bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A10: In vivo models of pancreatic cancer for translational medicine.
Authors: Behrens Diana , Hallas Cora , Anders Diana , Fichtner Iduna 
Published: August 2014

Abstract
In Germany pancreatic cancer remains a lethal disease with only 3-8% of patients surviving 5 years after diagnosis of the tumor (2005). Reasons for this poor situation are advanced and inoperable tumor stages at time of diagnosis and resistance to conventional therapies. One bottleneck in the development of novel therapies is the restricted availability of preclinical models with a high clinical relevance. The aim of our study was to develop well-defined in vivo xenografts derived from patient pancreatic carcinomas to address translational questions. These xenografts can be used for identification of biomarkers and cancer related pathways as well as for the evaluation of targeted therapies. The genesis of pancreatic neoplasm, the progression of tumor growth as wells as the development of resistance can be elucidated with animal models of patient-derived material. And last but not least, preclinical data can be used prospectively for efficient stratification of patients. Fifty-two patient tumors were collected from the clinical cooperation partner and transplanted immediately into immune-deficient mice. Nine out of 52 samples could be established so far as passagable pancreatic cancer xenografts (PDX), 5 were identified as inflammations of the pancreas. Interestingly, we observed 4 out of 52 as post-transplant lymphoproliferative disorders (PLTD). Twenty-nine failed to grow in mice and 5 are still under observation and potential candidates for the model library. All of the engrafted PDX are poor or moderate differentiated adenocarcinomas. Global gene expression analysis and determination of cancer associated mutations were performed from engrafted tumor models. According to clinical data we found K-ras mutations in 8 and additionally p53 mutations in 4 out of 9 PDX. Chemosensitivity was evaluated by transplanting tumor material into cohorts of immune-deficient mice. Beginning from palpable tumor sizes mice were treated with 5-fluorouracil, Irinotecan, Vincristine, Avastin, Gemcitabine and Sorafenib at optimized schedules and doses. The most efficient therapeutics were Gemcitabine and Irinotecan, whereas the growth of PDX was only marginally inhibited by Vincristine and Avastin. Patient-derived xenografts are a crucial tool for the prediction of therapy and potentially relevant for the implication into clinical decisions. We have successfully developed a panel of 9 pancreatic cancer PDX for translational research projects.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A10.
Citation Format: Diana Behrens, Cora Hallas, Diana Anders, Iduna Fichtner. In vivo models of pancreatic cancer for translational medicine. [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 A10.
Abstract A100: KLF8 induces breast stemness and chemoresistance via miRNAs associated with EMT.
Authors: Wang Xianhui , Lu Heng , Li Tianshu , Yu Lin , Liu Gang , Peng Xu , Zhao Jihe 
Published: August 2014

Abstract
The mechanisms behind the induction of stem cell properties by the epithelial to mesenchymal transition (EMT) remain largely undefined. Here we report the identification of the microRNA-146a (miR-146a) as a common target of the known EMT-inducers Krüppel-like factor 8 (KLF8) and TGF-β. Upon KLF8 overexpression or TGF-β treatment, a significant portion of the MCF-10A cells gained stem cell traits as demonstrated by an increase in the expression of CD44high/CD24low, the activity of aldehyde dehydrogenase (ALDH) and the mammosphere forming capability. Along with this change, the expression of miR-146a was highly upregulated in the cells. Consistently, we found that miR-146a was aberrantly co-overexpressed with KLF8 in a panel of invasive human breast cancer cell lines. Ectopic expression of KLF8 failed to induce the stem cell traits in the MCF-10A cells if the cells were pre-treated with miR-146a inhibitor, whereas overexpression of miR-146a in the MCF-10A cells alone was sufficient to induce the stem cell traits. Importantly, this induction of miR-146a-dependent stem traits by KLF8 was well correlated to the cell resistance to the cytotoxic effects of chemotherapeutic drugs such as paclitaxel. Co-staining and luciferase reporter analyses indicated that miR-146a targets the 3’-UTR of the Notch signaling inhibitor NUMB for translational inhibition. Overexpression of KLF8 dramatically potentiated the tumorigenecity of MCF-10A cells expressing the H-Ras oncogene, which was accompanied by a loss of NUMB expression in the tumors. Taken together, this study identifies a novel role and mechanism for KLF8 in inducing pro-tumorigenic mammary stemness and chemoresistance via miR-146a potentially by activating Notch signaling. This mechanism could be exploited as a therapeutic target against drug resisting breast cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A100.
