bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B52: Phase 1 study of XMT-1001, a novel water soluble camptothecin conjugate, given as an intravenous infusion once every three weeks to patients with advanced solid tumors
Authors: Sausville Edward A. , Garbo Lawrence , Weiss Glen J. , Shkolny Dana , Yurkovetskiy Alexander V. , Bethune Claudette , Ramanathan Ramesh K. , Fram Robert J. 
Published: June 2012

Abstract
Introduction: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro-drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 has an improved therapeutic window compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development.
Methods: This is an open label, dose escalation study of XMT-1001 given as an IV infusion once every 3 weeks. The objectives of the Phase 1 study are to determine the maximum tolerated dose (MTD) and to assess safety and pharmacokinetics (PK) of XMT-1001. Initially 3 patients (pts) are entered at each dose level, with expansion to 6 pts if there is a dose limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT.
Results: Forty six patients with refractory solid tumors have received 141 cycles of XMT-1001 at 13 dose levels ranging from 1.0–64.2 mg CPT equivalents (equiv.)/m2. Two pts had Grade (Gr) 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. Upon introduction of new clinical trial material with an improved formulation, no infusion reactions suggestive of hypersensitivity have occurred (25 pts, 79 cycles). No hemorraghic cystitis or ≥ Gr 3 diarrhea was noted. Gr 2 neutropenia occurred in 1 pt treated at 15.4 mg CPT equiv./m2. Stable disease was observed in 12 of 43 evaluable pts with the following tumor types and dose levels expressed in mg CPT equiv./m2: NSCLC (1.0 mg/m2, 6 wks; 20.5 mg/m2, 30 wks to date; 36.3 mg/m2, 18 wks to date), nasopharyngeal (36.3 mg/m2, 12 wks to date), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6mg/m2, 6 wks), colon (15.4 mg/m2, 18 wks), gastric (20.5 mg/m2, 12 wks), and rectal (27.3mg/m2, 6 wks). The PK of XMT-1001 (conjugated CPT) demonstrates dose proportional increases in exposure XMT-1001 and confirms the formation of its expected release products. Levels of free CPT in urine have been low.
Conclusions: 1. XMT-1001 can be given safely to patients; 2. XMT-1001 has a favorable PK profile; 3. Prolonged stable disease lasting ≥ 12 weeks was seen in 9 patients with advanced, refractory tumors at doses below MTD.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B52.
Abstract B6: A phase II study of the efficacy and safety of foretinib, a novel receptor tyrosine kinase inhibitor, given on an intermittent 5-days-on/9-days-off (5/9) schedule in patients with recurrent or metastatic squamous cell cancer of the head and neck
Authors: Seiwert Tanguy , Swann Suzanne , Kurz Hazel , Bonate Peter , McCallum Stewart , Sarantopoulos John 
Published: June 2012

Abstract
Foretinib (also known as GSK1363089 and XL880) is a small-molecule, spectrum-specific receptor tyrosine kinase inhibitor, with potent activity against MET, VEGFR2, and multiple additional tyrosine kinases with tumor growth-promoting and angiogenic properties. Antitumor activity has been observed in 2 previous phase I studies. This phase II study was conducted to evaluate responses in squamous cell cancer of the head and neck (SCCHN).
An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted, with a total of 41 patients to be enrolled in the study. One or more responses in the first 14 subjects were required to progress to the second stage. Foretinib was administered as a 240-mg oral dose once daily on days 1–5 of a 14-day cycle to subjects with recurrent and/or metastatic SCCHN. Other eligibility requirements included measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 1 or 0, and no history of uncontrolled tumor bleeding. Exclusions included more than 1 prior therapy for recurrent or metastatic disease, history of brain metastasis, and rapid progression within 6 months after curative-intent therapy for local/loco-regional disease. Endpoints were objective response rate, safety, duration of response, progression-free survival (PFS), overall survival (OS), and characterization of the pharmacokinetics. Tumor volume was assessed every 8 weeks by Response Evaluation Criteria in Solid Tumors.
