bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B263: Mechanistic, functional, and in vivo efficacy of inhibiting ETK/BMX in cancer models
Authors: Gourley Eric S. , Liu Xiao-Hui , Hewitt William , Walker Rusty , Warner Steven L. , Vankayalapati Hariprasad , Bearss David J. 
Published: June 2012

Abstract
Epithelial and endothelial tyrosine kinase (ETK), also known as bone marrow tyrosine kinase gene in chromosome X (BMX), belongs to the Burton's Tyrosine Kinase (BTK) family. ETK is a nonreceptor tyrosine kinases involved in tumorigenicity, adhesion, motility, angiogenesis, proliferation, and differentiation. It is overexpressed in metastatic breast and prostate cancers and is implicated in the neuroendocrine transformation of prostate cells. Significant oncogenes such as Src, focal adhesion kinase (FAK), and phosphatidyl-inositol (PI)-3 kinase are upstream regulators of ETK while several hub proteins, also critical for cancer development and progression, such as AKT, STAT3, and p21 activated kinase 1 (PAK1), are downstream of ETK. Cell-based validation studies also demonstrate that inhibition of ETK diminishes cellular transformation, proliferation, and migration. Such evidence provides substantial reasoning for developing new small molecule inhibitors against ETK. Applying SuperGen's proprietary small molecule drug discovery process, CLIMB™ a series of lead compounds were effectively developed to potently and selectively inhibit ETK. Biochemical data from kinase screens against ETK demonstrated nanomolar potency of SuperGen's inhibitors and good selectivity toward ETK from a panel of 75 kinases. To mechanistically demonstrate ETK inhibition in cell-based models, immunoprecipitations were carried out and phospho-ETK levels were detected. These compounds exhibited a dose-dependent response against phospho-ETK. Functionally, the inhibition of ETK will produce changes in phospho-AKT (S473) levels as well as phospho-STAT3 (Y705) levels downstream of EGF stimulation. Using Luminex bead-based technology and western blot techniques respectively, SuperGen's lead ETK compounds also yielded concentration-dependent responses with EC50 values in the nanomolar region. Given ETK's reported angiogenic role in endothelial cell migration and proliferation, these compounds were evaluated in an in vitro tube formation assay. Likewise, these ETK inhibitors demonstrated potent nanomolar inhibition of endothelial tube formation. Finally, having shown mechanistically and functionally the efficacy of ETK inhibitors through in vitro assays, the compounds were tested with in vivo solid tumor efficacy models in nude mice. All five lead inhibitors effectively decreased tumor burden volume relative to the vehicle treatment group in an AN3CA xenograft model. Taken together, these data suggest SuperGen's small molecule ETK inhibitors represent a potentially new therapeutic avenue for treating patients with solid tumor malignancies in the future.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B263.
Abstract B265: A Phase 1 safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients (pts) with malignant glioma
Authors: Wen Patrick Y. , Omuro Antonio M. , Batchelor Tracy T. , Lai Albert , Mellinghoff Ingo K. , Nghiemphu Leia , Norden Andrew , Gendreau Steven B. , Laird A. Douglas , Nguyen Linh , Cloughesy Timothy 
Published: June 2012