Citation Format: Xianhui Wang, Heng Lu, Tianshu Li, Lin Yu, Gang Liu, Xu Peng, Jihe Zhao. KLF8 induces breast stemness and chemoresistance via miRNAs associated with EMT. [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 A100.
Abstract A107: In vivo screen of regorafenib in a panel of low passage START-PDX colorectal models: Working to identify a sensitive patient subpopulation.
Authors: Wick Michael J. , Gamez Lizette , Diaz Armando , Vaught Teresa L. , Tolcher Anthony W. , Rasco Drew , Patnaik Amita , Smith Lon , Drengler Ron , Papadopoulos Kyriakos P. 
Published: August 2014

Abstract
Background: Regorafenib is a multi-tyrosine kinase recently approved for unresectable and drug refractory gastrointestinal stromal tumors (GIST) and treatment-refractory colorectal cancers regardless of Ras status. While a subset of colorectal cancer patients have reported benefit from regorafenib therapy, the majority does not benefit and attempts to identify a subpopulation of sensitive colorectal patients have not been successful. To better understand which colorectal cancer patients may respond to regorafenib we screened a panel of low passage colorectal models from the START patient-derived xenograft (PDX) platform and compared results to model characteristics.
Methods: PDX colorectal models were established in athymic nude mice from primary or metastatic patient tissue or fluid and once established were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each model DNA was extracted and subjected to mutation profiling and growth factor receptor expression was interrogated using immunohistochemistry. Drug sensitivity studies were performed evaluating regorafenib at 25-30 mg/kg once daily for at least twenty-one days. Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion.
Results: To date forty colorectal START-PDX models have been screened against regorafenib. Three models (ST201, ST238 and ST800) reported tumor regressions or partial responses even with activating K-Ras or B-Raf mutations present. An additional 30% of evaluated models reported tumor stasis (T/C= 0-10%) and remaining models demonstrated varying degrees of sensitivity or resistance to regorafenib. High expression of EGFR was reported in two of the most sensitive models and was reduced in the models resistant to regorafenib.
Conclusion: We have screened preclinical activity of regorafenib towards a panel of colorectal START-PDX models and identified sensitive and resistant models. Additional genomic and characterization studies are underway to better understand activity of regorafenib with the goal of identifying a sensitive patient subpopulation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A107.
Citation Format: Michael J. Wick, Lizette Gamez, Armando Diaz, Teresa L. Vaught, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Lon Smith, Ron Drengler, Kyriakos P. Papadopoulos. In vivo screen of regorafenib in a panel of low passage START-PDX colorectal models: Working to identify a sensitive patient subpopulation. [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 A107.
Abstract A144: Inhibition of 2-HG production in IDH mutant xenograft models.
Authors: Slocum Kelly L. , Downall Julia , Gould Ty , Zafari Mohammad , Dodd Stephanie , Firestone Brant , Pagliarini Ray , Levell Julian 
Published: August 2014

Abstract
Isocitrate dehydrogenase 1 and 2 (IDH1/2) oxidize isocitrateto α-ketoglutarate (α-KG), a cofactor needed for the function of over 100 enzymes1. Heterozygous mutations of IDH1/2 occur in a variety of tumor types including glioma, acute myeloid leukemia (AML), cholangiosarcoma, chondrosarcoma and melanoma2. Mutant IDH is crippled for wild-type function but gains the ability to convert α-KG to 2-hydroxyglutarate (2-HG), a believed “oncometabolite” that may alter cell biology through, in part, changes in global histone and DNA methylation 1,3,4.
