bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B257: Identification of new CYP26 inhibitors with efficacy in breast cancer xenograft models.
Authors: Oehlen Bert , Ma Gaifeng , McCormack Siobhan , Lim Dong Sung , Tarrant Jim , Zhu Xiaokang , Panicker Bijoy , Goldberg Itzhak D.
Published: August 2014

Retinoids, such as the prototypical retinoid all trans retinoic acid (ATRA), have been used successfully in the treatment of acute promyelocytic leukemia (APL) patients. They have also been tested for efficacy in solid tumors, including breast cancer. Despite promising preclinical data, the clinical success of using ATRA for breast cancer patients has been limited so far. We hypothesize that this is largely due to three factors: (1) a lack of understanding of the patient population that is likely to respond to retinoid therapy, (2) a significant induction of retinoic acid metabolism with retinoid therapy, resulting in sub-optimal retinoid exposure in tumors and (3) the narrow therapeutic index of ATRA. Several recent studies indicate that breast cancer cells that express the Retinoic Acid Receptor Alpha (RARA) are more likely to respond to retinoic acid than cells without RARA expression. This provides a rationale for selection of patients that are likely to benefit from retinoid therapy in future clinical trials. The cytochrome P450 enzyme CYP26 is the key enzyme involved in ATRA metabolism. CYP26A1 expression is elevated in breast cancer tissue compared to normal tissue and CYP26A1 expression is negatively correlated with patient survival. Angion has identified orally bioavailable small molecule inhibitors of CYP26. Angion's lead inhibitor blocks retinoid metabolism in tumor cells and enhances serum and tumor retinoic acid levels. The compound shows robust single agent efficacy in several murine breast cancer xenograft models. By elevating endogenous serum and tumor retinoic acid levels in a physiological range, CYP26 inhibition therapy is likely to result in a better therapeutic index than systemic retinoid therapy. The identification of orally bioavailable, potent, and selective CYP26 inhibitors eliminates two major drawbacks of systemic retinoid therapy, and– in combination with new insights in selecting patients that are more likely to respond to retinoid therapy– may provide a new impetus for evaluation of retinoic acid signaling modulators as a treatment for breast cancer patients.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B257.

Citation Format: Bert Oehlen, Gaifeng Ma, Siobhan McCormack, Dong Sung Lim, Jim Tarrant, Xiaokang Zhu, Bijoy Panicker, Itzhak D. Goldberg. Identification of new CYP26 inhibitors with efficacy in breast cancer xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B257.
Abstract B265: Targeting Wnt signaling: Discovery and characterization of novel thiazole-based Traf2- and NCK-interacting kinase (TNIK) inhibitors.
Authors: Uno Yuko , Moriyama Hideki , Kashimoto Shigeki , Kawase Yusuke , Shitashige Miki , Sawa Masaaki , Yamada Tesshi
Published: August 2014

Introduction: Aberrant activation of Wnt pathway is a major force driving colorectal carcinogenesis, and therefore the Wnt pathway has been thought of as an attractive anticancer drug target. However, its complexity has made it difficult to find druggable targets in the Wnt pathway. Recently, we reported Traf2- and NCK-interacting kinase (TNIK) plays important roles in the Wnt signaling pathway by making a complex with beta-catenin and T-cell factor-4 (TCF4) in a nucleus. We also found that TNIK is activated in human colorectal cancer cell lines, and proliferations of those cells are highly dependent upon the expression and catalytic activity of TNIK. Therefore inhibitors of TNIK may represent a promising therapeutic approach for treating colorectal cancer. Here we describe a discovery and characterization of a novel TNIK inhibitor.

Methods: To identify compounds that inhibit TNIK acitivity, we have produced a recombinant catalytic domain of human TNIK, and developed a high throughput screening (HTS) assay system using a peptide substrate. TCF/LEF reporter gene assay using HEK293 was established to validate hit compounds. To study the effects of TNIK inhbitors on the Wnt signal pathway, Wnt target genes were analyzed by RT-PCR and Western blotting. The selected compounds were subjected to a kinase selectivity panel assay.

Results: By performing a high throughput screening campaigns of our 10K kinase-focused compound library against a recombinant human TNIK, we identified a series of novel thiazole compounds as a potent inhibitor of TNIK. Hit compound, NCB-0001 exhibited potent inhibitory activity for TNIK with an IC50 value of 8.6 nM. After subsequent optimization, N1662 was identified as a lead compound having a strong anti-proliferative activity in colorectal cancer cell lines. N1662 inhibited tumor growth in a mouse xenograft model of colorectal cancer. Further optimization led to compound N5355 that showed good TNIK enzyme inhibition and potent Wnt signal inhibition in the TCF reporter gene assay, as well as down-regulation of Wnt target genes. N5355 showed excellent kinase selectivity against a panel of 311 kinases. Detailed results will be presented in the conference.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B265.

