bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A148: Targeting cholesterol pathway genes sensitizes cancer cells to EGFR inhibitors.
Authors: Gorin Andrey 
Published: June 2012

Abstract
EGFR signaling is one of the main mechanisms of providing cancer cell growth. Although blockade of this pathway is among the most widely used therapies in cancer, only 10% of patients show positive response to it. There is an unmet need in the clinic to improve the efficacy of anti-EGFR drugs.
We recently conducted siRNA screening and identified the sterol biosynthesis pathway enzymes as synergistic co-targets that strongly sensitize cells to EGFR inhibitors (Astsaturov et al., 2010). SC4MOL (sterol C4-methyl oxidase-like) and NSDHL (NADP-dependent steroid dehydrogenase-like) work in complex and catalyze the C4-demethylation step of cholesterol biosynthesis. We have found that depleting either of these enzymes sensitizes cancer cell lines to anti-EGFR therapy. Blockade of upstream and downstream enzymes of the cholesterol pathway do not cause such effect. Moreover depletion of upstream enzyme CYP51A1 abrogates the effect of SC4MOL and NSDHL blockade to response of cancer cells to EGFR inhibitors. Bioinformatic search of the evolutionarily conserved protein interactions of SC4MOL and NSDHL orthologs showed multiple connections with proteins regulating vesicular trafficking.
We postulated that blockade of sterol biosynthesis pathway at the C4-demethylating level alters regular EGFR traffic towards its degradation. We observed that loss of SC4MOL and NSDHL leads to profound loss of EGFR and its family members ErbB2 and ErbB3 and to distortion of receptor distribution inside the cells. In evidence skin keratinocytes of mosaic NSDHL-deficient Bpa1H/+ mice appeared to have reduced EGFR level comparing to normal skin.
Altogether, these data indicate that SC4MOL and NSDHL are related to trafficking of EGFR in cells that finally leads to its degradation. And, inasmuch as this receptor is one of the most usable targets in anti-cancer therapy, the blockade of these enzymes can be potentially used to prevent the resistance to EGFR inhibitors and thereby increase the efficacy of anti-EGFR therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A148.
Abstract A157: Targeting MYC dependence in cancer by inhibiting BET bromodomains.
Authors: Sims Robert 
Published: June 2012

Abstract
The MYC transcription factor is a master regulator of diverse cellular functions and has long been considered a compelling therapeutic target because of its role in a wide range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging due to both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in a variety of genetic contexts. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of cell lines. Genetic reconstitution experiments indicate that MYC predominantly mediates the phenotypes observed with BET inhibition. MYC suppression was also accompanied by deregulation of the MYC transcriptome. Treatment with a BET inhibitor resulted in significant anti-tumor activity in lymphoma and leukemia xenograft models. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A157.
Abstract A162: Targeting chromatin: Small molecules reactivating H3K27me3 silenced genes.
Authors: Chapman-Rothe Nadine , Shamsaei Elham , Cherblanc Fanny , Ganesh Thota , Snyder James P. , Fuchter Matthew J. , Brown Robert 
Published: June 2012

