bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B261: A novel small molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vivo
Authors: Ireson Christopher R. , Jamieson Stephen , Stribbling Stephen , Sutherland Rachel , Raynham Tony , Williams Juliet , Charles Mark , Bagherzadeh Azadeh , Farooq Muddasar , Harikumar Kuzhuvelil B. , Kunnumakkara Ajaikumar B. , Deorukhkar Amit , Tong Zhimin , Maru Dipen , Diagaradjane Parmeswaran , Matsuo Yoichi , Krishnan Sunul , Gelovani Juri , Aggarwal Bharat , Guha Sushovan 
Published: June 2012

Abstract
Background: Protein kinase D (PKD) is a novel family of serine-threonine kinase with diverse biological functions including cell proliferation and growth. Pancreatic Cancer (PaCa) is a devastating disease with few therapeutic options. We showed earlier that PKD signaling pathways promote mitogenesis in multiple PaCa cell lines. However, nothing is known about targeting biological functions of PKD in PaCa. Our PKD inhibitor discovery program yielded CRT0066101 that specifically blocks PKD activation.
Aim: The aim of our study was to determine the effects of CRT0066101 in PaCa, both in vitro and in vivo.
Methods and Results: Our immunohistochemical analysis showed that activated PKD (pS916PKD1) is significantly upregulated in PaCa as compared to normal ducts (91% vs 22%; p&lt;0.001). Using Panc-1 as a model system, we demonstrated that CRT0066101 blocked proliferation and BrdU incorporation with an IC50 of 1 µM. We showed that CRT0066101 given orally (80 mg/kg/day) for 4 weeks significantly abrogated growth in a subcutaneous Panc-1 xenograft model (n=8; p&lt;0.01). The expression of activated PKD (pS916PKD1) in the treated tumor explants was significantly inhibited (p&lt;0.05) with peak concentration (12 M) of CRT0066101 achieved within 6 hours of oral administration. Further, we showed that CRT0066101 given orally (80 mg/kg/day) for 21 days in an orthotopic model potently blocked Panc-1 tumor growth (n=7; p&lt;0.01). CRT0066101 significantly reduced Ki-67+ proliferation index (p&lt; 0.01), increased apoptosis (measured by in situ TUNEL assay) of PaCa tumors (p&lt;0.05) and potently abrogated expression of multiple proliferative and pro-survival proteins including Cyclin D1, survivin, Bcl-2, Bcl-xL, activated PKD1 (pS916PKD1), and activated PKD2 (pS876PKD2).
Conclusion: Our results demonstrate for the first time that the PKD-specific small molecule inhibitor CRT0066101 blocks PaCa growth both in vitro and in vivo. Thus, PKD is a novel therapeutic target in PaCa.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B261.
Abstract B273: A phase I trial of topotecan and sorafenib for patients with recurrent, platinum-resistant epithelial ovarian cancer
Authors: Matei Daniela E. , Schilder Jeanne , Perkins Susan , Khan Mohammad , Calley Cynthia , Menning Nancy , Sutton Gregory 
Published: June 2012