Citation Format: Yuko Uno, Hideki Moriyama, Shigeki Kashimoto, Yusuke Kawase, Miki Shitashige, Masaaki Sawa, Tesshi Yamada. Targeting Wnt signaling: Discovery and characterization of novel thiazole-based Traf2- and NCK-interacting kinase (TNIK) inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B265.
Abstract B28: Identification of drug-response biomarkers for combined mTORC1/2 and MEK1/2 investigational agents using a large-scale cancer cell line screen.
Authors: Shin Hyunjin , Blair Derek , Li Bin , Hather Greg , Trepicchio William L. , Ecsedy Jeffrey , Gangolli Esha
Published: August 2014

Combination therapy in oncology drug development has the potential to overcome resistance against single agent-based therapy. In many cancers, the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways confer major cell growth and survival mechanisms. Therefore, a greater treatment effect may be achieved by inhibiting both pathways simultaneously through drug combination. In this study, the enhanced anti-proliferative activity of investigational drug MLN0128 (mTORC1/2 investigational agent) when combined with TAK733 (MEK1/2 investigational agent) was assessed using an in-vitro cell viability assay on 240 cancer cell lines. Cells were administered with MLN0128 and TAK-733 in DMSO in ten 2-fold serial dilutions and cell viability was measured using Promega's CellTiter-GLO® assay after a 72 hour incubation period. The data points were fit to a 9-parameter model to obtain a response surface and the effect of the combined administration for each cell line was measured using a non-linear blending score estimated from the response surface. Statistical analysis was conducted to determine if the estimated combination effect was associated with known mutated oncogenes, tumor suppressor genes, or cancer histology reports of the 240 cell lines. Interestingly, the synergy of combined agents appeared to be mainly driven by TAK733, as cell lines sensitive to TAK733 as a single agent demonstrated beneficial combination effect with the addition of MLN0128. Furthermore, cell lines with mutations in KRAS, NRAS, and BRAF showed greater synergy scores of the combination. Likewise, cell lines of colon, pancreatic, and skin origins were more sensitive to the combination. Of particular interest are cell lines with mutated KRAS/NRAS or colon origins since they were generally resistant to single agent MLN0128, but became sensitized to the combination with TAK733. In conclusion, our study of drug combination assays on a large-scale in-vitro cell line panel revealed that mutant KRAS/NRAS or colorectal cancers may be sensitive to combined MLN0128 with TAK733.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B28.

Citation Format: Hyunjin Shin, Derek Blair, Bin Li, Greg Hather, William L. Trepicchio, Jeffrey Ecsedy, Esha Gangolli. Identification of drug-response biomarkers for combined mTORC1/2 and MEK1/2 investigational agents using a large-scale cancer cell line screen. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B28.
Abstract B292: HDACi immunosensitizes CTL-resistant human melanomas to adoptive cell transfer (ACT) by modulating TRAIL/DR5apoptotic pathway.
Authors: Jazirehi Ali R. , Kurdistani Siavash K. , Economou James S.
Published: August 2014

Modern immune therapies [PD-1/PD-L1 and CTLA-4 checkpoint blockade, adoptive cell transfer (ACT)] have remarkably improved the clinical treatment of metastatic melanoma. These modalities rely on the killing potential of cytotoxic T lymphocytes (CTL) as primary mediator of their anti-melanoma responses. The mechanisms of resistance to and the predominant cytotoxic pathway(s) employed by melanoma-reactive CTLs remain largely elusive. Moreover, strategies to bypass CTL-resistance are urgently needed in clinical melanoma therapy. We hypothesized that down-modulation of death receptors in addition to aberrant apoptotic signaling might confer resistance to death signals delivered by CTLs. To test this hypothesis, we used an in vitro model of resistant sublines generated from MART-1+/A*0201+ parental lines sensitive to MART-1 TCR transgenic CTL (F5 CTL) under serial F5 CTL-selective pressure. Here, we report that F5 CTLs mainly use the TNF-related apoptosis-inducing ligand (TRAIL) cytotoxic pathway, explicitly via DR5, in killing sensitive melanomas. Further, F5 CTL-resistance was due to DR5 down-regulation and abnormal ratio of anti- to pro-apoptotic molecules, both of which were reversed by the FDA-approved epigenetic modifier SAHA. Restoration of sensitivity by SAHA was confirmed using transgenic and patient-derived MART-1-specific CTLs, rhTRAIL and DR5 agonist Drozitumab. Mitochondrial destabilization and cytosolic release of apoptotic molecules was only evident by combination of SAHA and rhTRAIL or Drozitumab. These findings suggest that exposure to SAHA of immune-resistant melanomas can skew towards an intracellular pro-apoptotic milieu, increase death receptor expression, and overcome acquired immune-resistance.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B292.

Citation Format: Ali R. Jazirehi, Siavash K. Kurdistani, James S. Economou. HDACi immunosensitizes CTL-resistant human melanomas to adoptive cell transfer (ACT) by modulating TRAIL/DR5apoptotic pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B292.
Abstract B42: The study on molecular targets of classification of head and neck squamous cell carcinoma.
Authors: Chen Wantao , Cao Wei , Zhang Ping , Cui zhibin , Xu Qin , Wang Xu
Published: August 2014

Objective: Molecular classification are the basis for designing strategies of individual diagnosis, treatment and prediction of prognosis in head and neck sqamous cell carcinoma (HNSCC). The purpose of this study is to establish the methods of molecular classification, screen and validate the potential biomarkers, and identify the molecular targets of molecular pathological diagnosis, progressive and lymph node metastasis for HNSCC.