Abstract
There is a need for the development of compounds allowing more targeted and efficient reversal of aberrant epigenetic silencing in cancer. Recently, the discovery of histone lysine methyltransferases (HKMT) being involved in tumorgenesis as well as tumor stem cell like maintenance has sparked interest in this particular class of enzymes. We have set-up a cell based assay (MDA-MB-231) in order to identify small molecule inhibitors which are able to re-express endogenous genes where EZH2 has been shown to be involved in the silencing process. In order to identify compounds which inhibit a specific chromatin remodeler class (silencing of chromatin), we chose two DNA unmethylated EZH2 target genes (KRT17, FBXO32), which we would be expect to be re-expressed and one DNA methylated EZH2 target gene (RUNX3) which we would expect to be unaffected in case of an HKMT inhibitor. SiRNA to EZH2 increases expression of KRT17 and FBXO32, but not RUNX3. We have assayed compounds chemically related to a known HKMT inhibitor and identified compounds that up-regulate KRT17 as well as FBXO32 but fail to act on RUNX3. These compounds inhibit tumor cell growth in the low microMolar range. Chromatin immunoprecipitation (ChIP) experiments verified a decrease in silencing marks (H3K27me3, H3K9me3) and importantly an increase in active chromatin marks (e.g. H3K4me2, H3K4me3) at the promoter region of KRT17 and FBXO32. Of note, the H3K27me3 demethylase JMJD3 also showed increased binding at the promoter region which correlated with the presence of H3K4me2/3. In conclusion, we have identified compounds that induce re-expression of genes, reverse H3K27me3 mediated gene silencing and induce inhibition of tumor cell growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A162.
Abstract A167: First-in-patient study of PF-05212384, a small molecule intravenous dual inhibitor of PI3K and mTOR in patients with advanced cancer: Update on safety, efficacy, and pharmacology.
Authors: Millham Robert , Houk Brett , Borzillo Gary , Tabernero Josep , Bell-McGuinn Katherine , Bendell Johanna , Molina Julian , Kwak Eunice , Shapiro Geoffrey 
Published: June 2012

Abstract
Background: Activation of the PI3K pathway, by PIK3CA mutation or amplification or PTEN deletion, has been implicated in a wide variety of human cancers. PF-05212384 is a dual-specificity inhibitor of PI3K and mTOR that is formulated for intravenous (IV) administration. PF-05213384 is the first IV PI3K/mTOR inhibitor to be tested in a clinical trial.
Methods: In this ongoing phase 1 trial, PF-05212384 was administered once weekly, using a modified continual reassessment method (CRM) for estimation of the maximum tolerated dose (MTD). Assessments included safety (NCI CTC AE v4.0), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (RECIST v1.1). PD assessments included blood glucose and immunohistochemistry analysis of phosphoprotein biomarkers in tumor and surrogate tissue (hair follicles). The population was actively enriched for patients with dysregulation in the PI3K pathway.
Results: As of 15 March 2011, 47 patients have been enrolled at doses ranging from 10 mg to 319 mg. Median age was 58. Represented tumor types included CRC (8), NSCLC (4), ovarian/endometrial/cervical (8), salivary (3) and gastric/esophageal (3). Analysis of archived tumor biopsies revealed PI3K pathway alterations in 12/26 evaluable patients; alterations included PTEN loss, PIK3CA mutation or amplification. PF-05212384 was well tolerated with the most common AEs being mucositis (44%), nausea (42%), fatigue (28%), rash (28%), and hyperglycemia (26%). DLTs included mucositis, rash, transaminase elevation, and hyperglycemia. An MTD of 154 mg weekly has been estimated. PF-05212384 is eliminated with a half-life of approximately 16 hours, with low clearance (5–9 L/h) and relatively high volume of distribution (54–144 L). Changes in blood glucose have been observed in 13 patients, including 2 patients with Grade 3 hyperglycemia, a known effect of PI3K/Akt pathway suppression. No objective tumor response has been observed; 12 patients have achieved stable disease (SD) in excess of 16 weeks, with 9 patients on study for ≥24 weeks and one patient (salivary) on study for &gt;46 weeks. Enrollment to MTD expansion cohorts is ongoing.
Conclusions: Weekly administration of PF-05212384 is safe and tolerable across dose levels with multiple patients deriving clinical benefit with prolonged SD. The occurrence of hyperglycemia is suggestive of target modulation. Updated data for safety, PK, PD and antitumor activity will be presented
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A167.
Abstract A17: Mode of action of trabectedin in myxoid liposarcomas.
Authors: Giandomenico Silvana Di , Frapolli Roberta , Bello Ezia , Pilotti Silvana , Casali Paolo , Grosso Federica , Sanfilippo Roberta , Gronchi Alessandro , Galmarini Carlos , D'Incalci Maurizio 
Published: June 2012