Abstract
Background: The objectives of the study were to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and objective response rate to combination therapy with sorafenib and topotecan in patients with platinum resistant epithelial ovarian cancer (EOC).
Methods: This multi-institutional phase I trial used a fixed dose of weekly topotecan and escalating doses of sorafenib. Eligible patients had recurrent platinum-resistant EOC, measurable or detectable disease, and up to three prior cytotoxic treatments. Prior anti-angiogenic therapy was not allowed. Sorafenib was administered orally daily and topotecan was given iv weekly at a fixed dose of 4 mg/m2, 3 weeks on and 1 week off. Each treatment cycle was 28 days. A standard 3 + 3 dose escalation design was used, testing two sorafenib dose levels: 400 mg daily (level 1) and 800 mg daily (level 2). The topotecan dose was de-escalated to dose level −1 (3.5mg/m2 weekly). The primary endpoints of the phase I study were to determine the MTD and the toxicity profile of this combination.
Results: 16 patients were enrolled between 12/12/07 and 11/13/08. Median number of prior regimens was 2 (range 1–7), median age was 52.5 (range 41–66), and all 16 patients had EOC. Distribution of patients per dose level and DLTs encountered are summarized in the table below. Five patients were inevaluable because of intercurrent illness or withdrawal of consent. Grade 3–4 toxicities during cycle 1 included: thrombocytopenia (3), neutropenia (2), febrile neutropenia (1), nausea and vomiting (2), rash (2), abdominal pain (1) and abnormal liver function tests (1). Grade 3–4 toxicities occurring after cycle 1 included: neutropenia (2), thrombocytopenia (1), anemia (2), nausea and vomiting (1), anorexia (1), and insomnia (1). Clinical activity was an exploratory endpoint. There was 1 partial response by RECIST lasting for over 12 months, but no complete responses. Six patients had stable disease.
Conclusions: Sorafenib can be safely combined with topotecan in EOC patients. The dose recommended for phase II investigation is sorafenib 400mg daily with topotecan 3.5 mg/m2 weekly.
Toxicities during dose escalation Topotecan dose (mg/m2) Sorafenic dose (mg) No patients No patients DLT/Decision DLT/Decision 4 400 6 2; not tolerated 3.5 400 4 0, tolerated, phase 2 3.5 800 6 2, not tolerated
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B273.
Abstract B43: Determination of biomarkers responsible for sensitivity and resistance of RGB-286638 action in vitro
Authors: Loferer Hannes , Amon Peter , Ivanov Igor 
Published: June 2012

Abstract
Understanding of molecular markers responsible for activity/resistance profiles of anti-cancer agents is essential for successful drug development. Here we demonstrate an approach to identify genes selectively regulated in either sensitive or resistant cell lines following treatment with RGB-286638, a multi-targeted protein kinase inhibitor currently in Phase I development. In order to assess whether the experimental conditions for in-vitro treatment of cancer cell lines with RGB-286638 used in this study resembles the mouse in-vivo situation, we adopted an in vitro assay based on the time growth curve rather than dose response curve. We found that the time growth curves were very similar to “standard” tumor growth curves observed in the mouse xenograft models. Next, a range of concentrations (25–100 nM of RGB-286638) was selected in which the shape of the in vitro growth curves closely resembled the shape of the in vivo growth curves. In addition to the similarity of growth curves, the pharmacodynamic markers PARP cleavage and RB-phosphorylation were used to confirm similarity of responses observed in xenograft models and in vitro cell culture. Using eight concentrations within the selected range and 6 cell lines with different responsiveness to RGB-286638, we analyzed gene expression profiles following RGB-286638 treatment for 24 hours. We could identify genes that were specifically deregulated in sensitive or resistant cells. In addition, some genes were down-regulated upon treatment independent of responsiveness of the cell lines to RGB-286638 treatment. Surprisingly, some of these genes are involved in cell cycle, e.g. regulation of cyclin B1, and were previously considered as pharmacodynamic markers but now appear to be nonspecific for the action of RGB-286638.
These results facilitate the selection of relevant biomarkers and can provide a rational for future combination studies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B43.
Abstract B46: Collagen XXIII: A biomarker for non-small cell lung cancer
Authors: Spivey Kristin A. , Banyard Jacqueline , Solis Luisa M. , Wistuba Ignacio I. , Barletta Justine A. , Gandhi Leena , Feldman Henry A. , Rodig Scott J. , Chirieac Lucian R. , Zetter Bruce R. 
Published: June 2012