Abstract
Methods: Pts with glioblastoma or anaplastic/mixed gliomas receive TMZ 200 mg/m2/day on Days 1–5, and XL765 qd in 28-day cycles. Pts must be on a maintenance TMZ dose of 200 mg/m2/day for at least one 28-day cycle prior to enrollment. Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed by the modified Macdonald criteria every 8 weeks.
Results: As of 24Aug2009, 15 pts (12 with glioblastoma, 2 with mixed glioma and 1 diagnosed with anaplastic oligodendroglioma) have been treated with XL765 in combination with TMZ across 3 dose levels of XL765 (30, 40, and 60 mg qd). The MAD has been identified as 60 mg for the once-daily schedule. Two of 6 pts at the 60 mg XL765 dose level experienced DLTs: one pt experienced DLTs of Grade 3 brain edema and Grade 4 thrombocytopenia (these events were also reported as related SAEs) and the other pt experienced a DLT of Grade 3 diffuse maculopapular rash. Three additional pts experienced SAEs that were not attributed to study treatment. With the exception of the DLTs described above, all AEs reported for 12 pts (as of 03Aug2009) were Grade 1 or Grade 2. Preliminary data suggest no PK interaction between XL765 and TMZ. XL765 PK when given in combination with TMZ are consistent with the PK of single-agent XL765 (Exelixis study XL765-001), and TMZ exposure in this study is similar to that published for single-agent TMZ. At the 30 and 40 mg qd XL765 dose levels, inhibition of PI3K pathway signaling has been demonstrated in paired skin biopsies using immunofluorescent analysis of pAKT-T308, pAKT-S473, and p4EBP1. Based on an initial molecular assessment of archival tumor material the most common molecular alterations detected included MGMT promoter methylation (5 of 12 evaluated pts), PTEN point mutations (8 of 14 evaluated pts), and EGFR gene amplification (7 of 11 evaluated pts). Of the first 12 pts that were enrolled, six pts have remained on study for at least 16 weeks, one of whom continues on study for 50+ weeks (a total of 78+ weeks following chemoradiation). Archival tumor tissue from this pt exhibited MGMT promoter methylation, PTEN mutation, and EGFR amplification.
Conclusions: XL765 in combination with TMZ is generally well tolerated at doses up to 40 mg qd. No apparent PK interaction between XL765 and TMZ has been observed.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B265.
Abstract B268: Tyrosine kinase profiling in head and neck cancer tumors in combination with clinical prognosis factors guides therapeutic combination strategies
Authors: Rodriguez-Barrueco Ruth , Ortiz-Ruiz Maria , Lopez-Castro Rafael , Cruz Juan Jesus , Ocana Alberto , Pandiella Atanasio 
Published: June 2012

Abstract
Background: Tyrosine kinases (TK) are a particular subgroup of proteins implicated in the genesis/progression of Squamous cell carcinoma of the head and neck (SCCHN). Therapeutic inhibition of several of them has shown to be clinically useful, as is the case of EGFR inhibition with the antibody cetuximab. Identification of the TKs activated in SCCHN is a must in order to adequately target these kinases with available inhibitors.
Methods: Here we have investigated activated tyrosine kinases in head and neck cancer tumors derived from patients using a human phospho protein array for 42 receptor tyrosine kinases (RTK). Clinicopathological parameters were reviewed from patient charts to associate activated kinases with prognosis. In vivo xenografted models were used to study the antiproliferative effect of the combination of specific TK inhibitors against them.
Results: TK receptors of the EGF and the VEGF family were the mostly activated in tumors derived from patients. EGFR/HER family receptors, such as HER3, were also activated (phosphorylated). These data were corroborated in SCCHN cell lines. In these cells, Akt and FAK kinases, other RTK signalling intermediates, were also activated. Combination of the anti-EGFR-HER2 TK inhibitor lapatinib with dasatinib (that targets FAK) was synergistic in vitro. Combination of lapatinib with the anti-VEGFR TK inhibitor pazopanib resulted in a better trend in response in the in vivo xenografted models.
Conclusions: Rational target drug combinations should be based on the identification of activated TK receptors or downstream signalling molecules in association with prognosis. Combination strategies using anti-EGFR/HER, anti-FAK, and anti-VEGFR compounds increases the action of individual treatments and should be considered when design rational clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B268.
Abstract B28: Selective antagonism of IAP proteins for regulating apoptosis and TNF pathways
Authors: Ndubaku Chudi 
Published: June 2012

Abstract
The inhibitor of apoptosis (IAP) proteins are important regulators of cancer cell survival, making them important targets for oncological intervention. There are eight known members of the IAP family of proteins. Using a combination of structure-based design and a merger of existing inhibitor motifs, we generated selective inhibitors that will interrogate the biological relevance of antagonism of XIAP and c-IAP1 and 2. The cellular biology of selective antagonism of these proteins will be presented.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B28.
Abstract B33: Prognostic role of Wnt/beta-catenin pathway in colorectal carcinoma
Authors: Stanczak Aleksandra , Stec Rafal , Bodnar Lubomir , Olszewski Wojciech , Ciechowicz Marzena , Kozlowski Wojciech , Szczylik Cezary , Lamparska-Przybysz Monika , Wieczorek Maciej 
Published: June 2012

