bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C274: FGF receptor mutations and fusions are therapeutic targets for inhibition by AZD4547.
Authors: Denz Christopher R. , Guan Nin , Jacques Kelly , Kilgour Elaine , Jenkins Emma , Guichard Sylvie , Smith Paul 
Published: August 2014

Abstract
Aberrant fibroblast growth factor (FGF) signaling has been implicated in tumorgenesis and chemoresistance in a number of cancer types including lung, breast, gastric, endometrial as well as others. The small molecule FGF receptor (FGFR) kinase inhibitor, AZD4547, is currently in Phase I/II clinical development (gastric, squamous lung and breast cancer) to test the FGFR amplified tumor-driven hypothesis. Our aim was to identify and characterize additional genetic subtypes based on reported FGFR aberrations and determine the sensitivity to AZD4547. Eight mutations in FGFR2: G614V, W290C, H544Q, D238N, N211I, T786K, K659N, and N550K and 3 mutations in FGFR3: S249C, R248C, Y373C, plus the FGFR fusions FGFR3-TACC3 and FGFR1-TACC1 found in ∼3% of glioblastoma [Singh et al., Science 337, 1231 (2012)] were assessed for in vitro transformation of normal breast epithelial cells (MCF10A) in a 3D soft agar colony formation assay. Several FGFR mutations/fusions were able to drive in vitro transformation as well as increase downstream signaling (pFGFR, pFRS2) in MCF10A engineered lines. For most FGFR mutations AZD4547 inhibited colony formation and downstream signaling at concentrations comparable to the WT isoforms (10-&lt;1nM). Although AZD4547 inhibited N550K, a shift in potency was observed (&gt;100nM). Taken together, these findings characterized gain-of-function mutations in FGFR2, FGFR3, and FGFR-TACC fusions and demonstrated the antiproliferative activity of AZD4547 against key genetic sub-types of FGFR aberrant cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C274.
Citation Format: Christopher R. Denz, Nin Guan, Kelly Jacques, Elaine Kilgour, Emma Jenkins, Sylvie Guichard, Paul Smith. FGF receptor mutations and fusions are therapeutic targets for inhibition by AZD4547. [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 C274.
Abstract C276: Ruxolitinib induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells.
Authors: An Ho Jung , Choi Eun Kyoung , Kim Jin-Sun , Hong Seung-Woo , Moon Jai-Hee , Shin Jae-Sik , Ha Seung-Hee , Kim Kyu-Pyo , Hong Yong Sang , Lee Jae-Lyun , Choi Eun Kyung , Lee Jung Shin , Jin Dong-Hoon , Kim Tae Won 
Published: August 2014

Abstract
Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated to role of JAKs in colorectal cancer in order to develop effective therapeutic targets for ruxolitinib, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of ruxolitinib on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. Ruxolitinib inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. Ruxolitinib causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow ruxolitinib-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by ruxolitinib results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C276.
Citation Format: Ho Jung An, Eun Kyoung Choi, Jin-Sun Kim, Seung-Woo Hong, Jai-Hee Moon, Jae-Sik Shin, Seung-Hee Ha, Kyu-Pyo Kim, Yong Sang Hong, Jae-Lyun Lee, Eun Kyung Choi, Jung Shin Lee, Dong-Hoon Jin, Tae Won Kim. Ruxolitinib induces apoptotic cell death through the suppression of pJAK1 in human colon cancer 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 C276.
Abstract C278: Topoisomerase 1 immunoassay provides proof of target engagement by the indenoisoquinoline class of topoisomerase 1 inhibitors in canine lymphomas.
Authors: Pfister Thomas D. , Ferry-Galow Katerine V. , Mohabbat Tariq , Kinders Robert J. , Khanna Chand , Mazcko Christina , Parchment Ralph E. , Pommier Yves , Tomaszewski Joseph E. , Doroshow James H. 
Published: August 2014