Abstract
Purpose: To determine the protein expression of collagen XXIII in tumor tissues from a variety of cancers and in tumor tissues and urine samples from non-small cell lung cancer (NSCLC) patients and to assess collagen XXIII's utility as a biomarker for NSCLC.
Experimental Design: A multi-cancer tissue microarray (TMA) was used to immunohistologically examine collagen XXIII protein expression in a variety of cancers. Subsequently, collagen XXIII expression was analyzed in three separate cohorts using TMAs with representative tumor and normal control lung tissues from patients with NSCLC. In addition, urine samples from NSCLC patients were analyzed for the presence of collagen XXIII via Western blot.
Results: Collagen XXIII staining was present in tissue samples from a variety of cancers. Within lung cancer tissues, collagen XXIII staining was enriched in the NSCLC subtypes. Tissues from 296 of 335 (81%) lung adenocarcinoma and 99 of 135 (73%) squamous cell carcinoma (SqCC) patients had detectable collagen XXIII. In urine, collagen XXIII was present in 23 of 29 (79%) NSCLC patient samples and only 15 of 54 (28%) of control samples. There was a significant association between collagen XXIII positivity in tissue or urine and presence of NSCLC (p&lt;0.001, Fisher's exact test).
Conclusions: We demonstrate that collagen XXIII staining is increased in a variety of carcinomas. Specifically, collagen XXIII is expressed in a large subset of NSCLC patient tissue and urine samples, suggesting its utility as a potential NSCLC biomarker.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B46.
Abstract B58: Decreasing the time to activate clinical trials: Initial data from the Multiple Myeloma Research Consortium (MMRC) model
Authors: Wear Sandra , Kelley Susan , Quinn-Young Anne , Lonial Sagar , Kumar Shaji , Jakubowiak Andzej , Anderson Kenneth 
Published: June 2012

Abstract
Background: Activation of oncology trials is a lengthy and complex process. Recent literature has identified numerous opportunities to improve activation timelines1, 2. The Multiple Myeloma Research Consortium (MMRC) has implemented several processes to identify and overcome myeloma clinical trial activation barriers within the consortium network of 14 North American cancer centers. We examined the impact of these processes preand post- implementation and also compared activation times with published clinical trial metrics data.
Methods/Results: 12 MMRC-facilitated trials had sufficient trial data available for review within the study period of May 2006 to March 2009. Activation time was defined as the time from a center's receipt of the final clinical trial protocol from the sponsor, to the time the first patient was enrolled into a trial at any MMRC participating center. The earlier group (EG) of MMRC trials (n=7) required a mean of 257 calendar days for activation, comparable to the mean published data of 251 calendar days1. The more recent group (RG) of MMRC trials (n=5) required a mean of 158 calendar days for activation, representing a 38% shortening of activation time. Additionally, implementation of standardized processes and rigorous project management resulted in a reduction in activation times for all MMRC centers in a given trial from a mean of 7.5 months to a mean of 5.1 months. Improving the mean time of several several specific steps in the process including time to initial protocol review submission from receipt (EG=37 vs. RG=19 days), scientific review committee time (EG=98 vs. RG=55 days), and the time from trial opening to first patient dosed (EG=74 vs. RG=27 days) contributed to the overall decrease in activation times. The EG metrics data are comparable to published data1 for each process step.
Conclusion: The MMRC member institutions have seen substantial improvements in trial activation times and are in the process of implementing additional processes to further improve protocol development and trial conduct metrics. The efficiencies and process improvements realized from application of rigorous MMRC project management resources and the standardization of contracting and other key activities may be applied in other areas of oncology clinical trials beyond multiple myeloma. With increasing numbers of new oncology agents to be evaluated and greater pressure on trial sponsors to introduce efficiencies into trial timelines, overcoming such barriers is of critical importance.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B58.
Abstract B79: Antitumor activity of lapatinib as a single agent and in combination with capecitabine in a HER2-amplified human gastric tumor model
Authors: Liu Li , Avrutskaya Anna , Godfrey Beverly , Britt Carmella C. , Meshaw Alan , Mullin Robert J. , Gilmer Tona 
Published: June 2012