Abstract
Background: Trabectedin (ET-743, Yondelis) is a marine alkaloid isolated from the tunicate Ecteinascidia turbinata, cytotoxic against a variety of tumor cell lines in vitro and human tumor xenografts in vivo. It has been approved by EMEA for the 2nd line therapy of soft tissue sarcomas in 2007 and for the 2nd line therapy of ovarian cancer in 2009. Myxoid liposarcoma (MLS) is a specific histological subtype within the family of adults soft tissue sarcomas. Specifically &gt;90% of usual myxoid/round cell liposarcomas (MLS/RCLS) are characterized by the chromosomal translocation t(12;16) (q13;p11), which produces the FUS-CHOP oncogene. Different variants of the fusion gene have been previously described but with no demonstrable prognostic effect although the type III MLS seem correlate with a more severe outcome than type II MLS.
Materials and Methods: To elucidate the mechanisms behind the differential sensitivity to trabectedin, myxoid liposarcomas type II and type III were xenografted in nude mice. When tumor load achieves about 200–400 mg mice were divided into the experimental groups. Trabectedin was administered at 0.15 mg/kg, i.v. every 7 days for three times. Tumor growth was monitored by Vernier caliper. The binding of FUS-CHOP to some of its target promoters was monitored by Chromatin Immuno Precipitation (ChIP) to verify the drug ability to displace the binding. ChIP were performed with ProtG Sepharose and the anti-FUS and anti-CHOP antibody. The immunoprecipitated DNAs were analyzed by quantitative Real Time PCR. FN1, PTX3, CDK4, IL8 and CHOP were used as target genes.
Results: We found that trabectedin was more effective on type II than type III MLS xenografts. The response to trabectedin in type II xenografts was associated with partial regression and pathological response. Type III MLS xenografts appeared much less sensitive to trabectedin and tumors did not regress. Molecular analysis revealed that trabectedin was able to remove FUS-CHOP type II and III from its own target genes 24 hours after treatment. 72 hours after treatment, FUS-CHOP Type III was attached to its targets whereas FUS-CHOP Type II remained unbound. These data explain why in order to achieve a significant regression of type III MLS xenografts a more prolonged treatment with trabectedin is required.
Conclusions: These results suggest that the different sensitivity of type II and type III MLS to trabectedin are related to a different duration of the drug ability to display FUS-CHOP from the selected target genes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A17.
Abstract A183: Whole-genome sequencing to find potential targets for therapy in patients with refractory K-ras mutated metastatic colorectal cancer.
Authors: Ramanathan Ramesh K. , Shanmugam Viji , Sinari Shripad , Chadha Manpreet , Liang Winnie , Izatt Tyler , Christoforides Alexis , Benson Hollie , Phillips Lori , Baker Angela , Hostetter Galen , Von Hoff Daniel , Craig David , Carpten John 
Published: June 2012

Abstract
Introduction: The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy, especially with a K-ras mutation is poor with median survival of less than one year. The purpose of this study was to perform whole genome sequencing (WGS) to identify therapeutically actionable somatic events in mCRC patient samples, so as to select targeted treatment strategies for individual patients.
Methods: IRB approval was obtained and 3 patients have been enrolled. All had &gt; 2 prior regimens and had known K-ras mutations (age 73, 45 and 50 years, all were male). Percutaneous needle biopsies of liver metastases were performed with whole blood collection for the extraction of constitutional DNA. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing system, which yielded coverage of greater than 30X for both the normal and tumor samples. Somatic genomic alterations (point mutations and indels, copy number alterations, translocations and rearrangements) were analyzed using our custom pipeline for paired analysis.
Results: In all 3 samples sufficient DNA was extracted for sequencing. WGS and bioinformatics analysis took 3–4 weeks for completion. We found that all 3 tumor samples had KRAS mutations, while 2 samples had mutations in the APC gene and the PIK3CA gene. Other genes with therapeutic implications in single tumor samples were INPPL1, INPP4B and SMAD4. No EGFR amplifications were detected in our sample set. The concomitant mutations in MAPK (K-ras) and PI3K (PIK3CA, INPPL1, INPP4B) pathways suggest that combination therapies might be required for effective treatment of these tumors. In two instances, tumors were sent to a CLIA laboratory to allow for clinical validation of genomic events.
Conclusions: WGS is feasible from DNA obtained from percutaneous biopsies in a clinical setting. Our study has revealed a series of therapeutically actionable events in mCRC and prospective clinical trials are needed to validate this approach.
Funded by the Bisgrove-Scottsdale Healthcare and TGEN foundations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A183.
Abstract A186: KIF14 is a novel therapeutic target for ovarian cancer.
Authors: Theriault Brigitte L. , Pajovic Sanja , Bernardini Marcus Q. , Shaw Patricia A. , Lim Harvey , Gallie Brenda L. , Gallie Brenda L. , Bernardini Marcus Q. 
Published: June 2012

