cancer cell lines (SQ20B, HT29, and COLO205 cell lines, range 3–9µM). In contrast, HEP2 and DU145 cell lines appear to be resistant to PTX-008 (&gt;27µM). The antiproliferative effects of PTX-008 were mainly associated with G2/M accumulation with marginal apoptosis induction. No correlation was found between the antiproliferative effects of PTX-008 and the mRNA expression of several growth factors and tyrosine kinase receptors such as VEGF/VEGFR, EGF/EGFR, and PDGF/PDGFR as determined by qRT-PCR analysis. In our panel, epithelial cancer cells - expressing high mRNA levels of E-cadherin and low levels of N-cadherin and vimentin - were more sensitive to PTX-008 than mesenchymal cells. Interestingly, antiproliferative effects of PTX-008 in cancer cells were more pronounced in cancer cells with low galectin-1 mRNA and protein expression. Exogenous semaphorin-3A exposure potently inhibits cell proliferation, mimicking the effects of PTX-008, while concomitant exposure to PTX-008 with exogenous semaphorin-3A has strong antiproliferative effects in SQ20B cells. Furthermore, modulation of galectin-1 with PTX-008 followed by VEGFR/PDGFR inhibition with sunitinib resulted in enhanced antiproliferative effects in SQ20B. In SQ20B cells, PTX-008 as well as exogenous semaphorin-3A activate rapidly p-AKT473 and p-ERK1/2Thr202/Tyr204 but have no effect of p-S6KSer235/236, further suggesting that some of the antiproliferative effects of PTX-008 may be related to the modulation of neuropilin-1. These findings suggest that PTX-008 may have direct antiproliferative activity in cancer cells, with a novel mechanism that differs from the currently available kinase inhibitors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B166.
Abstract B242: A phase I/II study of oncolytic reovirus plus chemotherapy (carboplatin/paclitaxel) in patients with advanced solid tumors (with emphasis on patients with squamous cell carcinoma of the head and neck (SCCHN)
Authors: Harrington Kevin J. , Karapanagiotou Eleni M. , Hardev Pandha , Nutting Christopher M. , Gore Martin , Karl Mettinger , Geoff Hall , Melcher Alan , Mercel Ball , Coffey Matt , Thompson Brad , Chester John 
Published: June 2012

Abstract
Background: Reovirus is a double-stranded RNA virus which replicates in cells with activated Ras signaling pathway, while sparing normal cells. Following our recent study of intravenous (i.v.) reovirus in patients with advanced malignancies1, we have conducted a Phase I/II dose escalation study of i.v. reovirus in combination with chemotherapy.
Methods: REOLYSIN® was administered to cohorts of 3 patients in escalating doses (3 × 109, 1 × 1010, 3 × 1010 TCID50) on days 1–5 while carboplatin AUC 5 and paclitaxel 175 mg/m2 were administered on day 1 of a 3-weekly schedule. Eligible patients had good performance status (ECOG PS: 0–2) with advanced cancers which were not amenable to curative treatment or were refractory to standard therapy for which paclitaxel/carboplatin was appropriate palliative chemotherapy.
Results: Twenty-three patients (15 males, median age 56.9 years) with head and neck cancer (n=17), melanoma (n=4) or peritoneal/endometrial cancer (n=2) received 106 cycles (median 6, range 1–8) of combination treatment. In the dose-escalation phase of the study, there were no dose-limiting toxicities. Grade 3/4 toxicities included anaemia, leucopenia, neutropenia, lymphopenia, thrombocytopenia, infection and hypotension. Viral shedding (as assayed by reverse transcription PCR) has been documented in 2 patients. Neutralising anti-reovirus antibody responses have been measured using a previously reported technique2 and will be presented.
In the Phase 1 study partial responses (PR) were noted in one of four patients with melanoma and in two of five patients with head and neck cancer. An expanded cohort of head and neck cancer patients was therefore treated at the maximum dose level (3 × 1010 TCID50) in order to further assess tumor response in this setting.
To date, 14 patients with head and neck cancer have received at least two cycles and are evaluable for response. Most of them were refractory to previous platinum-based chemotherapy for recurrent/metastatic disease. PR was seen in 6 patients (43%), SD in 5 (36%) and PD in 3 (21%). The study is ongoing.
Conclusion: Intravenous administration of reovirus in combination with carboplatin/paclitaxel is a safe and well-tolerated combination with promising anticancer activity in SCCHN. Further evaluation of this combination in a randomized Phase III trial in SCCHN is planned.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B242.
Abstract B256: A novel targeted oral insulin-like growth factor 1 (IGF-1) receptor inhibitor in clinical phase I/II testing
Authors: Harmenberg Johan , Ekman Simon , Bergqvist Michael , Frödin Jan-Erik , Larsson Olle , Axelson Magnus 
Published: June 2012