Methods: Based on previous study of gene expression profile on HNSCC, our research group preliminarily screened 78 HNSCC-related genes. In this present study, the mRNA expressions of 78 candidate genes were evaluated by real-time PCR in 240 tissues, including 120 HNSCCs and 120 independent normal mucosa and quantified according to an internal control β-actin. And the differentially expressed genes, aggressive-related genes and metastasis-related genes in HNSCC were selected and validated.

Results: 1. The gene expression profile signature “SPP1 et al.” was the optimal group as the differential genes between cancer and normal tissues (AUC:0.986,95% CI:0.961-0.997; sensitivity: 96.4%, specitivity: 94.74%). 2. The gene expression profile signature “CDK2 et al.” was the optimal group to predict the pathological grade (AUC: 0.811, 95% CI: 0.726 to 0.879; sensitivity: 86.7%, specitivity: 63.5%). And the gene expression profile signature “MMP7 et al.” was the optimal group to predict the histologic signs of severity (AUC: 0.749, 95% CI: 0.661 to 0.823; sensitivity: 60.3%, specitivity: 87.7%). 3. The gene expression profile signature “PDGFRA et al.” was the optimal group to predict lymph node metastasis (AUC: 0.769, 95% CI: 0.675 to 0.846; sensitivity: 71%, specitivity: 75%).

Conclusions: The gene-expression signatures validated in this study on molecular diagnosis, progressive and lymph node metastasis may be served as a potential biomarker of molecular diagnosis/molecular classification for HNSCC in future.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B42.

Citation Format: Wantao Chen, Wei Cao, Ping Zhang, zhibin Cui, Qin Xu, Xu Wang. The study on molecular targets of classification of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B42.
Abstract B45: Gene expression alteration in chronic hypoxic MCF7 breast cancer cell line.
Authors: Zihlif Malek A. , Hamdan Feda' Hisham
Published: August 2014

Background: As solid tumors outgrow their vasculature, areas of low oxygen concentration arise where the oxygen demand surpasses supply. Hypoxia plays a significant role in tumor progression and aggressiveness. It is also implicated in therapy resistance to radiotherapy and chemotherapy.

Objective: The aim of this study is to characterize the changes in gene expression associated with chronic hypoxia in MCF7 breast cancer cell line with the goal of identifying a possible biomarker for hypoxia in breast cancer.

Methodology: Breast cancer cells (MCF7) were exposed to 8-hour hypoxic episodes (<1% oxygen) three times a week for a total of 38 episodes. The alterations in gene expression were measured using the real-time based PCR array technology after 19 and 38 episodes of hypoxia and compared to normoxic cells. Chemoresistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay.

Results: Marked gene expression changes were indentified after 19 and 38 episodes of hypoxia. Only few changes were common in both stages with most genes rebounding at the level of 38 episodes. A notable gene (HNF4A) has been up-regulated by 2 folds after 19 hypoxic shots and further up-regulated by 6.43 folds after 38 hypoxic shots. The half maximal inhibitory concentration (IC50) of doxorubicin in MCF7 cells has increased by 1.5 folds after 19 episodes of hypoxia and quadrupled after 35 episodes compared to normoxic cells.

Conclusions: This study provide evidence that exposing cells to prolonged periods of hypoxia (weeks) results in different expression changes than those induced by short-term hypoxia (<72 hours). It also confirms induction of chemoresistance by chronic hypoxia. Finally, it proposes HNF4A as a potential biomarker for hypoxia in breast cancer and as a main player in the cellular response to chronic hypoxia.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B45.

Citation Format: Malek A. Zihlif, Feda’ Hisham Hamdan. Gene expression alteration in chronic hypoxic MCF7 breast cancer cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B45.
Abstract B53: Induction of cells with cancer stem cell properties from p53-deficient somatic cells.
Authors: Nishi Mayuko , Ryo Akihide
Published: August 2014

The tumor suppressor p53 prevents the initiation of tumor formation by inducing cell cycle arrest, senescence and apoptosis during the process of oncogenesis. Although p53 deficiency promotes the efficiency of somatic cell reprogramming to a pluripotent state upon the transduction of four reprogramming genes Oct4, Sox2, Klf4, and c-Myc, it often gives rise to induced pluripotent stem cells (iPSC) with cancer-like features. We attempted to generate cells with cancer stem cell (CSC) properties from p53-deficient mouse embryonic fibroblasts (MEFs) in vitro. The introduction of iPS reprogramming factors into p53-/- MEFs, followed by partial differentiation via embryoid body formation, transformed the bulk of cells into tumorigenic cells with CSC features. These transformed cells displayed a malignant phenotype and formed tumors of multiple lineages when injected into immunocompromised mice. Immunohistochemical analysis revealed the presence of epithelial (E-cadherin), mesenchymal (Vimentin) and myogenic (Desmin) positive cells in the tumor tissues. These transformed CSC-like cells can be maintained in regular cell culture media in vitro with 10% fetal bovine serum, permitting easy manipulation and amenability to large-scale drug screening. Our current approach could therefore provide a valuable basis for the further analysis of CSC characteristics and drug development strategies designed to target CSCs.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B53.

