bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A25: Establishment and characterization of primary human Biomerk Tumorgraft™ Models: Application to oncology drug development
Authors: Strawn Steven J. , Wick Michael , Nieves Francis , Sidransky David , Bruckheimer Elizabeth M. 
Published: June 2012

Abstract
One of the key challenges facing oncology drug development is the high attrition rates of compounds that enter the drug development pipeline, where very few achieve successful approval and marketing. Champions Biotechnology, in an effort to enhance the value of preclinical compounds and accelerate oncology drug development, has developed a novel preclinical platform derived from Biomerk Tumorgraft™ models; an innovative approach that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor. Biomerk Tumorgrafts™ differ from traditional xenograft models in that they are not passaged in tissue culture, and are instead exclusively passaged in vivo. Additionally, the Biomerk Tumorgraft™ models: (a) maintain the fundamental genotypic features of the original cancer, (b) represent the genetic heterogeneity of the cancer, and (c) do not change over several passages. Champions has established a bank of over 200 Tumorgraft models encompassing all major solid tumor types, all of which have been extensively characterized. Here we describe a panel of NSCLC lung, colon, and pancreatic tumorgraft models including gene expression profiling, mutational analyses and responses to standard of care agents. Of the NSCLC lung models, 6/8 demonstrated resistance to Erlotinib with 2/8 demonstrating an intermediate response, 2/6 also possessed a mutant K-ras or a mutant EGFR. Similarly, 3/6 K-ras mutant colon Tumorgraft models demonstrated sensitivity to irinotecan. In the case of the pancreatic models, 7/8 showed resistance to Erlotinib with the remaining model showing only a modest response. Through Champions' Personalized Oncology Services, we have also shown a high correlation between the Tumorgraft response and the clinical response. Together, these results demonstrate that each model differs with respect to its genetic composition and response to standard agents, and thus represents the efficacy of a compound on an individual patient. Given the diversity of models, the maintenance of the genomic and phenotypic characteristics of the original patient tumor, and the correlation between Tumorgraft and clinical responses, Champions Biomerk Tumorgraft™ models represent a novel preclinical in vivo platform capable of optimizing drug regimens for cancer patients and predicting the clinical effectiveness of preclinical drug candidates. Overall, the application of Biomerk Tumorgraft™ models has the potential to accelerate and enhance oncology drug development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A25.
Abstract A253: Acquired Bcr-Abl kinase domain mutations are not responsible for persistence of dasatinib-refractory disease in murine Ph+ ALL
Authors: Boulos Nidal , Calabrese Christopher R. , Sherr Charles J. , Williams Richard T. 
Published: June 2012