Abstract
Introduction: The dismal prognosis associated with ovarian cancers (OvCa) is a consequence of late detection and ineffective strategies to prevent progression. Hence, identification and targeting of genetic events underlying OvCa tumor initiation and progression may have greater potential to achieve cure. Our study of the paediatric eye cancer retinoblastoma revealed mechanisms of cancer initiation and development, where progression is associated with specific genomic aberrations shared among multiple cancers. We identified the novel oncogene KIF14 (kinesin family member 14, chromosome 1q31–1q32), gained in many cancers including retinoblastoma, lung, breast, and ovarian. We demonstrated that KIF14 overexpression in breast and lung cancers is predictive of poor outcome. In normal cells, KIF14 acts during cytokinesis to ensure proper cell division, however its mechanism of action in cancer cells is unknown. Knowledge of the biology of KIF14 in OvCa may therefore define an important therapeutic target.
We hypothesize that KIF14 overexpression contributes to OvCa tumorigenesis.
Results: Real-time QPCR analysis of primary OvCa tumors demonstrated that KIF14 mRNA is overexpressed in the majority of OvCa tumors studied (111 out of 122 samples), regardless of histological subtype. Close to 30% of serous OvCas display genomic gain of KIF14, with similar gains in early and late stages, suggesting that gain of KIF14 could be an early event in the development of serous OvCa. Multivariate Cox regression analyzes revealed that KIF14 mRNA levels were independently predictive of poor outcome and increased rates of recurrence in serous OvCa patients, demonstrating the value of KIF14 expression as a potential marker for “high risk” serous OvCa patients. Stable in vitro overexpression of KIF14 in OvCa cells increased proliferation and soft agar colony formation, while stable shRNA knockdown of KIF14 decreased proliferation and dramatically reduced soft agar colony formation. In vivo tumor formation is also dependent on KIF14 expression, as KIF14 knockdown significantly reduced subcutaneous xenograft formation by 20-fold. These findings demonstrate the transformed phenotype is dependent on KIF14.
Conclusions: KIF14 expression is tumor-specific, can predict poor prognosis, and OvCa cells depend on KIF14 for maintenance of the transformed phenotype. Thus KIF14 overexpression is an oncogenic stimulus in OvCa, pointing to the potential utility of KIF14 expression as a prognostic biomarker, and KIF14 knockdown as a novel therapy to slow or halt OvCa progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A186.
Abstract A188: MET inhibition by SU11274 impairs proliferation, motility, and invasion in hepatocellular and cholangiocarcinomas.
Authors: Tijeras-Raballand Annemilai , Serrate Camille , Riveiro Maria Eugenia , Serova Maria , Guedj Nathalie , Bieche Ivan , Paradis Valerie , Raymond Eric , Faivre Sandrine 
Published: June 2012