However, the dearth of in vivo models dependent upon mutant IDH has made understanding the biological relevance of IDH mutations and 2-HG production in cancer challenging. To better understand the role that IDH mutations play in oncogenesis, and the potential effects of inhibition of these mutations, we introduced a heterozygous point mutation of IDH1 (R132H) into the endogenous locus of the HCT116 colon carcinoma cell line. When compared with the parental IDH1 wild-type HCT116 model, HCT116 IDH1R132H/+ xenograft tumors produce significantly higher levels of 2-HG. In addition, we have identified a patient-derived melanoma model, HMEX2838, which harbors an endogenous IDH1R132C/+ mutation and expresses high levels of 2-HG.
To better explore the biology of mutant IDH inhibition, we developed a mutant-selective IDH inhibitor with favorable in vivo properties. Using this compound we demonstrate that 2-HG production is strongly inhibited in both the engineered HCT116 IDH1R132H/+ xenograft model and the endogenously mutant HMEX2838 patient-derived xenograft model. The data we have generated suggests that this inhibition of 2-HG directly correlates with the area under the curve (AUC) of free-drug above the HCT116 IDH1R132H/+ cellular IC50, as determined in vitro. Using these models and our IDH inhibitors we hope to gain a better understanding of how IDH mutations contribute to cancer and how inhibition of the mutant enzyme could benefit patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A144.
Citation Format: Kelly L. Slocum, Julia Downall, Ty Gould, Mohammad Zafari, Stephanie Dodd, Brant Firestone, Ray Pagliarini, Julian Levell. Inhibition of 2-HG production in IDH mutant 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 A144.
Abstract A164: Targeting PDK1 in breast cancer: Kinase-dependent regulation of tumor growth and kinase-independent regulation of cell migration and invasion.
Authors: Gagliardi Paolo Armando , di Blasio Laura , Seano Giorgio , Sessa Roberto , Puliafito Alberto , Bussolino Federico , Primo Luca 
Published: August 2014

Abstract
3-Phosphoinositide Dependent Kinase 1 (PDK1) is the kinase that phosphorylates the activation loop of several protein kinases such as Akt, PKC or SGK. In breast carcinomas PDK1 was found frequently overexpressed and this correlates with a more aggressive phenotype. This study is aimed to understand the role of PDK1 in breast tumor progression and the molecular mechanisms involved. Using stable gene silencing and kinase inhibitors we studied PDK1 role in different in vitro and in vivo assays including anchorage independent growth, anoikis, xenografts, migration and invasion assays. In our study we found that PDK1 promotes resistance to anoikis, anchorage independent growth and tumor growth in breast cancer cell lines through the phosphorylation of its substrates, since the kinase-dead mutant abrogates all the PDK1-mediated effects. For this reasons either PDK1 gene silencing or its chemical kinase inhibition are sufficient to promote anoikis, to reduce anchorage independent growth and tumor growth. We also found that PDK1 silencing is able to reduce, while its overexpression to increase cell migration and invasion in mammary cells. Surprisingly, the regulation of cell migration is operated in a kinase independent manner, in fact PDK1 kinase inhibitor failed to recapitulate the effects of gene silencing in cell migration. The molecular mechanism, underlying this unconventional kinase-independent regulation of cell migration involves the binding of PDK1 to Myotonic Dystrophy kinase-related Cdc42-binding Kinase α (MRCKα). This binding increases MRCKα kinase activity on Myosin Light Chain-2 (MLC2) and on myosin phosphatase target subunit 1 (MyPT1). Both these phosphorylations promote increase of non-muscular myosin activity, which is required to pull forward the cell body during directional migration and invasion. In summary, our findings unveil that PDK1 regulates tumor growth, survival in absence of adhesion, resistance to anoikis, but also migration and invasion of breast cancer cells by two different mechanisms. These findings should be taken in account for a rational targeting of PDK1 in cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A164.