Citation Format: Mayuko Nishi, Akihide Ryo. Induction of cells with cancer stem cell properties from p53-deficient somatic cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B53.
Abstract B6: CEA affects tumor- angiogenesis via integrin-dependent activation of endothelial cells.
Authors: Prager Gerald W. , Braemswig Kira , Poettler Marina , Zieleinski Christoph
Published: August 2014

CEA, first identified in 1965 by Phil Gold and Samuel O. Freedman, is aberrantly overexpressed by up to 70% of human cancers. In clinical use as extracellular marker for monitoring adenocarcinoma growth as well as treatment efficacy, CEA has become included into the routine practice of clinical oncology. In addition to its’ clinical relevance, CEA was so far only described to be pro-tumorigenic in an autocrine manner by inducing anti-apoptosis. Any potential paracrine effects of soluble CEA affecting tumor microenvironment including angiogenesis have not been described.

Here, we report that CEA released by tumor cells induced angiogenesis by directly inducing pro-angiogenic endothelial cells behavior. As shown by gain and loss of function in vivo tumor transplant models, CEA directly stimulated endothelial cell proliferation and migration in vitro and endothelial cell invasion and functional active capillary-tube formation in directed in vivo angiogenesis assays. Thereby, CEA activated endothelial cells via integrin beta-3, leading to FAK phosphorylation and c-src activation as well as induction of MEK/ERK- and PI3kinase/Akt- pathways. Interfering with this chain of events at different steps, such as downregulation of its putative receptor for CEA (CEAR) by shRNA bearing lentivirus or blockage of integrin activity, abrogated CEA-induced endothelial cell activation and tumor-angiogenesis leading to tumor growth arrest. Notably, CEA acted independently and partially additive to the VEGF / VEGFR-2 (KDR or flk-1) system. The biological relevance was further verified by analysis of paraffin-embedded tumor-tissue samples derived from colon cancer patients, whereas vascularization of the tumor microenvironment was significantly higher whenever CEA plasma levels were high.

Thus, our data indicate that the tumor marker CEA acts as a novel angiogenic molecule and might offer a potential therapeutic target in the treatment of tumor-angiogenesis.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B6.

Citation Format: Gerald W. Prager, Kira Braemswig, Marina Poettler, Christoph Zieleinski. CEA affects tumor- angiogenesis via integrin-dependent activation of endothelial cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B6.
Abstract B7: Angiopoietin like 7, a novel pro-angiogenetic factor over-expressed in cancer.
Authors: Parri Matteo , Pietrovito Laura , Grandi Alberto , campagnoli susanna , Pileri Piero , De Camilli Elisa , Bianchini Laura , Grandi Guido , Viale Giuseppe , Chiarugi Paola , Grifantini Renata Maria
Published: August 2014

Angiopoietin like (ANGPTL) proteins are secreted proteins showing structural similarity to members of the angiopoietin family. Some ANGPTL proteins possess pleiotropic activities, being involved in cancer lipid, glucose energy metabolisms and angiogenesis. ANGPTL7 is the less characterized member of the family whose functional role is only marginally known. In this study we provide experimental evidences that ANGPTL7 is over-expressed in different human cancers. To understand the role played by ANGPTL7 in tumor biology, we asked whether ANGPTL7 is endogenously expressed by malignant cells or in response to environmental stimuli. We found that ANGPTL7 is marginally expressed under standard growth condition while it is specifically up-regulated by hypoxia. The regulatory mechanism underlining the ANGPTL7 response to hypoxia need to be elucidated. Interestingly, the protein is secreted and partially associated with the exosomial fraction, suggesting that it could be found in the systemic circulation of oncologic patients and act in an endocrine way. Moreover we found that ANGPTL7 exerts a pro-angiogenetic effect on human differentiated endothelial cells by stimulating their motility, invasiveness and capability to form capillary-like networks while it does not stimulate bone marrow derived progenitor endothelial cells. Finally, we showed that ANGPTL7 promotes vascularization in vivo in the mouse matrigel sponge assay, thereby accrediting this molecule as a pro-angiogenic factor. This suggests that ANGPTL7 could be an attractive therapeutic target for anti-angiogenic tumor therapy.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B7.

Citation Format: Matteo Parri, Laura Pietrovito, Alberto Grandi, susanna campagnoli, Piero Pileri, Elisa De Camilli, Laura Bianchini, Guido Grandi, Giuseppe Viale, Paola Chiarugi, Renata Maria Grifantini. Angiopoietin like 7, a novel pro-angiogenetic factor over-expressed in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B7.
Abstract B83: Phase I trial of panobinostat and fractionated stereotactic radiation therapy for recurrent glioma.
Authors: Shi Wenyin , Lawrence Yaacov R. , Werner-Wasik Maria , Andrews David , Bar Ad Voichita , Evans James , Moshel Yaron , Farrell Christopher , Judy Kevin , Glass Jon , Kim Lyndon , Dicker Adam P.
Published: August 2014

Introduction: Panobinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitivity effect. This is an interim report of the phase I study to evaluate the safety and tolerability of panobinostat combined with fractionated stereotactic radiation therapy (FSRT) for patients with recurrent glioma.