This study did not meet the predefined criteria for continuing to the second stage. Response and safety data are available for 14 patients with a data cut off date of July 24 2009 (median age = 59.0; males/female = 13/1: ECOG PS 0/1 = 9/5 patients). A maximum of 30 cycles was administered (median = 4.5). The most common reason for withdrawal was progressive disease. Treatment-emergent adverse events occurring in &gt;25% of individuals included (# [%]): fatigue (7 [50%]), constipation (5 [36%]), hypertension (5 [36%]), anorexia (4 [29%]), dysphagia (4 [29%]), weight loss (4 [29%]), increased alanine transaminase (4 [29%]), increased aspartate transaminase (4 [29%]), dyspnea (4 [29%]), headache (4 [29%]), and mucosal inflammation (4 [29%]). Investigator-assessed median PFS (95% confidence interval) was 3.65 (3.42, 5.32) months; median OS was 5.59 (3.71, not reported) months. The best overall response was stable disease (SD), with a median duration of 4.11 (3.65–13.86) months.
Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best observed response. The safety and efficacy results support further investigation in combination with other targeted agents or cytotoxic chemotherapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B6.
Abstract B64: Gene expression profile of a liposarcoma mixoid cell line selected in vitro for resistance to Trabectedin
Authors: Marchini Sergio M. , Bernasconi Sergio , Erba Eugenio , Uboldi Sarah , Clivio Luca , Chiorino Giovanna , Santarsier Annapaola , Fuso Ilara , Marangon Elena , Sala Federica , Galmarini Carlos , Tercero Juan Carlos , Mantovani Roberto , D'Incalci Maurizio 
Published: June 2012

Abstract
Introduction: Trabectedin is a marine alkaloid originally isolated from Ecteinascidia turbinata approved in Europe for the second line of therapy in soft tissue sarcomas (STS). Here we characterize and compare the gene expression profile of 402-91/ET Res liposarcoma cells obtained after continuous exposure to trabectedin in vitro with that of their parental cell line 402-91.
Methods: Drug sensitivity was measured by colony assay and Flow Cytometric analysis was used to analyze cell cycle perturbations. Microarray analysis between sensitive and 402-91/ET Res cells was performed using commercially available arrays onto which 44K oligos were pre-spotted. Gene expression analysis was performed with “R” package software. Pathway analysis was performed using Metacore software. qRT-PCR was used for data validation. Statistical analysis was performed using Graphpad software.
Results: 402-91/ET Res cells were selected in vitro for their stable resistance to trabectedin by step-wise increase in the drug concentration (25 nM) lasting 14 months. Resistance to Trabectedin was stable over 22 months without compound exposure. Cells were cross resistant to melphalan, but more sensitive to taxanes, vinblastine, temozolomide and UV rays. Resistance was not associated to the expression of MDR proteins as well as different uptake/efflux. Cell cycle analysis revealed that trabectedin is able to induce a G2-M block in the sensitive cell line but not in the resistant one. The expression levels of the FUS-CHOP gene were comparable between the 402-91 and 402-91/ET Res cells but with a different trans-activation ability. Microarray analysis identified 511 probes set able to discriminate between sensitive and resistant cell lines. Pathway analysis revealed that most of the genes altered in the 402-91/ET Res cells were associated with liposarcoma phenotype and functionally involved in the CREB pathway as well as control of apoptosis.
Conclusion: Data suggests that in the 402-91/ET Res cells FUS-CHOP trans-activation activity has been impaired. Studies are in progress to address whether these mechanisms are implicated in sensitivity of liposarcoma cell lines to trabectedin.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B64.
Abstract B65: Overexpression of MRP4 or MRP5 confers resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine
Authors: Adema Auke D. , Floor Karijn , Smid Kees , Honeywell Richard J. , Peters Godefridus J. 