Abstract
Topoisomerase I (Top1) is the molecular target for a number of drugs used in cancer chemotherapy. Several third generation Top1 inhibitors are being evaluated, including the indenoisoquinolines (NSC 725776 and NSC743400) which are currently in clinical trials at the National Cancer Institute. We previously reported the development and validation of a quantitative ELISA to measure Top1 levels in cells and solid tissues [PloS ONE (2012) 7(12)]. We observed a large variation in baseline Top1 levels in xenografts and human patient biopsies using the published method. Baseline Top1 levels in needle biopsies for some patients were too low to allow for the reporting of a drug effect. We have modified our tissue processing procedures to improve assay sensitivity. We have also demonstrated the fitness of the assay in a clinical trial of the indenoisoquinolines for canine lymphoma as a stepping stone to human clinical trials. Baseline Top1 levels in canine lymphoma patients varied greatly, consistent with our previous findings in xenografts and a limited number of human tumor biopsies. These data suggest that it may not be possible to measure drug effect based on post-dose Top1 levels alone, but will require paired pre-dose and post-dose specimens from the same patient. Decreased Top1 levels following therapy (compared to pre-dose) were detected in tumors from a number of dogs, each treated with one of three indenoisoquinolines (NSC706744, NSC 725776 and NSC743400), demonstrating evidence of target engagement as predicted by in vitro and xenograft models. Measurement of baseline Top1 levels in this trial will be correlated with the degree of drug-related target reduction and evidence of drug efficacy in the dogs enrolled on this study. Funded by NCI Contract No. HHSN261200800001E.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C278.
Citation Format: Thomas D. Pfister, Katerine V. Ferry-Galow, Tariq Mohabbat, Robert J. Kinders, Chand Khanna, Christina Mazcko, Ralph E. Parchment, Yves Pommier, Joseph E. Tomaszewski, James H. Doroshow. Topoisomerase 1 immunoassay provides proof of target engagement by the indenoisoquinoline class of topoisomerase 1 inhibitors in canine lymphomas. [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 C278.
Abstract C279: Novel anthracenedione derivatives demonstrating several potential modes of actions.
Authors: Pumuye Paul P. , Medan Jelena E. , Sleebs Brad , Watson Keith , Evison Benny J. , Phillips Donald R. , Cutts Suzanne M. 
Published: August 2014

Abstract
DNA has been regarded as the primary target of numerous non-specific cytotoxic anticancer agents such as the nitrogen mustards and anthracycline antibiotics. The anthracyclines, most notably doxorubicin, proved to be highly potent and were thus incorporated into numerous chemotherapeutic regimens. However, their dose dependent redox activity that presumably contributes to their broad spectrum versatility is also associated with potentially lethal cardiotoxic adverse effects and thus, inspired the development of synthetic analogues including the anthracenediones. Like the anthracylines, their structural frame constitutes the DNA intercalating anthraquinone chromophore with functional amino groups stabilizing its insertion via hydrogen bonds and Van der Waal interactions. This interaction poisons the topoisomerase II cleavable complex which induces widespread DNA strand breaks culminating in the induction of apoptosis.
We have shown that the availability of the methyl donating molecule, formaldehyde, generates adduct formation via a covalent aminal linkage between the exocyclic N2 amino group of guanine residue at specific CpG dinucleotides and an amino group on the anthracenediones side chains. The formaldehyde mediated DNA adduct formation, achievable via simultaneous formaldehyde-releasing prodrug administration, increases cancer cell toxicity and potentially endows general cardioprotective activity. Such cardioprotection has been associated with formaldehyde-mediated doxorubicin-DNA adducts
We have synthesised a new series of anthracenediones that vary in their potential to induce covalent DNA adducts. We now show that the new anthracenediones including pixantrone (unlike the anthracyclines) also exhibits a preference for forming adducts with single stranded DNA and RNA, and these have similar characteristics to adducts that are formed with DNA.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C279.
Citation Format: Paul P. Pumuye, Jelena E. Medan, Brad Sleebs, Keith Watson, Benny J. Evison, Donald R. Phillips, Suzanne M. Cutts. Novel anthracenedione derivatives demonstrating several potential modes of actions. [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 C279.
Abstract C281: The carcinogen cadmium promotes activation of lysine 63 (K63)-linked ubiquitin-dependent signaling by inhibiting selective autophagy and CYLD K63 deubiquitination.
Authors: Chargui Abderrahman , Belaid Amine , Imbert-Rezzonico Véronique , Samson Michel , Guigonis Jean-Marie , L'hoste Sebastien , Tauc Michel , Peyron Jean François , Poujeol Philippe , Hofman Paul , Mograbi Baharia 
Published: August 2014