Abstract
Background: Hepatocellular carcinomas (HCC) and cholangiocarcinomas (CK) are the most common primary tumors of the liver and are recognized among the most difficult tumors to treat. Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Advanced HCC and CK are often displaying aberrant MET signaling and MET overexpression was observed in many tumors resistant to tyrosine kinase inhibitors (TKI). The aim of present study was to evaluate the effects of MET inhibition by SU11274 on HCC and CK cell proliferation and invasion.
Materials and Methods: SU11274 is a pyrrole indolinone that specifically inhibits overexpressed and oncogenic MET activation at nanomolar concentrations. MET expression was assessed on human paraffin-embedded liver section by immunohistochemistry. Antiproliferative effects of SU11274, were evaluated in human HCC (SK-Hep1 and its sunitinib-tolerant counterpart SK-Suni) and CK (Mz-chA-1, Mz-chA-2, SK-ch) cell lines using a MTT assay. mRNA expression and protein levels were respectively assessed by qRT-PCR and Western blot. Cell mobility was investigated by wound-healing and matrigel invasion assays.
Results: Higher MET protein expression was observed in human HCC and CK samples respect to normal tissues. MET-protein and -mRNA expression were detectable in all tested cell lines, Mz-ChA-1 and Mz-ChA-2 expressing higher MET levels. HGF-induced MET activation was associated with increase of p-METTyr1234/35, p-GAB1, p-ERK1/2, and p-AKTser473 in SK-CH, Mz-chA-2, SK-Hep1 and SK-Suni cells. We show that SU11274 inhibited HGF-induced downstream signaling by reducing p-METTyr1234/35, p-GAB1, p-AKT473 and p-ERK1/2 in HCC and CK cells at concentrations ranging from 0.5 to 2μM. However, antiproliferative effects were only observed for concentration above 2 μM (2,5 and 5 μM), In SK-Suni cells that are tolerant to high dose of sunitinib, proliferation was not inhibited even at the higher SU11274 dose (5μM). Interestingly, SU11274 potently decreased the spontaneous and HGF-dependent cell motility and invasion of Mz-chA-2 cells.
Conclusion: In HCC and CK cells, inhibition of MET-signaling by SU11274 resulted in inhibition of cell proliferation, motility and invasion. HCC and CK may be interesting tumor types to evaluate novel MET inhibitors either as single agents and/or in combination with other targeted therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A188.
Abstract A190: Effect of anti-VEGF acute treatment on tumor uptake of trastuzumab in a xenograft model.
Authors: Pastuskovas Cinthia V. , Boswell C. Andrew , Mundo Eduardo E. , Williams Simon P. , Tibbitts Jay , Khawli Leslie A. 
Published: June 2012

Abstract
Overexpression of both human epidermal growth factor receptor 2 (HER-2/neu) and vascular endothelial growth factor (VEGF) are associated with aggressive disease and decreased survival among breast cancer patients. Accordingly, the combination of bevacizumab (anti-VEGF) with trastuzumab (anti-HER2) has demonstrated promising results in both preclinical and clinical studies. However, little is known about anti-VEGF antibody's effects on the disposition and pharmacokinetics of other antibodies. This study assessed the biodistribution of trastuzumab in the presence or absence of an anti-VEGF antibody, with a particular emphasis on tumor uptake. Mice bearing HER2 expressing KPL-4 breast cancer xenografts received trastuzumab or a non-HER2 binding antibody radiolabeled with either 125I or 111In to assess the real time kinetics and cumulative tumor uptake with and without pre-administration of an anti-VEGF antibody. Acute anti-VEGF treatment reduced tumor uptake of trastuzumab. This effect was consistently observed by tissue distribution, autoradiography, and SPECT-CT imaging despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2. Reduced tumor blood flow was observed following anti-VEGF treatment, and immunohistochemistry showed evidence of reduced vascular density. In conclusion, anti-VEGF pre-administration resulted in decreased tumor uptake of trastuzumab, and this phenomenon may be explained, at least in part, by reduced vascular permeability and blood flow. These findings add to the current understanding of combination anti-HER2/anti-VEGF therapy and may ultimately lead to improved clinical outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A190.