Published: June 2012

Abstract
Multidrug resistance proteins (MRP) confer resistance to drugs from different classes. MRP4 and MRP5 are related MRP proteins and can transport organic anions. Hence their overexpression has been associated with resistance to several purine analogs, such as 6-mercaptopurine and adefovir (PMEA; 9′-(2′-phosphonylmethoxyethyl)adenine)), and antifolates, such as methotrexate (MTX). 6MP itself is not a substrate for MRP4 and 5, but its monophosphate is, in contrast to the di- (DP) and triphosphates (TP). Similarly MTX (a monoglutamate) is a substrate for various MRPs but the higher glutamates are usually not. Resistance to MTX was not observed at a long exposure because of accumulation of polyglutamates, but a 4-hr exposure to MTX conferred resistance. The aim of this study was to investigate whether MRP4 and 5 overexpression would confer resistance to the widely used nucleoside analogs cytarabine (ara-C) and gemcitabine (GEM), and the novel L-nucleoside analog Troxacitabine (TROX). As model systems we used HEK293 cells transfected with either MRP4 (HEK/MRP4; 59-fold increased MRP4 level) or MRP5 (HEK/MRP5i; 991-fold increased MRP5 level) and determined sensitivity after an exposure for 4 hr (followed by 68 hr drug-free medium) and 72 hr. Uptake and accumulation of GEM and TROX were measured with HPLC coupled to either UV or MS-MS, that of ara-C with the radioactive drug. HEK293 cells were moderately sensitive to ara-C (IC50 1.8 µM) and TROX (2.1 µM) and more sensitive to GEM (46 nM) at 72 hr exposure. At 4 hr exposure, the IC50s increased 5-, 5- and 10-fold, respectively. At 4 and 72 hr exposure a 2-3-fold resistance to TROX and ara-C was found in HEK/MRP4 cells, and a 2.5-fold resistance to ara-C in HEK/MRP5 cells. No resistance to GEM was found. PMEA showed a 3-fold resistance in both cell lines. Resistance in the MRP4/5 cells could be reversed by the specific inhibitors probenecid and indomethacine. In order to explain this resistance, accumulation and retention of the active nucleotides were evaluated. GEM-TP even tended to be higher in the MRP4/5 cells. However, accumulation of ara-C nucleotides after 4 hr was 3- and 2-fold lower in MRP4 and MRP5 cells, respectively. After washing with drug-free medium (DFM), the concentration of ara-CTP declined more rapidly in MRP4 compared to the wild-type. Although TROX accumulation was similar in the 3 cell lines, in MRP4 and MRP5 cells it decreased 4- and 2-fold faster, respectively, after the DFM period. TROX-phosphates were about 25% lower in MRP4/5 cells and decreased rapidly in MRP4, but not in MRP5 cells. In conclusion, MRP4 and MRP5 overexpression confer resistance to TROX and ara-C, but not to GEM, which was associated with a rapid decline of the ara-C and TROX-nucleotides in HEK/MRP4-5 cells.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B65.
Abstract B66: Resistance to bortezomib in myeloma cell lines is mediated by increased IGF-1/Akt signaling to activate Cot kinase and NF-κB
Authors: Kuhn Deborah J. , Bjorklund Chad C. , Orlowski Robert Z. 
Published: June 2012

Abstract
Background: Targeting the proteasome as an anti-cancer therapy was first realized with bortezomib, now one of the standards used in relapsed/refractory multiple myeloma and mantle cell lymphoma. Despite this advance, response rates have been as low as 23%, indicating the importance of innate or acquired resistance to bortezomib.
Methods: To improve our understanding of the mechanisms responsible for bortezomib resistance, we developed cell line models of interleukin (IL)-6-dependent (ANBL-6 and KAS-6/1) and -independent (RPMI 8226 and OPM-2) bortezomib-resistant (BR) myeloma by continuously exposing drug-naïve cells to increasing bortezomib concentrations. All of the lines where characterized by gene expression profiling to identify potential mechanisms of resistance.
Results: Cell lines resistant to bortezomib retained their viability in the presence of 50 nM or more of bortezomib with degrees of resistance up to 4.3. Gene expression profiling revealed up-regulation of insulin-like growth factor (IGF)-1 transcripts (5.2-fold), Akt (3.2-fold), and cancer Osaka thyroid (Cot) kinase (2.3-fold). Consistent with our profiling data, BR clones had increased soluble IGF-1 levels, increased IGF-1 protein, and phospho-IGF-1R activation. Next we examined the effect of overexpression of Cot on BR clones. Cot functions to regulate nuclear factor kappa B (NF-κB)-dependent transcription in response to Akt by promoting post-translational processing of inactive NF-κB p105 to active p50. Basel levels of nuclear activated p50 were increased up to 4.7-fold in BR clones. Activated NF-κB dimers were also found to be significantly increased in ANBL-6.BR and 8226.BR cells as evidenced by phosphorylation of p65 (RelB). Our examination into Cot expression in drug-naive and BR cells showed a large increase of Cot protein and phospho-Cot (Thr290) activation in 8226.BR cells that was enhanced with 24-hour bortezomib treatment. A transcriptional target of NF-κB is Bcl-2 was also found to be increased in profiling studies (5.5-fold) and correlates with increased expression in BR cell lines tested. Treatment with 10 nM bortezomib for 6 hours led to a decreased in Bcl-2 protein both drug-naïve and drug-resistant cells. A decrease in Bcl-2 protein was also observed in ANBL-6.BR, RPMI 8226.BR, and OPM-2.BR cells in response to 24-hour treatment with picropodophyllin, a pharmacologic inhibitor of IGF-1R activation, consistent with the hypothesis that the IGF-1/Akt signaling axis in important in Bcl-2 protein expression in bortezomib-resistant clones.