Abstract
Despite the dramatic efficacies of imatinib and second-generation BCR-ABL kinase inhibitors (dasatinib and nilotinib) in chronic myelogenous leukemia (CML), these drugs fail to provide durable therapeutic benefit in patients with Philadelphia-chromosome positive (Ph+) BCR-ABL-induced acute lymphoblastic leukemias (ALLs). In contrast to chronic-phase CML, deletion of the CDKN2A (INK4A-ARF) tumor suppressor locus occurs in 65% of Ph+ ALL cases. Accordingly, introduction of cultured Arf−/− p185BCR-ABL-expressing (p185+) pre-B cells, but not their Arf+/+ counterparts, into healthy syngeneic recipient mice induces fulminant B cell leukemia; virtually every p185+, Arf−/− cell is a leukemia-initiating cell (LIC). We have now monitored disease progression and dasatinib-responsiveness in vivo by following the fate of p185+ Arf−/− luciferase-expressing LICs. In animals bearing high leukemic burdens (simulating the human clinical condition at diagnosis), two weeks of dasatinib therapy induced dramatic reductions in luminescent signals, but all animals harbored persistent, measurable deposits of drug-refractory cells. The vast majority of BCR-ABL alleles from these residual cells were free of kinase domain (KD) mutations, but rare leukemic clones harboring the T315I KD mutation, known to confer near-complete drug resistance to imatinib, dasatinib and nilotinib, were detectable in a subset of recipients. Following several weeks of continued dasatinib therapy, all mice developed clinical relapse preceded by dramatic increases in luminescent signals, both in the hematopoietic compartment and central nervous system. Many of these drug-resistant leukemic cells now harbored the T315I KD mutation. Animals that had been maintained in remission with 4 weeks of continuous dasatinib therapy quickly relapsed upon therapy discontinuation, almost always without evidence of KD mutations. In this clinically-relevant Ph+ ALL model, several factors including Arf loss-of-function, disease burden, intensity of therapy, and length of drug exposure interact to determine therapeutic outcome and to trigger confluent mechanisms of drug resistance. Critically, while continuous dasatinib therapy efficiently selects for and maintains cells harboring drug-resistant KD mutations that mediate eventual clinical relapse, most drug-refractory leukemic cells survive in hematopoietic tissues in the absence of KD mutations during maintenance therapy, implying that mutation-independent factors sustain LIC survival. We propose that Arf inactivation in Ph+ ALL (but not in CML) enhances the biological ‘fitness’ of leukemic cells and diminishes the efficiency with which targeted therapy can successfully eradicate drug-refractory disease. This facilitates the subsequent emergence of cell-intrinsic drug resistance, most frequently manifested as BCR-ABL KD mutations.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A253.
Abstract A255: Activity of VEGFR inhibitor tivozanib as a single agent or in combination with EGFR inhibitor erlotinib in engineered lung adenocarcinoma models
Authors: Sun Xiaojian , Bressel Angela , Rideout William M. , Zhou Yinghui , Heyer Joerg , Chiu Isabel , Robinson Murray O. , Lin Jie 
Published: June 2012

Abstract
Tivozanib (AV-951 or KRN951) is an ATP competitive small molecule VEGFR antagonist that exhibits picomolar inhibitory activity against all three VEGF receptors. It has demonstrated robust clinical activity in renal cell carcinoma and is currently being evaluated in multiple clinical studies including a monotherapy phase 1b/2a trial in NSCLC. NSCLC is a highly heterogeneous disease, in which tumor histology and genetics have defined sensitivities and settings to targeted therapeutics. To model and explore potential clinical settings, we created genetically engineered lung adenocarcinoma models driven by EGFRL858R, EGFRL858R/T790M or KRAS G12V, propagated these models in vivo both subcutaneously and orthotopically and evaluated tumor inhibitory activity of tivozanib as a single agent or in combination with EGFR inhibitor erlotinib. To further explore activity of metastatic lesions to the lung, we also evaluated the activity of tivozanib using an engineered breast tumor metastatic model.
Treatment of subcutaneous lung KRAS tumors or lung EGFRL858R/T790M tumors with tivozanib alone resulted in complete tumor growth inhibition. Histological analysis revealed substantial central necrosis with proliferating (Ki67+) tumor cells present only at the tumor periphery, typical of an anti-angiogenesis mechanism. When tivozanib was given to treat lung EGFRL858R+T790M tumors in an orthotopic setting in the lungs after tumors were well established, significant antiangiogenic and antitumor effects, as demonstrated by histology and extended survival period, were observed. However, the necrotic lung lesions showed no sign of resorption or elimination after 6 weeks of treatment. Similar results were also observed in a HER2 driven breast tumor lung metastatic model. This prompted us to further explore the activity of tivozanib in an orthotopic lung tumor minimal disease model. Tivozanib treatment in this setting did not alter tumor lesion numbers but effectively blocked the progression of micro pre-angiogenic lesions. Finally, we explored the combined activity of tivozanib and erlotinib in a model constructed to reflect the emergence of erlotinib resistance by implanting tumor material comprising both EGFRL858R and EGFRL858R/T790M tumor cells. In this setting, the combination of tivozanib and erlotinib resulted in significantly greater control of tumor progression than erlotinib alone.
Our results suggest that tivozanib may have activity as a single agent in lung tumors with KRAS or EGFR L858R/T790M mutations and that combinations with other targeted lung cancer drugs such as erlotinib may provide meaningful clinical benefit.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A255.
Abstract A38: Members of the noncanonical WNT pathway confer resistance to the MEK 1/2 inhibitor AZD6244 in colorectal cancer cell lines
Authors: Tentler John J. , Nallapareddy Sujatha , Tan Aik Choon , Spreafico Anna , Flanigan Sara A. , Pitts Todd M. , Eckhardt S. Gail 
Published: June 2012