Abstract
K63-linked ubiquitination– i.e. conjugation of a chain of ubiquitins (Ub) linked through lysine 63– has emerged as a key mechanism regulating signaling transduction pathways. Although critical, very little information is currently available about how subversion of K63 ubiquitination might contribute to inflammatory diseases and cancers. The present study provides the first evidence that cadmium (Cd), a widespread environmental carcinogen, is a powerful activator of K63 ubiquitination. Indeed, Cd induces accumulation of K63 polyubiquitinated proteins, independently of oxidative damage, activation of ubiquitin ligase or proteasome impairment. Rather, we demonstrate that Cd activates K63 ubiquitination by inhibiting both CYLD and autophagy, two tumor suppressors that selectively deubiquitinate and degrade K63-linked ubiquitinated proteins, respectively. As a result, we found that cadmium treatment induces sustained activation of NF-κB, a pathway critically dependent on K63 ubiquitination. Given the role of NF-κB in survival, proliferation, and inflammation, these findings provide a potential molecular link between cadmium exposure and the increased incidences of inflammatory diseases and cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C281.
Citation Format: Abderrahman Chargui, Amine Belaid, Véronique Imbert-Rezzonico, Michel Samson, Jean-Marie Guigonis, Sebastien L'hoste, Michel Tauc, Jean François Peyron, Philippe Poujeol, Paul Hofman, Baharia Mograbi. The carcinogen cadmium promotes activation of lysine 63 (K63)-linked ubiquitin-dependent signaling by inhibiting selective autophagy and CYLD K63 deubiquitination. [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 C281.
Abstract C29: Characterization and identification of specific EGFR mutations in circulating tumor cells (CTCs) isolated from non-small cell lung cancer patients using an antibody independent method, ApoStream™: An update report.
Authors: Tran Hai T. , Melnikova Vladislava , Tsao Anne S. , Fossella Frank V. , Johnson Faye M. , Papadimitrakoupoulou Vali , Richardson Katherine , Lewis Marcia E. , Legendre Ben , Anderes Kenna L. , Davis Darren W. , Heymach John V. 
Published: August 2014

Abstract
Background: A variety of methods for capture of rare CTCs of epithelial origin are available; most employ antibodies to epithelial cell adhesion molecule (EpCAM) and cytokeratin (CK). Using a classic phenotypic definition, a CTC is nucleated, CK(+), CD45(-) cell. However, some CTCs may elude capture as they originate from primary tumor cells which have undergone epithelial-mesenchymal transition (EMT). We report here the use of ApoStream™, a novel dielectrophoresis field-flow-assisted, antibody-free method to isolate CTCs from blood.
Methods: Blood was collected from consented NSCLC patients and processed using ApoStream™. For CTC enumeration comparison, the CellSearch® FDA-approved kit was used. Isolated cells were evaluated with a multiplexed immunofluorescent assay and laser scanning cytometry was applied to identify multiple combinations of positive and/or negative staining for CK/CD45/DAPI and EpCAM. To determine specific EGFR mutations from captured CTCs, samples were analyzed using Improved and Complete Enrichment with CO-amplification at Lower Denaturation temperature (ICE COLD-PCR).
Results: Blood samples from 37 NSCLC patients and 8 healthy volunteers were processed and the results of the cell populations isolated using ApoStream™ are summarized in table. EGFR mutations [exon 19 deletion and exon 21 L858R] were determined and found to be concordant when compared to tumor tissue analysis by Sanger sequencing.
Conclusions: The ApoStream™ platform enriched EpCAM(+) and EpCAM(-) CTCs from the blood of NSCLC patients demonstrating utility in recovering cancer cells with multiple phenotypes. From recovered CTCs, detection of EGFR mutations was possible indicating the clinical relevance and potential utility of CTCs as an alternative to tissue biopsy. Additional sensitivity and complete mutation analysis will be presented. (a portion of this data was presented at 2013 ASCO Annual Meeting, Chicago, IL, USA)

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C29.
Citation Format: Hai T. Tran, Vladislava Melnikova, Anne S. Tsao, Frank V. Fossella, Faye M. Johnson, Vali Papadimitrakoupoulou, Katherine Richardson, Marcia E. Lewis, Ben Legendre, Kenna L. Anderes, Darren W. Davis, John V. Heymach. Characterization and identification of specific EGFR mutations in circulating tumor cells (CTCs) isolated from non-small cell lung cancer patients using an antibody independent method, ApoStream™: An update report. [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 C29.
Abstract C298: Conformational characterization of tumor suppressor protein Merlin and phosphomimetic Merlin(S518D) mutant in solution.
Authors: Ali Khajeh Jahan , Atchiba Moussoubaou , Bu Zimei 
Published: August 2014