Methods: This is a phase I trial with 3+3 design. Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was 30-35 Gy delivered in 10 daily fractions. Panobionostat was administrated by mouth, once daily, every Monday, Wednesday, and Friday with radiation treatment. Panobionostat was escalated from 10 to 30 mg.

Results: Fifteen patients were enrolled in the trial. Four patients were excluded from the analysis. One patient had tumor progression prior to initiation of treatment, and didn't receive panobinostat. Three patients didn't finish protocol treatment due to increase in QTc exceeding the protocol limit due to panobinostat toxicity. There was no treatment related grade 3 or higher toxicities in the 10 mg and 20 mg dose levels. Four patients were enrolled in the final dose level, 30 mg. One developed grade 3 leukopenia, and grade 4 low ANC (absolute neutrophil count). The hematological toxicities were possibly related to the treatment. Two more patients are required to compete the final dose level and determine the maximum tolerated dose of panobionostat when combined with FSRT in patients with recurrent glioma. Median follow up for living patient is six months. Median progression free survival, and overall survival have not been reached.

Conclusions: Panobinostat administrated with FSRT is well tolerated to the dose of 20 mg. The tolerability of 30 mg dose level is still under evaluation.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B83.

Citation Format: Wenyin Shi, Yaacov R. Lawrence, Maria Werner-Wasik, David Andrews, Voichita Bar Ad, James Evans, Yaron Moshel, Christopher Farrell, Kevin Judy, Jon Glass, Lyndon Kim, Adam P. Dicker. Phase I trial of panobinostat and fractionated stereotactic radiation therapy for recurrent glioma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B83.
Abstract B9: Tumor growth rate analysis enables cost efficient design of preclinical pharmacology studies.
Authors: Guo Sheng , Li Jun , Zhang Juan , Qian Wubin , Shi Qian
Published: August 2014

Xenograft models are widely used in the oncology drug discovery and development process. However, the lack of available information regarding the xenograft models, such as growth curves, standard of care treatment results, IHC analysis of biomarkers, as well as target gene expression, mutation, and amplification, hampers the selection of suitable models for accurate evaluation of therapeutic molecules. We have created XenoBase™ that combines public cell line profiling data with our own pharmacology data on >180 xenograft models. A searching engine is also built in the database to search for models based on gene mutation, expression, amplification, as well as SOC information, types (orthotopic, subcutaneous, systemic) of the xenograft models. The XenoBase™ will enable informed decision in selecting the most relevant models for the development of targeted therapeutics.

Armed with hundreds of xenograft studies available in the XenoBase™, we analyzed the tumor growth rate of each study to compare the results with traditional T/C analysis. The T/C analysis is the current standard, and a T/C value less than 0.42 is widely accepted as an indication of efficacy in evaluating a test article. However, this T/C analysis is limited in using only the data points on one day, overlooking the fact that tumor growth curves are generated over a long period of time (months) and with many days of data collection. To take advantage of the tumor growth curves, we analyzed tumor growth rate utilizing every data point, and derived growth rate based on slopes. Our analysis with the XenoBase™ data indicated that the growth rate based approach is more powerful in evaluating test articles for efficacy compared to T/C analysis or area under the curve (AUC) analysis. If adopted by the industry, this approach may save hundreds of millions of dollars spent in excess number of animals and prolonged observations that may not be necessary.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B9.

Citation Format: Sheng Guo, Jun Li, Juan Zhang, Wubin Qian, Qian Shi. Tumor growth rate analysis enables cost efficient design of preclinical pharmacology studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B9.
Abstract B92: Nedd8-activating enzyme inhibitor MLN4924 provides synergy in nonclinical models with mitomycin C through interactions with ATR, BRCA1/BRCA2 and chromatin dynamics pathways.
Authors: Lightcap Eric S. , Garcia Khristofer , Blank Jonathan L. , Bouck David C. , Liu Xiaozhen J. , Hather Greg , Berger Allison , Cosmopoulos Katherine , Thomas Michael P. , Kuranda Mike , Pickard Michael D. , Liu Ray , Bandi Syamala , Smith Peter G.
Published: August 2014

MLN4924 is an investigational small molecule inhibitor of the Nedd8-activating enzyme (NAE) currently in Phase 1 clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standards of care, including other DNA damaging agents. We studied the interaction of MLN4924 with other DNA damaging agents in a panel of 4 cell lines and found that mitomycin C, cisplatin, carboplatin, cytarabine, ultraviolet radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in at least 1 cell line. Further testing in xenograft-bearing mice demonstrated synergy of MLN4924 with mitomycin C and with carboplatin, and additivity with gemcitabine. Based in part on this data, MLN4924 is currently being evaluated in a Phase 1b trial (NCT01862328) with 3 combination arms: MLN4924 + carboplatin and paclitaxel, MLN4924 + gemcitabine, and MLN4924 + docetaxel. To evaluate the mechanism of synergy between MLN4924 and mitomycin C, in vitro experiments with RNAi were performed. Depletion of genes within the ATR and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924, results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may be applied to additional combinations currently under clinical evaluation.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B92.