Citation Format: Paolo Armando Gagliardi, Laura di Blasio, Giorgio Seano, Roberto Sessa, Alberto Puliafito, Federico Bussolino, Luca Primo. Targeting PDK1 in breast cancer: Kinase-dependent regulation of tumor growth and kinase-independent regulation of cell migration and invasion. [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 A164.
Abstract A172: PM060184 is a new tubulin binding agent that induces strong antitumor activity in xenografted tumors.
Authors: Guillén Maria José , Cataluña Oscar , Palomares Mandy , Aviles Pablo M. 
Published: August 2014

Abstract
PM060184 is a new synthetic tubulin-binding agent, originally isolated from the marine sponge Lithoplocamia lithistoides. PM060184 has demonstrated to display a very strong in vitro antitumor activity against a broad panel of tumor cell lines. The in vivo evaluation for antitumor activity of PM060184 was accomplished by using a panel of five human-derived xenografted tumors: colon (HCT-116), gastric (HGC-27), NSCLC (H460), prostate (22RV1) and renal (Caki-1). Briefly, 4 to 6 week-old athymic nu/nu mice were subcutaneously implanted into their right flank with 0.050 mL of a mixture (50:50; v/v) of cell suspension and Matrigel. When tumors reached ca. 150-200 mm3, tumor bearing animals (N=10/group) were randomly allocated into the following treatment groups: i) Placebo; ii) PM060184 (8 mg/kg); and, iii) PM060184 (16 mg/kg). Treatments were intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14). Tumor dimensions were recorded 3 times per week starting from the first day of treatment (Day 0). Tumor volume was calculated using the equation (a·b2)/2, where a and b were the longest and shortest diameters, respectively. Antitumor effect was calculated by using ΔT/ΔC, defined as the percentage of the change in tumor volume for each treated (T) and placebo (C) group. Complete tumor regressions (CR) were monitorized during the experimental period. Results are summarized in Table 1. PM060184 induced very strong antitumor effect in all the tumors evaluated and was able to induce complete tumor regressions in HCT-116, HGC-27 and 22RV1 xenografted tumors. Also, PM060184 demonstrated its capability to in vivo induce extensive necrotic areas in H460 and 22RV1 tumors. Taken together, the results presented in this work support the development of PM060184 as an anticancer agent in the clinic.
Table 1.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A172.
Citation Format: Maria José Guillén, Oscar Cataluña, Mandy Palomares, Pablo M. Aviles. PM060184 is a new tubulin binding agent that induces strong antitumor activity in xenografted tumors. [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 A172.
Abstract A185: Menin functions as a gatekeeper of the proliferative MAPK arm of K-Ras signaling.