Abstract
HER2 has been reported to be amplified or over-expressed in approximately 20% of gastric tumors and is an attractive target for treatment of gastric cancer. Lapatinib, a potent, oral, small-molecule, dual inhibitor of EGFR and HER2 tyrosine kinases, is approved in combination with capecitabine for the treatment of advanced HER2-positive metastatic breast cancer. It inhibits the phosphorylation of EGFR, HER2, HER3, down stream signaling pathways, and cell growth in HER2-amplified gastric tumor cells in vitro. The preclinical in vivo efficacy of lapatinib monotherapy and the combination of lapatinib with capecitabine, an oral prodrug of 5-fluorouracil was evaluated in the HER2-amplified N87 gastric xenograft model established in female SCID mice. Anti-tumor activities were determined from analyses of tumor growth inhibition (TGI), defined as the decrease in median tumor volume for treated versus vehicle control mice and tumor growth delay (TGD), defined as the increase in median time to end point in treated versus vehicle control mice. Twice daily oral administration of lapatinib resulted in 57% and 62% TGI and 111% and 113% TGD at 50 mg/kg and 65 mg/kg, respectively. Capecitabine monotherapy (dosed once daily at 350 mg/kg for 7 consecutive days, followed by 7 days off and repeated for 2 cycles) inhibited tumor growth by 57% and produced 159% TGD. The combinations of lapatinib (both 50 mg/kg and 65 mg/kg) with capecitabine (350 mg/kg) were well tolerated and resulted in significantly greater tumor volume reduction (71% and 74% TGI, respectively) and tumor growth delay (203% and 179%, respectively) compared to either single agent alone. These data demonstrate that lapatinib is highly efficacious as a single agent and combination of lapatinib with capecitabine is beneficial in HER2-positive gastric tumors, and support ongoing clinical trials of lapatinib, oxaliplatin, and capecitabine in patients with HER2-amplified gastric cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B79.
Abstract C102: Reactive oxygen species-related killing of lung adenocarcinoma cells in culture and in vivo by diazeniumdiolate-based nitric oxide-releasing prodrugs
Authors: Maciag Anna E. , Chakrapani Harinath , Shami Paul J. , Saavedra Joseph E. , Anderson Lucy M. , Keefer Larry K. 
Published: June 2012

Abstract
Lung cancer is the most common and among the most deadly of human malignancies. Early detection is unusual and there are no completely effective therapies in most cases. Diazeniumdiolate-based nitric oxide (NO) - releasing prodrugs are a growing class of promising NO-based therapeutics. Here we show that JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) and its homopiperazine analogue JS-36-25 are potent tumoristatic agents against lung adenocarcinoma cells both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction of the growth of H1703 cells in vivo, and JS-36-25 appears to be even more effective, leading to 85% reduction of the tumors. We have shown previously that JS-36-25 has diminished reactivity towards glutathione. This drug property may translate to a prolonged half-life in blood, allowing selective accumulation of JS-36-25 in the tumor. This would explain its possibly higher in vivo efficacy compared to JS-K.
Differential lung cancer cells’ responsiveness to both prodrugs appears to be related to their endogenous levels of reactive oxygen species (ROS). The level of endogenous ROS correlated significantly with the drugs’ toxicity measured as IC50 values. The treatment of the lung adenocarcinoma cells with JS-K or JS-36-25 resulted in significant, 2-fold increase in ROS/RNS generation in the cells with high basal levels of ROS. The oxidative/nitrosative stress resulted in significant DNA strand break damage in less than 1 hour of incubation with 1 µM drug. Activation of SAPK/JNK stress pathway was observed within 30 minutes after the treatment was initiated. Initiation of apoptosis occurred early, after 1 hour of incubation with 1 µM compound, as indicated by FACS analysis, as well activation of caspases 3 and 7 and PARP cleavage. Taken together, the data suggest that diazeniumdiolate-based NO - releasing prodrugs may have application as a personalized therapy for lung cancer in patients whose tumors are characterized by high levels of ROS.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C102.
Abstract C110: Abstract B: Hedgehog pathway inhibition in young mice results in severe bone defects
Authors: Brechbiel Jillian L. , Ng Jessica MY , Curran Tom 
Published: June 2012