Abstract
Background: The ERK pathway is constitutively activated in several human cancers including CRC. The MAPK/ERK kinase, MEK, occupies a central role in the ERK pathway and therefore, MEK inhibitors constitute a promising class of novel targeted cancer therapies. AZD6244 (ARRY-142886) is a potent, selective MEK1/2 inhibitor with nanomolar potency against cell lines and activity in several in vivo models of CRC. Despite initial enthusiasm for this class of agents in tumors with a high incidence of RAS or BRAF mutations, clinical studies indicate that resistance to MEK inhibitors remains a problem, and therefore, improved patient selection strategies are needed. The goal of this study was to identify and target predictive markers of resistance to AZD6244 in order to develop a rational basis for patient selection and combination therapy in CRC.
Methods and Results: In order to identify predictive markers of responsiveness to AZD6244, 27 CRC cell lines were exposed to the agent, of which five highly sensitive (S) or resistant (R) cell lines were selected with IC50 values of &lt;0.1 and &gt;1.0 µM, respectively, and subjected to Affymetrix U133 plus 2.0 gene array analysis. ANOVA comparison of gene expression profiles between S and R cell lines revealed over 100 differentially expressed genes with a global p-value of &lt;0.04, whereas 64 transcripts met the p&lt;0.001 criteria. Of note, two genes, frizzled homolog 2 (FZD2) and wingless integrated 5B (WNT5B) were overrepresented in AZD6244 R cell lines by 17 and 7.5-fold, versus the S cells, respectively. These two genes comprise a receptor-ligand pair that has been shown to signal via the non-canonical, β-catenin-independent WNT signaling pathway. To determine the functional significance of over-expression of the non-canonical WNT pathway in resistance to AZD6244, we silenced FZD2 or WNT5B expression with stably transfected shRNAs and assessed the responsiveness of SW480 R cells to AZD6244. We observed a greater than 50% reduction in the IC50 to AZD6244 in the FZD2 knock-down cells and greater than 65% reduction in the WNT5B knock-down compared to wild-type and scrambled shRNA controls. Finally, we tested the effects of combining cyclosporine A (CsA) and tacrolimus, inhibitors of the non-canonical WNT pathway, with AZD6244. We observed synergistic inhibition of proliferation of SW480 cells treated with the combination of either inhibitor with AZD6244.
Conclusions: Members of the non-canonical WNT pathway confer functional resistance to AZD6244 and thereby may represent not only predictive biomarkers of responsiveness to AZD6244, but also the basis for rational combination partners. These biomarkers and combination strategies are currently being validated in vivo with cell line and patient-derived CRC xenograft models.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A38.
Abstract A43: Detection of tumor-associated KRAS mutations in the plasma and tumor tissue of colorectal cancer patients
Authors: Jeffers Michael , Pena Carol , Henderson David , Wilhelm Scott , Christensen Olaf , Lathia Chetan 
Published: June 2012