Abstract
Introduction: Beta-catenin is a member of a cadherin-catenin complex mediating cell adhesion. It is also a key protein of Wnt/Beta-catenin pathway responsible for cell cycle and proliferation. This is important for initiation and progression of colorectal cancer. The aim of this study was to determine expression and localization of E-cadherin, Beta-catenin and Wnt-1 proteins in colorectal tumors.
Description: Forty-four unrelated patients with advanced colorectal carcinoma (CRC) were enrolled consecutively from CRC patients attending palliative care. Expression of Beta-catenin, E-cadherin and Wnt-1 was determined by immunohistochemistry on formalin-fixed, paraffin-embedded primary colorectal tissue. The expression was scored by two independent observers who had no knowledge of the clinical data. Correlation was measured with Spearman test, overall survival were analyzed with Kaplan-Meier method. Log-rank test was used for univariate analysis, while Cox regression model for multivariate analysis. A value of p &lt; 0,05 was considered significant.
Results: Decreased expression of membrane E-cadherin and Beta-catenin was observed in 34% and 27% of patients, respectively. Abnormal cytoplasmic E-cadherin was detected in 32% of cases and abnormal cytoplasmic and nuclear Beta-catenin was detected in 50% and 25% of patients, respectively. 60% of patients had decreased cytoplasmic Wnt-1 expression. Correlation was seen between cytoplasmic E-cadherin and cytoplasmic Beta-catenin (R 0,35; p=0,019). Nuclear localization of Betacatenin was correlated with localization of primary tumor (the highest expression in rectum) (R 0,48; p=0,001) and tumor size (R 0,32; p=0,035). Lower Wnt-1 expression was correlated with higher nodal stage (R -0,31; p=0,047). Nuclear Beta-catenin was an adverse prognostic factor in univariate analysis (log-rank test p=0,034) which was confirmed in multivariate analysis (HR 4,27 95% CI 1,70–10,72; p=0,002). Higher CEA serum level before treatment (HR 4,30 95% CI 1,35–13,66; p=0,013) and female sex (HR 2,75 95% CI 1,24–6,10; p=0,013) were also independent prognostic factors.
Conclusions: This finding supports that Beta-catenin is an independent prognostic factor for colorectal carcinoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B33.
Abstract B44: Survivin protein detection is a promising biomarker in the serum of gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients
Authors: Georgieva Inna , Hein Sibyll , Wang Yawen , Kiewe Philipp , Hopfenmüller Werner , Bläker Michael , Zeitz Martin , Grabowski Patricia 
Published: June 2012

Abstract
Background: The bifunctional protein survivin is a powerful prognostic marker in GEP-NET disease as measured by immunohistochemical methods in tumor tissues. The present study was focused to investigate if survivin can also be detected in the serum of GEP-NET patients and to evaluate its potential diagnostic role.
Aim: To establish a method by which the serum levels of survivin can be used as a predictive value in the treatment outcome of patients with GEP-NET disease.
Materials and Methods: In 2007, serum samples were obtained from patients with well-differentiated GEP-NET disease (n=22) either at Charité-Campus Benjamin Franklin (n=8) or at the University Hospital of Hamburg-Eppendorf (n=14), hematological malignancies (HM) and solid cancers (n=22), as well as healthy volunteers (n=25), the last all obtained at the Charité. All patients had given their informed consent to this pilot study. The patients of the GEP-NET group had either stable disease with metastasis, predominantly to the liver (n=14), or were progressive at the time of venipuncture (n=6). 9 foregut tumors, 10 midgut tumors and 3 hindgut tumors were included, a third of those functionally active. Most of the patients received any kind of bio- or chemotherapy. The mean age of GEP-NET patients was 61.1 years (range 29–81), whereas the mean age of patients with HM and solid tumors was 55.9 years (range 30–82). Enzyme-linked immunosorbent assay (ELISA) analysis was used for determination of survivin protein serum levels.
Results: There was a statistically significant increase of the survivin protein serum levels in patients with HM and solid cancers compared to the healthy controls (p=0.009). The difference in survivin serum levels between healthy controls and patients with GEP-NETs did not reach statistical significance (p=0.089). No correlation to clinical features like localization of the tumor, functional activity, Chromogranin A levels or kind of therapy was found. However, survivin serum levels tended to be higher in patients with a greater tumor burden.
Conclusion: This is the first study to quantify survivin protein levels in the serum of GEP-NET patients. The results of this small pilot study should be evaluated in further clinical trials by correlating survivin serum levels before and after therapy in order to define its potential diagnostic and prognostic use.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B44.
Abstract B49: FOLPI (picoplatin/5-fluorouracil/leucovorin) versus modified FOLFOX-6 as a neuropathy-sparing first-line therapy for colorectal cancer (CRC)
Authors: De Jager Robert , Cheporov Sergey , Gladkov Oleg , Biakhov Mikhail , Breitz Hazel , Earhart Robert 
Published: June 2012