Citation Format: Eric S. Lightcap, Khristofer Garcia, Jonathan L. Blank, David C. Bouck, Xiaozhen J. Liu, Greg Hather, Allison Berger, Katherine Cosmopoulos, Michael P. Thomas, Mike Kuranda, Michael D. Pickard, Ray Liu, Syamala Bandi, Peter G. Smith. Nedd8-activating enzyme inhibitor MLN4924 provides synergy in nonclinical models with mitomycin C through interactions with ATR, BRCA1/BRCA2 and chromatin dynamics pathways. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B92.
Abstract B95: Statin hydroxamates, novel inhibitors targeting histone deacetylases and HMG-CoA reductase, suppress colorectal carcinogenesis associated with colitis.
Authors: Wei Tzu-Tang , Lin Yi-Ting , Yang Pei-Ming , Chen Jhih-Bin , Fang Jim-Min , Chen Ching-Chow
Published: August 2014

We synthesized statin hydroxamates (JMF3086, JMF3171, and JMF3173), which are small molecules that simultaneously inhibit histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). These statin hydroxamates were found to be cytotoxic in numerous human cancer cell lines, but not in normal cells, and to induce caspase-dependent apoptosis in HCT116 colon cancer cells. A genome-wide ChIP-on-chip analysis demonstrated that JMF3086 downregulated the expression of inflammatory and stemness genes and upregulated tumor suppressor genes. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) predicted that several of the inflammatory genes were regulated by NF-κB and that the apoptosis-related genes were regulated by NR3C1. The oral administration of statin hydroxamates prevented dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colorectal cancer (CRC) in mice by inhibiting inflammation. JMF3086 and JMF3173 exerted a therapeutic effect in mice with CRC by inducing apoptosis. CRC metastasis to the lungs was inhibited by JMF3086. A positive correlation was detected between the inhibition of HMGR and HDACs and the preventive or therapeutic effects of JMF3086. In addition, the self-renewal and stemness of colorectal cancer stem cells were inhibited by the statin hydroxamates both in vitro and in vivo. Thus, statin hydroxamates show potential as lead compounds for the future development of cancer prevention and treatment.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B95.

Citation Format: Tzu-Tang Wei, Yi-Ting Lin, Pei-Ming Yang, Jhih-Bin Chen, Jim-Min Fang, Ching-Chow Chen. Statin hydroxamates, novel inhibitors targeting histone deacetylases and HMG-CoA reductase, suppress colorectal carcinogenesis associated with colitis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B95.
Abstract B97: AS1411-Doxorubicin adduct for targeted liver cancer therapy.
Authors: Trinh Thu Le , Zhu Guizhi , Xiao Xilin , Zhang Xiaokui , Sefah Kwame , Tan Weihong , Liu Chen
Published: August 2014

Background: Aptamer-drug conjugates are promising to be applied to targeted cancer therapy, in which anticancer drugs were selectively delivered into cognate cancerous cells, but not to healthy tissues, in order to reduce side effects and enhance therapeutic efficacy.

Methodology/Principal Findings: In this study, the technology of drug-DNA adduct (DDA) was utilized to prepare drug-aptamer conjugates. Particularly, an anticancer drug, Doxorubicin (Dox), was conjugated with AS1411, a DNA aptamer which specifically recognizes human hepatocellular carcinoma Huh7 cells. The technology enabled a simple and high-payload conjugation of drugs onto aptamers. The resultant AS1411-Dox adduct maintained selectively recognition ability to target liver cancer cells with strong binding affinity (demonstrated by flow cytometry), was able to selectively deliver the conjugated Dox into target cancer cells (observed with confocal microscopy), and exhibited selective and potent cytotoxicity in target liver cancer cells (evaluated by MTS cell viability assay). More importantly, as the first of its kind, AS1411-Dox adduct demonstrated selectively antitumor therapeutic efficacy of this drug-aptamer conjugation technology in a mouse model. The ability of drug-aptamer adducts to deliver anticancer drugs into target cancer cells, while inhibiting nonspecific drug uptake in nontarget cells, enables this technology promising to be implemented in targeted cancer therapy.

Conclusions/Significance: Given the demonstrated ability of targeted liver cancer therapy combined with the aforementioned advantageous features as a simple preparation, the high drug payload capacity, and the wide applicability, this novel drug-DNA adduct technology is anticipated for wide implications for targeted cancer therapy.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B97.