Authors: Chamberlain Chester , German Michael 
Published: August 2014

Abstract
Activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas, but have never been found in pancreatic endocrine tumors, which more commonly inactivate tumor suppressors such as MEN1, the gene mutated in the autosomal dominant cancer syndrome Multiple Endocrine Neoplasia type 1, showing that outcomes of K-Ras signaling depend on cellular context. We have shown that K-Ras does not promote but instead strongly suppresses endocrine cell growth and that this paradoxical activity derives from the Men1 gene product Menin. We have proposed a model in which K-Ras activates both the pro-proliferative MAPK pathway, and the anti-proliferative RASSF1 pathway. In tissues susceptible to MEN1 gene mutation, Menin normally prevents the MAPK effector pathway from driving proliferation while leaving the inhibitory RASSF1 effector pathway intact. In this model, loss of Menin causes proliferation due to removal of the block in MAPK-driven proliferation downstream of K-Ras, while loss of K-Ras signaling increases proliferation by decreasing the unopposed RASSF1 activity in susceptible cells. To test this model, we assessed the effect of various inhibitors of the K-Ras pathway on beta cell proliferation in cultured mouse islets. We found that treatment with a combination of farnesyl- and geranyl-geranyl-transferase inhibitors, which block K-Ras signaling, stimulated beta cell proliferation; but blocking MAPK signaling with an inhibitor of Mek1/2 had no effect on proliferation rate. However, in beta-cells with reduced Men1 gene dosage, both K-Ras and Mek1/2 inhibition reduced the increased basal replication rate, consistent with our model that Menin specifically blocks pro-proliferative outputs of the MAPK arm of K-Ras signaling. Remarkably, complete loss of Men1 created a synthetic lethal interaction with Mek1/2 inhibition. Our study suggests that inhibitors of the Raf/MEK/ERK pathway offer a rational therapy for tumors with germline or somatic MEN1 mutations.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A185.
Citation Format: Chester Chamberlain, Michael German. Menin functions as a gatekeeper of the proliferative MAPK arm of K-Ras signaling. [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 A185.
Abstract A187: Matrix metalloproteinase-9 as a novel therapeutic target in B-cell chronic lymphocytic leukemia.
Authors: Bailón Elvira , Ugarte-Berzal Estefanía , Amigo-Jiménez Irene , Van den Steen Philippe , Opdenakker Ghislain , García-Marco José A. , García-Pardo Angeles 
Published: August 2014

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) cells secrete matrix metalloproteinase-9 (MMP-9) at higher levels than normal B-cells. We previously showed that MMP-9 is also constantly present on the surface of B-CLL cells, where it binds to a docking complex containing alpha4beta1 integrin and CD44v. Interaction of MMP-9 with these receptors contributes to B-CLL progression since: 1) elicits a signaling pathway that leads to cell survival, and 2) regulates in vitro cell migration (Redondo-Muñoz et al, Blood 2008, Cancer Cell 2010). We have now addressed the effect of MMP-9 overexpression at the cell surface, a situation likely occurring at B-CLL niches. We have used primary B-CLL cells as well as stable MEC-1 cell transfectants, containing either empty (Mock) or MMP-9-encoding lentiviral vectors. In vivo experiments using NOD/SCID mice showed that MMP-9-MEC-1 transfectants had significantly impaired homing to bone marrow and spleen, compared to Mock-cells. Importantly, incubation of primary B-CLL cells with MMP-9 inhibited their homing to these organs. Inhibition of migration was dose-dependent and only partially involved the catalytic MMP-9 activity, as the inactive mutant MMP-9MutE had a partial effect. MMP-9-MEC-1 cells or primary B-CLL cells incubated with MMP-9 showed reduced activation of key signaling pathways involved in cell migration, such as Akt, ERK, FAK and RhoAGTPase. In contrast, PTEN, a phosphatase that antagonizes Akt, ERK and FAK signaling and inhibits migration, and the RhoA inhibitor p190RhoGAP were upregulated in MMP-9-cells and B-CLL cells overexpressing MMP-9. Moreover, MMP-9-cells were more resistant to fludarabine or arsenic trioxide cytotoxic treatments than Mock-cells, indicating that MMP-9 also protected B-CLL cells from drug-induced apoptosis. Altogether our results reveal novel functions for MMP-9 likely contributing to malignant cell retention in lymphoid organs and drug resistance. MMP-9 thus contributes to B-CLL pathology and may represent a therapeutic target in this disease.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A187.
Citation Format: Elvira Bailón, Estefanía Ugarte-Berzal, Irene Amigo-Jiménez, Philippe Van den Steen, Ghislain Opdenakker, José A. García-Marco, Angeles García-Pardo. Matrix metalloproteinase-9 as a novel therapeutic target in B-cell chronic lymphocytic leukemia. [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 A187.