Abstract
Introduction: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. FOLFOX (5-FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose-limiting oxali-related neurotoxicity. The incidence of grade (G) 3–4 neurotoxicity with single-agent Pico across studies was &lt;2%, suggesting that Pico may be a neuropathy-sparing alternative to oxali. The present randomized Phase 2 study evaluates Pico when administered Q4W with Q2W FU and LV (FOLPI) vs modified FOLFOX-6 (FOLFOX) as 1st line treatment for patients (pts) with advanced CRC.
Methods: Each pt with no prior chemotherapy for advanced CRC received LV and infusional FU per FOLFOX Q2W. Pts received Pico Q4W (150 mg/m2) or oxali Q2W (85 mg/m2). Tumor response was assessed by RECIST using CT scans. Adverse events (AEs) were assessed with CTCAE and neuropathy was evaluated using the FACT-Neurotoxicity questionnaire and by a neurologist blinded to treatment.
Results: 51 pts received FOLPI and 50 received FOLFOX. Platinum exposure was similar between treatment arms. With FOLFOX, the most frequent G 3/4 AEs were neutropenia (22%), neuropathy (16%) and thrombocytopenia (12%). With FOLPI, the most frequent G 3/4 AEs were neutropenia (57%), thrombocytopenia (43%) and anemia (22%). There was no G3/4 neuropathy on the FOLPI arm. FOLPI had significantly less neurotoxicity (G 2–4) than FOLFOX (p&lt;0.0002). One FOLPI pt had febrile neutropenia, was retreated and achieved a CR. No pt was discontinued due to bleeding. Hematologic support (neutrophil growth factors, platelet transfusions, RBC transfusions and erythropoietin) were 4%, 2%, 12% and 12% for FOLPI, and 0%, 0%, 6% and 4% for FOLFOX, respectively. Drug-related AEs resulting in study drug discontinuation occurred in 20% of pts on both FOLPI and FOLFOX: neuropathy (0%, 10%), hematology (14%, 6%) and increased creatinine (6%, 2%), respectively. Most pts discontinued study drug for progressive disease on both FOLPI and FOLFOX. On FOLPI there were 2 CR (4%) and 13 PR (25%). On FOLFOX there were 3 CR (6%) and 16 PR (32%). Disease control (CR+PR+SD) was 75% for FOLPI and 76% for FOLFOX. Median overall survival has not yet been determined; however, 12-month survival rates (95% CI) for FOLPI and FOLFOX are 52% (37–65%) and 55% (40–68%), respectively.
Conclusions: Neurotoxicity with FOLPI was less frequent and less severe compared to FOLFOX. Hematologic toxicity with FOLPI was manageable. FOLPI treatment of 1st line CRC had similar disease control and survival rates to FOLFOX supporting picoplatin as a potential neuropathy-sparing alternative to the use of oxaliplatin.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B49.
Abstract B5: ACE-041, a soluble activin receptor-like kinase-1 fusion protein, is a novel antiangiogenic agent
Authors: Mitchell Dianne , Pobre Eileen G. , Mulivor Aaron W. , Grinberg Asya V. , Castonguay Roselyne , Monnell Travis E. , Solban Nicolas , Ucran Jeff , Pearsall R. Scott , Underwood Kathryn W. , Seehra Jasbir , Kumar Ravindra 
Published: June 2012