Abstract
The overall objective was to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related insulin receptor and to test such a compound in cancer patients with solid tumors.
IGF-1R belongs to a family of related receptors also including the insulin receptor (IR). The IGF-1R signaling pathway is crucial for the survival and growth of most types of cancer cells, but not of normal cells. The concept has general applicability with respect to many different cancers.
AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 demonstrates strong and unique anti-tumor efficacy, including complete regression of established tumors in animals xenografted with human malignant cells, including breast cancer, prostate cancer, glioblastoma (intracerebral implants), malignant melanoma, sarcoma and multiple myeloma. AXL1717 did not show any effect in animals with IGF-1R negative xenografts. Preclinical testing showed excellent tolerability together with good oral bioavailability.
AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7–28 days of increasing BID doses of AXL1717. The preliminary results as of September 3rd 2009 have identified possible Phase II dosages. Even though the study was not designed to evaluate tumor or biomarker response, 4 out of 6 patients have shown decreased density of IGF-1R on granulocytes. Two patients, with progressive non-small cell lung cancer, treated with AXL1717 as 3rd and 4th line treatment, respectively, were reported to have documented tumor necrosis.
The preliminary results from the Phase I/II clinical trial indicate a recommended phase II dose with good tolerability and with an oral bioavailability resulting in an exposure several fold higher than the exposure resulting in complete regression of tumors in animals.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B256.
Abstract C224: A novel validated quantitative pharmacodynamic topoisomerase I covalent-complex immunoassay
Authors: Pfister Thomas D. , Khin Sonny A. , Agama Keli , Hollingshead Melinda , Sooryakumar Dhriti , Pommier Yves , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H. , Kinders Robert J. 
Published: June 2012

Abstract
Topoisomerase I (Top1) is an established molecular target for anti-cancer therapeutics. Top1 inhibitors function by trapping the catalytic intermediate of Top1 covalently attached to the DNA substrate, termed the Top1 covalent complex (Top1cc). We have developed and validated an immunoassay to measure Top1cc directly, in support of Phase 0 clinical trials for experimental Top1 inhibiting drugs. A simple Top1cc isolation step which separates Top1cc from free Top1 is followed by a quantitative infrared immunoblotting detection technique. Recombinant Top1 is used as the standard for quantification. The assay was used to measure Top1cc in cell lines that exhibit varied growth inhibitory responsiveness to topotecan (A375, HCT-116, HT-29 and SKMEL28). Cells were treated with single doses of Top1 inhibitors, topotecan and indenoisoquinoline and Top1cc levels were found to be dose dependent with a maximal response at/or before 30 min to 1h of exposure. To establish fitness-for-purpose for clinical applications the assay was tested on samples of human tumor xenografts from mice treated with topotecan and indenoisoquinolines. These results demonstrate the potential to quantify Top1cc levels as a pharmacodynamic maker for Top1 inhibitors in solid tumor extracts. Funded by NCI Contract No. HHSN261200800001E.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C224.
Abstract C226: Clinical evidence of mechanism-based activity in voreloxin-treated AML patients
Authors: Conroy Andrew , Tan Nguyen , Wong Oi Kwan , Fox Judith A. , Hawtin Rachael E. 
Published: June 2012

Abstract
Voreloxin is a first-in-class anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II (Stockett et al. and Hawtin et al., AACR 2008). This leads to replication-dependent, site-selective DNA double strand breaks (DSB) targeting G/C-rich sequences that are characteristic sites of quinolone-induced DNA cleavage (Noble et al, 2003, Richter et al 2007, Stockett et al, AACR 2008). A consequence of this DNA damage is G2 arrest and cell death by apoptosis. Voreloxin is under clinical investigation in acute myeloid leukemia (AML) and ovarian cancer. Clinical responses have been observed in these indications (Lancet et al., ASCO 2009; Maris et al., ASCO 2009; McGuire et al., SGO 2008), as well as in NSCLC and SCLC (Burris et al., ECCO 2007).
The current analysis was performed in support of the ongoing phase 1b/2 study clinical study (SPO-0012) of voreloxin in combination with cytarabine in relapsed or refractory AML. The purposes were to; (1) characterize voreloxin-induced biomarkers of mechanism-based pharmacodynamic (PD) activity in cell lines and peripheral blood mononuclear cells (PBMC) from AML patients; (2) differentiate between the cellular PD DNA damage responses to voreloxin and cytarabine; (3) profile patient PBMC before and following the combination treatment with voreloxin and cytarabine in SPO-0012, to evaluate PD markers of cellular response; (4) investigate potential correlations between cellular PD markers of DNA damage and clinical outcome.
Based on our understanding of voreloxin's mechanism of action, pharmacodynamic (PD) markers of S phase delay, G2 arrest and DNA damage following treatment with voreloxin were profiled in cell lines and then evaluated in primary AML cells. These included markers of stalled replication forks (pRPA-32, pCHK1) and DNA DSB (DNA-PKcs, p53, and pCHK2). Cellular response to cytarabine was also characterized in these in vitro model systems. Cytarabine is a mainstay of treatment in AML, administered for 7 days per treatment cycle in combination with daunorubicin on days 1–3 (the “7+3” treatment schedule). Cytarabine is incorporated into DNA and causes inhibition of DNA polymerase resulting in decreased DNA synthesis and repair. DNA damage responses were observed with cytarabine, but these occurred later than with voreloxin treatment. Voreloxin induction of pDNA-PKcs and pCHK2 were chosen for PD assessments in the ongoing phase 1b/2 study of voreloxin in combination with cytarabine in relapsed or refractory AML. PBMC were purified from blood samples collected from patients at time points pre- and post-dosing. Upregulation of pDNA-PKcs and pCHK2 was detected within 2 hours post-dose, providing evidence of mechanism-based PD responses to voreloxin. Inconsistent quality of PBMC preparation at individual sites precluded correlation of PD response with clinical outcome.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C226.