Abstract
The mutational evaluation of tumor-derived genetic material is becoming increasingly important in the era of personalized medicine. DNA harvested from a variety of sources (e.g., tumor biopsies, plasma, serum, urine and stool) may be useful to determine the mutational status of a tumor. In addition, a variety of methods for performing mutational analyses are available. In the present study, DNA derived from tumor biopsies and plasma was evaluated for KRAS mutational status by two different methodologies: Sequenom and BEAMing. In an initial experiment, KRAS mutations were identified in 36/64 (56%) of colorectal tumors analyzed by the Sequenom method. Matched plasma samples corresponding to a subset of the patients with KRAS-mutant tumors (n = 18) were subsequently evaluated for KRAS mutational status by Sequenom and BEAMing methodologies. Each of these methods detected the expected tumor-associated KRAS mutation in approximately 70% of the plasma samples analyzed. An additional set of 38 plasma samples from late stage metastatic colorectal cancer patients was then evaluated by both Sequenom and BEAMing, which lead to the identification of KRAS mutations in 9/38 (24%) and 19/38 (50%) of the samples analyzed by the respective technologies. Biopsies from 8 of these 38 patients were available and evaluated for KRAS mutational status by Sequenom. In one case, a KRAS mutation was found in the tumor that had not been detected in the corresponding plasma sample, and in another case a KRAS mutation that had been detected in a plasma sample was not detected in the corresponding tumor. This study indicates that the Sequenom method can be successfully used to determine the KRAS mutational status in both tumor biopsies and plasma. The BEAMing method was also successfully used to determine KRAS mutational status in plasma, and appears to be more sensitive than the Sequenom method. Since the frequency of KRAS mutation detected in the plasma of 38 metastatic colorectal cancer patients using BEAMing (i.e., 50%) is similar to that reported in the literature for this patient population when using tumor biopsies for mutational analysis, the assessment of tumor-associated mutations in plasma may represent a viable option in this patient population. However, since the KRAS mutational status in plasma and tumor do not always correspond, data obtained from these two sources should be independently evaluated in the clinical setting.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A43.
Abstract A65: MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT
Authors: Sun Hong , Zhang Zhan , Grandori Carla 
Published: June 2012

Abstract
Intratumoral hypoxia is well known as a hallmark of most solid tumors. Here, we studied expression level of about 200 microRNAs in a panel of cancer cell lines from different tissues, and identified a microRNA miR210, its expression was prominently up-regulated by hypoxia. Over expression of miR210 in cancer cell lines partially reversed the hypoxic gene expression signature and allowed cells to escape from hypoxia-induced cell-cycle arrest. We then identified MNT, a known MYC antagonist, as a key miR-210 target. miR-210 directly down-regulated MNT transcript and protein via recognition sites in the transcript 3′ UTR. Consistent with a role for MNT as a miR-210 target, RNA interference-mediated knockdown of MNT phenocopied miR-210 over expression cell cycle effect. Furthermore, loss of MYC abolished the ability of miR-210 to override hypoxia-induced cell-cycle arrest. Thus, miR-210 could function as a modulator in cancer cells in response to hypoxic conditions through Myc network.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A65.
Abstract A66: Potent CDK4 inhibitor in human breast cancer therapy
Authors: Sun Yuan 
Published: June 2012