Conclusions: Our data support the hypothesis that increased signaling through the IGF-1/Akt axis and enhanced expression of Cot kinase is another mechanism that mediates stable bortezomib resistance in vitro through the activation of NF-κB and its downstream transcriptional targets, including Bcl-2.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B66.
Abstract B73: Lapatinib-mediated radiosensitization of EGFR+/basal breast cancer correlates withERK inhibition in vivo and requires MEK/ERK inhibition in vitro
Authors: Sambade Maria J. , Kimple Randall J. , Camp Terese , Peters Eldon , Livasy Chad A. , Sartor Carolyn I. , Shields Janiel M. 
Published: June 2012

Abstract
To determine whether the dual EGFR/HER2 kinase inhibitor lapatinib can radiosensitize EGFR+ breast cancer in vivo, mice bearing xenografts of basal-like/EGFR+ SUM149 breast cancer cells were treated with lapatinib and fractionated radiation therapy over a 10 d period and tumor growth inhibition determined and correlated with changes in activation of downstream signaling to ERK1/2 and AKT by immunohistochemistry. Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib + radiation exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.06 over the duration of the study. Immunohistochemical analysis demonstrated that radiosensitization by lapatinib correlated with inhibition of ERK1/2 but not AKT. In vitro analysis of other basal breast cancers consistently demonstrated a loss of radiation induced MEK1/2 inhibition with lapatinib treatment. Treatment of the SUM102 basal-like/EGFR+ cell line with the MEK inhibitor CI1040 resulted in radiosensitization at levels similar to that seen with lapatinib alone. Furthermore, constitutive activation of RAF in SUM102 cells abolished the ability of lapatinib to radiosensitize these cells and resulted in enhanced radioresistance relative to parental cells. Collectively, this work demonstrates that lapatinib radiosensitizes EGFR+/basal-like breast cancer both in vitro and in vivo in a MEK/ERK dependent manner, and suggests that lapatinib in combination with fractionated radiation therapy may provide an effective treatment option for breast cancers of this subtype.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B73.
Abstract B77: Erk phosphorylation predicts synergism between gemcitabine and EGFR inhibitor AG1478
Authors: Peter Luk P. , Links Matthew J. , Galettis Peter 
Published: June 2012

Abstract
Clinical trials combining epidermal growth factor receptor (EGFR) inhibitors with gemcitabine-based chemotherapy in non-small cell lung cancer (NSCLC) have not produced a survival advantage. This may be caused by antagonism between the two drugs or mutations that promote such, possibly KRAS mutation. It has been hypothesised that this antagonism relates to G1 arrest caused by EGFR inhibition. This study aimed to explore the relationship between synergy/antagonism, G1 arrest and phospho-ERK, as a measure of mitogen-activated protein kinase (MAPK) inhibition. Two NSCLC cell lines, A549 (mutant KRAS) and H322 (wildtype KRAS), were treated with gemcitabine and the EGFR inhibitor AG1478 alone and concurrently. Cytotoxicity was assessed using SRB assay and cytotoxic interaction was calculated using median effect analysis. Cell cycle distribution was assessed using flow cytometry and ERK phosphorylation was determined by ELISA. Cytotoxic interaction between gemcitabine and AG1478 were dose dependent with antagonism at high dose AG1478, particularly in the KRAS mutant cell line. Under conditions in which gemcitabine caused S phase arrest, antagonism was related to the G1 arrest effects of AG1478. However, synergy was also observed in the presence of gemcitabine-induced g1 arrest. Furthermore, gemcitabine increased ERK phosphorylation, the suppression of which by AG1478 was related to antagonism particularly in KRAS wildtype cell line. In the KRAS mutant cell line, synergy/antagonism was observed without a changed in phosphorylation of ERK. Our findings are consistent with a model in which gemcitabine causes cell cycle arrest and increased ERK phosphorylation. Low dose AG1478 is synergistic possibly due to suppression of EGFR-related survival signals. However, anti-proliferative effect of high dose AG1478 is antagonistic as it interferes with gemcitabine-induced cell cycle arrest as well as reduces ERK phosphorylation, which may be an important death signal. This data confirms the importance of EGFR inhibition-related G1 arrest in antatogism but also identifies that synergy can still occur in the presence of G1 arrest and highlights an important potential role for phospho-ERK in determining cell death. In summary, this study suggests that ERK phosphorylation is more predictive of synergism/antagonism than cell cycle changes when gemcitabine is combined with an EGFR inhibitor.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B77.