Abstract
Merlin is a tumor suppressor protein that inhibits cell proliferation upon establishing cell-cell contacts. Because Merlin is homologous to the Ezrin-Radixin-Moesin (ERM) family of proteins, the structural model of ERM proteins cycling between closed/resting and open/active conformational states is employed to explain Merlin function. Nevertheless, using the ERM protein model has generated confusion about the mechanisms of Merlin tumor suppressor activity. Here, using contrast-matching small angle neutron scattering (SANS), we have determined the molecular shapes of Merlin and its phosphomimetic Merlin(S518D) mutant. In solution, both Merlin and Merlin(S518D) adopted a closed conformation that is capable of binding to the scaffolding protein NHERF1 with comparable binding affinities. However, in the presence of the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), the wild-type Merlin shifts toward an open conformation whereas Merlin(S518D) remains locked in a closed conformation. Our data implied that although Merlin has similar molecular shape as ERM proteins, it has different protein-binding properties, and phosphorylation and PI(4,5)P2-binding modulate its conformational changes differently from ERM proteins.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C298.
Citation Format: Jahan Ali Khajeh, Moussoubaou Atchiba, Zimei Bu. Conformational characterization of tumor suppressor protein Merlin and phosphomimetic Merlin(S518D) mutant in solution. [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 C298.
Abstract C32: PTEN and p53 expression in endometrial cancer correlated with clinicopathological phenotype.
Authors: Kularatne Bihani , Capitanio Arrigo , Arora Rupali , Jones Philippa , Lopes Andre , Paterson Jennifer , Kristeleit Rebecca 
Published: August 2014

Abstract
p53 overexpression and loss of PTEN expression have been implicated in the pathogenesis of endometrial cancer. Our aim was to correlate expression levels of these proteins with clinicopathological parameters to characterise their utility as biomarkers.
Immunohistochemistry was done on 49 cases of formalin fixed paraffin embedded endometrial cancer tissue for p53 and 47 for PTEN expression. For p53 staining the Hue Saturation and Intensity mathematical model was used to evaluate different degrees of positivity of the immunohistochemical stain. The quick score was used for p53 and immunoreactive score for PTEN was done to score immunoreactivity. For PTEN, average percentage of positive cells and intensity was evaluated and the immunoreactive score was calculated. Both these scoring methods incorporated percentage of positive cells and staining intensity.
Univariate Cox regression analysis for cause specific survival showed a hazard ratio of 9.2 for p53 overexpression (P&lt;0.05). High levels of P53 were significantly associated with histologic type, grade, LVI and recurrent disease. There was no significant association between PTEN expression and clinicopathological features but it was noted that the 8 patients who relapsed were PTEN negative. Cause specific survival could not be assessed for PTEN expression due to the lack of events in this group. PTEN and p53 (n=46) combined analysis failed to demonstrate a significant association on prognostic features in this group.

Overexpression of P53 has a negative effect on disease specific survival and was associated with poor prognostic features. We did not demonstrate a significant association with clinicopathological features assessed and PTEN expression. However of the 8 patients who relapsed all were PTEN negative and 7 were p53 positive. Dual assessment of p53 and PTEN warrants further investigation as a prognostic indicator.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C32.
Citation Format: Bihani Kularatne, Arrigo Capitanio, Rupali Arora, Philippa Jones, Andre Lopes, Jennifer Paterson, Rebecca Kristeleit. PTEN and p53 expression in endometrial cancer correlated with clinicopathological phenotype. [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 C32.
Abstract C42: Development and validation of an IHC-based detection method for studying indoleamine 2,3-dioxygenase 1 (IDO1) expression in human cancers.
Authors: Liu Xiangdong , Yang Gengjie , Margulis Alexander , Wynn Rich , Scherle Peggy , Newton Robert 
Published: August 2014

Abstract
Indoleamine 2,3-dioxygenase-1 (IDO1) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. The depletion of tryptophan and the generation of tryptophan metabolites have been demonstrated to be an important regulator of immune function. IDO1 is induced by interferons and TLR agonists and is expressed in a wide variety of human cancers as well as in the tumor-draining lymph nodes. High IDO1 expression is significantly associated with more rapid disease progression and poor prognosis in multiple cancer types. Numerous studies have shown that IDO1 negatively regulates immune functions via several potential cellular mechanisms, which in turn allows tumor escape from host immune surveillance. Therefore, inhibition of IDO1 may have therapeutic potential in cancer and IDO1 expression may serve as a selective marker of a responsive population. INCB024360, a novel IDO1-selective inhibitor, is currently being evaluated in clinical trials of cancer patients. To support the clinical development of INCB024360, we have developed and validated an immunohistochemistry (IHC)-based method using rabbit polyclonal antisera that specifically detects IDO1 protein expression. The method has been used to determine IDO1 expression in primary biopsies from patients studied in INCB024360 clinical trials. The method can be used to determine the prevalence of IDO1 expression in a variety of human cancers, identify histologic subtypes that might be associated with IDO1 expression and examine IDO1 coexpression with other immune modifying pathways.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C42.
Citation Format: Xiangdong Liu, Gengjie Yang, Alexander Margulis, Rich Wynn, Peggy Scherle, Robert Newton. Development and validation of an IHC-based detection method for studying indoleamine 2,3-dioxygenase 1 (IDO1) expression in human cancers. [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 C42.