Abstract
The therapeutic targeting of angiogenesis has been associated with clinical benefit for a number of tumors including colorectal carcinoma, non-small cell lung cancer, breast cancer, renal cell carcinoma and glioblastoma. Activin receptor-like kinase-1, an endothelium specific member of the TGFβ-type I receptor family, is believed to play a role in modulating angiogenesis. Homozygous inactivation of Alk1 in mice leads to embryonic lethality resulting from severe vascular abnormalities, while heterozygous mice exhibit chronic hemorrhaging and arteriovenous malformation similar to hereditary hemorrhagic telangiectasia-2 (HHT-2) patients harboring mutations in ALK1. To examine the potential of ALK1 inhibition as a novel anti-angiogenic therapy for cancer, we developed a soluble form of the ALK1 receptor (ACE-041) by fusing the extracellular region of human ALK1 to the Fc of human IgG1. ACE-041 was shown to bind only BMP-9 and BMP-10 out of 29 ligands tested in TGFβ family. ALK1 inhibition blocks SMAD 1/5/8 signaling and blocks in vitro cord formation of endothelial cells. ACE-041 inhibited in vivo blood vessel formation using Matrigel plug assay and chick chorioallantoic assay (CAM). Moreover, ACE-041 decreased tumor volume in a modified tumor CAM assay and in an orthotopic breast cancer model induced by MDA-MD-231 and MCF-7 mammary adenocarcinoma cells. These data suggest that ALK1 inhibition may be a promising therapeutic strategy for patients with breast and other solid tumors and support advancement of ACE-041 into clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B5.
Abstract B51: A phase I dose-escalation study of MGCD265 in patients with advanced malignancies (study 265-102)
Authors: LoRusso Patricia , Kurzrock Razelle , Weise Amy , Heath Elisabeth , Drouin Michel , Juretic Manuela , Maroun Christiane , Karam Andre , Mehran Mariam , Besterman Jeffrey , Martell Robert , Wheler Jennifer 
Published: June 2012

Abstract
Introduction: MethylGene has developed a small molecule inhibitor, MGCD265, that inhibits c-Met, Ron, all three members of VEGFR family and Tie-2, thereby inhibiting multiple pathways involved in tumor growth, metastasis and angiogenesis. The primary objectives of this study are to determine the maximum tolerated dose and the safety profile of MGCD265 administered with interruption to patients with advanced malignancies.
Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered once daily on a 1 week on/1 week off schedule of each 28-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity was observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia, grade 4 thrombocytopenia, any ≥ grade 3 nonhematologic toxicity, severe/sustained hypertension or any toxic effect leading to a patient missing ≥ 4 doses of MGCD265. Treatment continued until disease progression or toxicity. Response, as a secondary objective, was assessed every 2 cycles by RECIST criteria.
Results: Twenty patients (20) have been recruited to date: 4 patients in cohort 24 mg/m2; 4 patients in cohort 48 mg/m2; 3 patients in cohort 96 mg/m2; 3 patients in cohort 192 mg/m2; 3 patients in cohort 255 mg/m2; and 3 patients in cohort 340 mg/m2. The overall age range is 40 to 72 years and the gender distribution among the cohorts is 13 female to 7 male patients. No DLTs have been observed to date but grade 2 adverse events (AE) considered at least possibly related to the treatment included diarrhea (n=2), nausea (n=1) and intermittent dizziness (n=1). No grade 3 or higher drug-related AE have been reported. To date, 5 patients have experienced stable disease per RECIST. One patient with a sarcomatoid bladder cancer (dosed at 96 mg/m2), who was progressing prior to study entry, has been treated for 12 cycles. An archived biopsy obtained prior to MGCD265 treatment from this patient shows c-Met expression and autophosphorylation. One patient with medullary thyroid cancer experienced tumor shrinkage (−10%).
Conclusions: To date, intermittent administration of MGCD265 was found to be well tolerated with preliminary signs of activity. Recruitment of additional cohorts is underway.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B51.