Citation Format: Thu Le Trinh, Guizhi Zhu, Xilin Xiao, Xiaokui Zhang, Kwame Sefah, Weihong Tan, Chen Liu. AS1411-Doxorubicin adduct for targeted liver cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B97.
Abstract B98: Development and evaluation of selective, reversible LSD1 inhibitors from fragment startpoints.
Authors: Stowell Alex , Hamilton Niall , Hitchin James , Blagg Julian , Burke Rosemary , Burns Samantha , Cockerill Mark J. , Fairweather Emma , Hutton Colin , Jordan Allan , Mould Daniel , Thomson Graeme , Waddell Ian , Ogilvie Donald
Published: August 2014

There is currently considerable interest in lysine-specific histone demethylase 1 (LSD1) as a therapeutic target in human malignancies. Specifically LSD1 has been demonstrated to be an essential regulator of leukaemia stem cell potential, inhibiting differentiation and apoptosis in the MLL-AML setting. There are a variety of potent irreversible LSD1 inhibitors available but here we present two series of reversible aminothiazole inhibitors obtained through the expansion of hits derived from a high concentration biochemical screen of a fragment library. The potency of the initial fragment hits was increased 32-fold through synthesis, with one series of compounds showing clear structure activity relationships (SAR) and inhibitory activities in the range of 7 to 187 µM in a biochemical assay. This series also showed selectivity against the homologous amine oxidase enzyme monoamine oxidase A (MAO-A).

This work represents one of the first reported examples of a reversible small molecule inhibitor of LSD1 with clear SAR and selectivity against MAO-A, and could provide a platform for the development of more potent reversible inhibitors. We also report the first Proof of Mechanism (POM) cell based assay utilizing CD86 expression as a surrogate marker of LSD1 activity in THP1 cells and its use to evaluate both our compounds and some recently reported reversible LSD1 inhibitors.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B98.

Citation Format: Alex Stowell, Niall Hamilton, James Hitchin, Julian Blagg, Rosemary Burke, Samantha Burns, Mark J. Cockerill, Emma Fairweather, Colin Hutton, Allan Jordan, Daniel Mould, Graeme Thomson, Ian Waddell, Donald Ogilvie. Development and evaluation of selective, reversible LSD1 inhibitors from fragment startpoints. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B98.
Abstract C112: Characterization of TAS-121, a novel mutant-specific EGFR-TKI, on pharmacokinetics, pharmacodynamics, and antitumor activity.
Authors: Kato Masanori , Miyadera Kazutaka , Shibata Yoshihiro , Ito Kimihiro , Aoyagi Yoshimi , Chiba Masato , Yonekura Kazuhiko , Iwasawa Yoshikazu , Utsugi Teruhiro
Published: August 2014

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), Gefitinib and Erlotinib, show good responsiveness in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Notably, skin rash and diarrhea, the most common EGFR-TKIs-related adverse effects, are due to wild type EGFR inhibition in dermal and intestinal tissue, respectively. Acquired resistance to EGFR-TKIs, however, arises in most cases and is caused in about half the cases by a secondary gatekeeper T790M mutation of EGFR. Therefore, an EGFR-TKI that specifically inhibits EGFR harboring mutations including T790M without affecting wild-type EGFR represents an attractive therapeutic agent.

Materials and Methods: Pharmacokinetics studies were performed in mice, rats, dogs and monkeys, and tumor growth and pharmacodynamics evaluation was analyzed in athymic nude mice bearing NSCLC cell lines, NCI-H1975 (harboring the EGFR T790M/L858R mutation) and HCC827 (harboring the EGFR exon 19 deletion).

Results: TAS-121 is a newly synthesized compound which is a mutant selective EGFR inhibitor with improved oral bioavailability in various animal species and in vivo antitumor potency compared to the previously described prototype compound, TAS-2913. TAS-121 showed a higher plasma concentration than TAS-2913 following oral administration in mice. Once daily dosing of TAS-121 inhibited NCI-H1975 (EGFR T790M/L858R) tumor growth at a low dose, with an ED50 of less than 12.5 mg/kg/day. TAS-121 also showed tumor growth inhibition of HCC-827 cells, harboring an EGFR activating mutation. In an orthotopic lung xenograft model, TAS-121 significantly prolonged survival in mice compared to first- and second-generation EGFR-TKIs. Pharmacodynamics analysis revealed that TAS-121 dose-dependently inhibited phosphorylation of EGFR T790M/L858R in a xenografted tumor, whereas it did not inhibit that of wild-type EGFR in mouse skin.

Conclusion: Our study demonstrates that TAS-121 is a highly potent and mutant-specific EGFR-TKI with a favorable oral bioavailability, and provides a promising therapeutic option for patients harboring T790M mutation after the failure of pre-existing EGFR-TKIs.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C112.

Citation Format: Masanori Kato, Kazutaka Miyadera, Yoshihiro Shibata, Kimihiro Ito, Yoshimi Aoyagi, Masato Chiba, Kazuhiko Yonekura, Yoshikazu Iwasawa, Teruhiro Utsugi. Characterization of TAS-121, a novel mutant-specific EGFR-TKI, on pharmacokinetics, pharmacodynamics, and antitumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C112.
Abstract C113: ERBB3 independent activation of the PI3K pathway in EGFR mutant lung adenocarcinomas.
Authors: Song Xiaoling , Fan Pang-Dian , Guha Udayan , Threadgill David , Varmus Harold , Politi Katerina
Published: August 2014

Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinomas are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. EGFR is one member of a family of four receptor tyrosine kinases (EGFR, ERBB2, ERBB3 and ERBB4) that can homo- and/or hetero-dimerize leading to activation of the RAS-MAPK and phosphoinositide 3-kinase (PI3K) pathways. In EGFR mutant lung cancer cell lines, ERBB3 has been implicated in activation of the PI3K pathway. However, the requirement for ERBB3 in the initiation, progression and therapeutic response of EGFR mutant tumors remains undetermined. Using genetically engineered mouse models we investigated the contribution of Erbb3 to the development of EGFR-induced lung adenocarcinomas and their response to TKIs. We found that upon conditional deletion of Erbb3 in the lungs of mice that express mutant EGFR tumorigenesis and erlotinib sensitivity were unaffected. In the absence of Erbb3, tumors retained activation of the Pi3k pathway via the adapter proteins Gab1 and Gab2. Acute loss of ERBB3 in human lung adenocarcinoma cell lines with sensitizing EGFR mutations had a modest effect on phosphorylation of AKT and cell viability that varied among cell lines. These data demonstrate that activation of the Pi3k pathway in EGFR mutant tumors is independent of Erbb3 and has implications for the potential of ERBB3 as a therapeutic target in lung cancer. Knowledge of the role EGFR heterodimerization partners play in mutant EGFR-driven lung cancer can help guide the selection of which EGFR family members to target in the treatment of this disease.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C113.

Citation Format: Xiaoling Song, Pang-Dian Fan, Udayan Guha, David Threadgill, Harold Varmus, Katerina Politi. ERBB3 independent activation of the PI3K pathway in EGFR mutant lung adenocarcinomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C113.
Abstract C114: Clinical response to a lapatinib-based therapy of a Li-Fraumeni Syndrome patient with a novel HER2-V659E mutation.
Authors: Serra Violeta , Vivancos Ana , Puente Xose , Felip Enriqueta , Silberschmidt Daniel , Caratù Ginevra , Parra Josep-Lluis , De Mattos-Arruda Leticia , Grueso Judit , Hernández-Losa Javier , Arribas Joaquín , Prudkin Ludmila , Nuciforo Paolo , Scaltriti Maurizio , Seoane Joan , Baselga José
Published: August 2014

Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline p53 mutation (Li-Fraumeni Syndrome) identified oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifications, an EGFR-exon 20 insertion, and the first-in-human HER2-V659E mutation showing a phenotypic convergent evolution towards HER2 and EGFR alterations. Following the identification of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A clinical response both symptomatic and radiologic was achieved. HER2-V659E sensitivity to lapatinib was confirmed in the laboratory.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C114.

Citation Format: Violeta Serra, Ana Vivancos, Xose Puente, Enriqueta Felip, Daniel Silberschmidt, Ginevra Caratù, Josep-Lluis Parra, Leticia De Mattos-Arruda, Judit Grueso, Javier Hernández-Losa, Joaquín Arribas, Ludmila Prudkin, Paolo Nuciforo, Maurizio Scaltriti, Joan Seoane, José Baselga. Clinical response to a lapatinib-based therapy of a Li-Fraumeni Syndrome patient with a novel HER2-V659E mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C114.
Abstract C116: Em08red, an emodin analog, exhibited anti-proliferative activity against oral cancer through down-regulation of ErbB2 signaling pathway and induction of apoptosis.
Authors: Juang Shin-Hun P. , Liang Fong-Pin , Lien Jin-Chern , Wu Yu-Hwa , Chen Chien-Shu
Published: August 2014

Over-activation of ErbB2 highly correlates with tumor progression and chemoresistance and has become an important biomarker and major target of cancer therapy treatments. Although several chemotherapy agents targeting ErbB2 show promising therapeutic effect, additional therapeutic approaches targeting ErbB2 are still urgently needed. Emodin, a major anthraquinone in the rhizome of Rheum palmatum, has been demonstrated to exhibit anticancer effects on several human ErbB2-overexpressing cancers. Computer modeling analysis determined emodin could be a suitable fit for the ErbB2 active pocket site however, the initial binding was unsatisfactory. In order to improve the anti-ErbB2 activity, a series of emodin analogs were synthesized and evaluated against several ErbB2-overexpressing oral cancer cells. Among them, 1,8-dihydroxy-9(10H)-anthraquinone (Em08red), showed potent antiproliferative effect against ErbB2-overexpessing oral cancers. Further studies showed Em08red treatment significantly reduced the levels of ErbB2 phosphorylation, resulting in G2/M arrested and apoptotic cell death. Moreover, treatment with Em08red, significant reduced the levels of anti-apoptosis proteins (Bcl-x and Bcl-2) and activated the caspase-3 and -9, but not caspase-8. Collectively, our results clearly indicate Em08red can down-regulate ErbB2-signaling, induce intrinsic apoptotic cell death and is a promising potent ErbB2-targeted therapeutic.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C116.

Citation Format: Shin-Hun P. Juang, Fong-Pin Liang, Jin-Chern Lien, Yu-Hwa Wu, Chien-Shu Chen. Em08red, an emodin analog, exhibited anti-proliferative activity against oral cancer through down-regulation of ErbB2 signaling pathway and induction of apoptosis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C116.