Abstract
Current treatment for the most common pediatric brain tumor, medulloblastoma (MB) compromises neurological and endocrine development, particularly in younger patients. Mutations in Patched (PTCH1), the receptor for Hedgehog (Hh) proteins, cause MB in approximately 30% of patients. Loss of PTCH1 leads to constitutive activation of Smoothened (SMO) and increased expression of downstream target genes such as GLI1. Previously, we investigated the use of the SMO inhibitor, HhAntag, in a mouse model of MB. Treatment of Ptch1+/−p53−/− mice with HhAntag completely eliminates spontaneous and transplanted tumors. However, treatment of young mice with HhAntag results in permanent defects in bone structure. Histological analyses of long bones from these mice showed a significant reduction in proliferating chondrocytes and an increase in the number of hypertrophic chondrocytes. In our current study, we have further characterized the bone toxicities caused by HhAntag treatment and are testing potential molecules that might lessen the severity of these toxicities. We treated P10-old mice for 4 or 6 days and analyzed their limbs at 0, 2, or 4 days after HhAntag treatment. We found that the severity of bone defects increases with the length of time the mice are treated with HhAntag. MicroCT and MRI analysis showed that exposure to HhAntag for as little as 4 days caused premature growth plate fusion and an increase in bone mineral density. In an effort to protect proliferating chondrocytes from the toxicities caused by HhAntag, we have identified several candidate molecules that have been shown to alter developing bone. One candidate, Parathyroid Hormone-Related Protein (PTHrP), is a downstream effector of the Hh pathway. Hh signaling activates the expression of PTHrP, which then signals to proliferating chondrocytes, preventing them from differentiating. Previous studies show that overexpression of PTHrP in developing bones delays chondrocyte hypertrophy. Therefore, exogenous PTHrP may offset the premature differentiation evident in HhAntag treated animals. We have identified a physiologically relevant dose of PTHrP that is sufficient to mediate a change in bone morphology. We are currently treating mice simultaneously with PTHrP and HhAntag, in an effort to reduce the HhAntag associated bone toxicities. Another candidate is the proteasome inhibitor, bortezomib. Bortezomib has been shown to alter Hh pathway activity and therefore may also reduce the toxicities associated with HhAntag treatment. We are currently establishing the proper dosing strategy appropriate for bortezomib treatment of young mice. We have shown that treatment of young mice with HhAntag leads to severe bone defects and are currently employing a multi-drug approach to lessen the severity of these defects.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C110.
Abstract C115: The KidsCancerKinome: Validation of Aurora kinases as potential drug targets in pediatric tumors
Authors: Westerhout Ellen M. , Kool Marcel , Molenaar Jan J. , Boer den Monique L. , Clifford Steve C. , Delattre Olivier , Geoerger Birgit , Lanvers Claudia , Pietsch Torsten , Serra Massimo , Shipley Janet , Vassal Gilles , Versteeg Rogier , Verschuur Arnauld C. , Caron Huib N. 
Published: June 2012

Abstract
The KCK consortium has validated Aurora kinase A and B as potential drug targets in six highly malignant pediatric tumor types (i.e Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL). The stepwise procedure started with the extensive analyses of expression of human kinases using Affymetrix mRNA profiles of over 500 tumors and cell lines. Clustering analyses on the combined data of all tumor types revealed a cluster containing many G2M kinases that showed significantly higher expression patterns than in the reference tissues. Prominently present in the G2M cluster were Aurora kinase A and B, which expression could be correlated to poor prognosis in the individual tumor types in further analyses. Subsequently, lentiviral shRNA-mediated knockdown of AURKA and AURKB protein expression has been performed in cell line panels for each tumor type to evaluate the kinases for their potential as drug targets. Inhibition of the Aurora kinases resulted in significant phenotypes in several pediatric tumor cell lines ranging from growth inhibition to extensive cell death. The knockdown of AURKA or AURKB often leads to induction of apoptosis, although preceded by a different type of cell arrest. These findings were promising for further evaluation of Aurora kinase inhibitors in the core panel of sensitive pediatric tumor cell lines.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C115.