Abstract B81: AUY922, a heat shock protein 90 inhibitor, actively inhibits human gastric cancer cells via down regulation of growth factor receptors, and acts synergistically with relevant chemotherapeutic agents
Authors: Yeh Kun-Huei , Gao Chiu-Hua , Lin Yu-Lin , Cheng Ann-Lii 
Published: June 2012

Abstract
Heat shock protein 90 (Hsp90) is the most abundant cellular chaperone and has nearly 100 pivotal client proteins, which are commonly dysregulated in cancers. The positive rate of Hsp90beta in gastric cancer tissue was approximately 30%, and was higher than non-cancerous gastric mucosa. Hsp90 inhibitors should have great potentials in the exploration for treatment strategy in gastric cancer (GC).
AUY922, kindly provided by Novartis Pharma AG, is a novel resorcinylic isoxazole amide Hsp90 inhibitor. A panel of human GC cell lines (N87, AGS, SNU-1, SNU-16, KATO-III from ATCC) was used in this study. Using 72-hour MTT colorimetric assay, we demonstrated that AUY922 has highly active growth inhibitory effects as a single agent of IC50 in the ranges between 8.1 ± 0.2 and 14.7 ± 0.8 nM (except the c-met-overexpressing KATO-III cells with a IC50 of 158.1 ± 5.1 nM), which is more active than 17-AAG (17-allylamino-17-demethoxygeldanamycin) and 17-DMAG (17-dimethylaminoethyl-amino-17-demethoxygeldanamycin) of IC50 between 17.2 ± 0.6 and 61.3 ± 1.9 nM, and IC50 between 10.5 ± 0.5 and 24.3 ± 1.0 nM, respectively. By MTT colorimetric assay and median effect analysis, AUY922 has significant synergistic cytotoxicity with cisplatin, oxaliplatin, 5-fluorouracil (5-FU), and irinotecan, while acts antagonistically with paclitaxel and docetaxel in GC cells.
Several important growth factor receptors are highly expressed in GC, namely 50-60% of EGFR (epidermal growth factor receptor, HER1), 15–22% of HER-2/neu, and 32–58% of c-met (hepatocyte growth factor receptor, HGF receptor), respectively. By immunoblotting analysis, AUY922 effectively down-regulates growth factor receptors (c-met, EGFR, and HER-2/neu) with a concentration of 25nM, 25nM, and 125nM in KATO-III GC cells, respectively. The c-met-overexpressing KATO-III cells are highly resistant to AUY922. In KATO-III cells, knocking-down of c-met by siRNA, then examining by 48-hour MTT colorimetric assay may partly abrogate the AUY922 resistance and increase sensitivity to AUY922 by decreasing IC50 from 790.0 ± 10.6 nM to 350.8 ± 5.4 nM.
Our data indicate that AUY922 actively inhibits human GC cells via down regulation of growth factor receptors, and acts synergistically with various relevant chemotherapeutic agents. It is reasonable to use AUY922 alone, or to combine AUY922 with relevant chemotherapeutic agents (cisplatin, oxaliplatin, 5-FU, or irinotecan) in future development of clinical trials for gastric cancers.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B81.