Abstract
Deregulated cell cycle is a common feature in many human cancers. Overexpression of cyclinD1 oncogene and highly activation of the cyclinD1/Cdk4Cdk6 kinase modulate the tumor initiation, tumor progression and the chemo-sensitivity of cancer cells. Targeting G1 phase of cell cycle leading cancer cell into senescence or quiescence stage or causing cell death has become a promising approach in cancer treatment. Here, we report the in vitro anti-tumor functions of the synthetic Cdk4 inhibitor, Naphtho [2, 1-α] pyrrolo [3, 4-c] carbazole-5, 7 (6H, 12H)-dione (NPCD) in a panel of human breast cancer cell lines. NPCD is able to inhibit cancer cell growth, arrest cancer cells at G1 phase and cause cell death as results of diminished Cdk4Cdk6 phosphorylation of the Rb protein without disrupting the cyclinD1/Cdk4Cdk6 complex formation or affecting G1 phase proteins intracellular localization. The sensitivity to NPCD is associated with the intracellular cyclinD1 and Cdk4 or Cdk6 proteins level. Upon NPCD treatment, the changes in several G1-S phase proteins levels differ between cell lines which could because different cell lines develop different signaling networks responding to same stimuli. The dramatically decreased p27kip protein is a common feature between cell lines we studied upon NPCD treatment; it could be either a result of NPCD induced G1 arrest and inactivation of cyclinD1/Cdk4Cdk6 or could be an upstream mediator to cause Cdk4Cdk6 inactivation and G1 arrest. In recent years, the functions of p27kip protein have been extended involving in cell cycle regulation, embryonic development, tumor genesis and tumor progression, consequently, pursuing the mechanisms resulting rapidly decreased p27kip protein in responding to NPCD may help us to better understand the function of this protein in deregulated cell cycle system.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A66.
Abstract A89: Synthesis and structure-activity relationship of 3-O-acylated (−)-epigallocatechins as 5α-reductase inhibitors
Authors: Huang Jiann-Jyh , Lee Ying-Shuan , Hiipakka Richard A. , Liao Shutsung 
Published: June 2012

Abstract
A series of 3-O-acylated (−)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared by the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (−)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids using DCC and DMAP and then desilylated with aqueous HF to provide the corresponding products. For 3-O-acylated (−)-epigallocatechins with saturated fatty acids, the 5α-reductase inhibitory activity increased with the increasing numbers of carbon atoms at the C3-O position, reaching maximum for 16 carbon atoms (compound 4h, with palmitic acid) with an IC50 of 0.53 µM, which was ∼12-fold more potent than EGCG (IC50 = 6.29 M). Introduction of monounsaturated fatty acid to the C3-O position of (−)-epigallocatechins enhanced the activity, providing the most potent compound 6 (IC50 = 0.48 µM, with palmitoleic acid), which showed moderate anti-tumor activity in a PC-3 prostate cancer xenograft model. Replacement of the ester moiety at C3-O with carbamate, or permethylation or peracylation of hydroxyl groups diminished 5α-reductase inhibitory activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A89.
Abstract A94: Preventive effects of naproxen and NO-naproxen in carcinogen induced models of urinary bladder, colon, and mammary cancers
Authors: Grubbs Clinton J. , Steele Vernon , Boring Daniel , Lubet Ronald , Rao Chinthalapally , Zhang Yuting , Patlolla Jagan 
Published: June 2012

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically; and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO-naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity as well as the expectation that the production of NO itself might be therapeutically effective. When examined in the hydroxybutyl(butyl)nitrosamine (OH-BBN) rat urinary bladder cancer model, naproxen at doses of either 400 or 200 ppm in the diet greatly decreased the development of large invasive bladder cancers when treatment was initiated shortly after the last OH-BBN dosing. In a second study, naproxen at 133 ppm or NO-naproxen at 183 or 550 ppm caused striking decreases in the incidence of large tumors. Surprisingly, if treatments were started three months after the last OH-BBN (when multiple microscopic lesions already exist) both NO-naproxen (550 ppm) and naproxen (400 ppm) were still highly effective (91–96% decreases); implying that most of their effects are late. In the azoxymethane (AOM)-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm reduced mean ACFs in the colon by approximatley 45–60%. NO-naproxen administered at roughly equimolar doses (300 and 600 ppm), reduced total ACF by 20–40%, respectively. In contrast, in the methylnitrosourea (MNU)-induced ER+ mammary cancer model in rats (where most NSAIDs are relatively ineffective) neither NO-naproxen nor naproxen showed significant inhibition at doses of 550 and 400 ppm. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon (but not mammary) carcinogenesis. Additional data showing the effects of sulindac and NO-sulindac in the urinary bladder model will also be presented. Data also imply that both naproxen and NO-naproxen are effective, but that the NO-derivative does not appear to be more effective.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A94.