bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A26: Autophagy acts as a safeguard mechanism against G-quadruplex ligand-mediated telomere damage.
Authors: Folini Marco , Orlotti Nicola I. , Cimino-Reale Graziella , Borghini Erika , Daidone Maria Grazia , Palumbo Manlio , Sissi Claudia , Zaffaroni Nadia 
Published: June 2012

Abstract
G-quadruplex structures have attracted considerable interest as targets for the development of novel anticancer therapies due to their capability to interfere with telomere structure and function. Elucidation of the structures of telomeric G-quadruplexes has led, in the past few years, to the rational development of effective G-quadruplex-stabilizing small molecules. In the present study we show that short-term exposure of melanoma cells to Ant1,5 (an anthracene-based telomeric G-quadruplex stabilizer) impaired cell growth without inducing cell senescence or apoptosis. Conversely, drug-treated cells were characterized by the occurrence of typical biochemical and morphological features usually associated to autophagy, such as an increase in the lipidated form of the autophagic marker LC3b and its co-localization with the lysosome marker LAMP2A. Such drug-induced autophagy occurred as a consequence of telomere uncapping and associated DNA damage response, through a pathway converging on the cyclin-dependent kinase inhibitor p21waf1. The inhibition of autophagy by the pharmacologic inhibitor Bafilomycin A1 or through RNAi-mediated depletion of ATG5 gene enhanced the cytotoxic activity of Ant1,5, as revealed by the marked increase in drug-induced apoptosis. Our data outline a molecular scenario in which G-quadruplex ligand-induced telomeric dysfunctions are translated into an autophagic response and provide the first evidence of autophagy as a safeguard mechanism activated by melanoma cells to counteract drug-mediated telomeric stress. As a consequence, interference with the autophagy pathway in melanoma could be a suitable approach to extend the therapeutic options for this malignancy.
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 A26.
Abstract A29: Bcl-2 overexpression provides short-term resistance to doxorubicin-DNA adducts but does not protect against longer-term treatments in HL-60 cells.
Authors: Ugarenko Michal , Rephaeli Ada , Nudelman Abraham , Koch Tad H. , Phillips Don R. , Cutts Suzanne M. 
Published: June 2012

Abstract
The anthracycline anticancer agent doxorubicin functions primarily as a topoisomerase II inhibitor but forms more cytotoxic DNA adducts in the presence of formaldehyde. For this reason, the efficacy of doxorubicin can be greatly enhanced with the co-administration of formaldehyde-releasing prodrugs such as AN-9. The combination of doxorubicin with AN-9 results in DNA adduct formation and synergistic apoptosis in HL-60 leukemic cells after 6 hr. Under the same conditions HL-60 cells overexpressing the anti-apoptotic protein Bcl-2 (HL-60/Bcl-2 cells) are completely resistant to doxorubicin/AN-9 treatments. This resistance can be overcome with the use of the small molecule Bcl-2/Bcl-xL/BCL-W inhibitor ABT-737.
While it appears that Bcl-2 overexpression confers resistance and thus may limit the therapeutic potential of doxorubicin-DNA adduct forming treatments, this is shown to be only a short-term effect. The use of a DNA adduct forming doxorubicin-formaldehyde conjugate, doxazolidine, produced similar results to the doxorubicin/AN-9 combination with HL-60/Bcl-2 cells being resistant to the drug after 4 hr treatment. This resistance was maintained up to 12 hr treatment, however, after 18 hr the HL-60/Bcl-2 cells started to display classical hallmarks of apoptosis including DNA fragmentation, and chromatin condensation which increased over time (18–36 hr). These results suggest that the Bcl-2 protection is only short-lived and that over time the resistance is overcome and the cells die via classical apoptosis. The exact mechanisms involved in overcoming this resistance in HL-60/Bcl-2 cells are currently being investigated and may involve changes in expression of Bcl-2 family proteins, or Bcl-2 interactions with pro-apoptotic proteins which tip the balance in favour of apoptosis. These findings imply that the damage caused by these DNA adduct forming compounds may be sufficient to overcome Bcl-2 mediated resistance observed in tumors in vivo.
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 A29.
Abstract A3: Axitinib combined with paclitaxel and carboplatin in melanoma: Response in genetically selected subsets.
Authors: Daud Adil , Cha Edward , Ziani Leslie , Cortez Brandon , Algazi Alain P. 
Published: June 2012

Abstract
Background: Axitinib is a potent VEGFR inhibitor. We tested the hypothesis that axitinib could increase the effectiveness of carboplatin/paclitaxel in specific subtypes of advanced melanoma.
Methods: A prospective single arm phase I/II trial of this combination was initiated August 2010 in metastatic melanoma (NCT01174238) at UCSF. Twenty seven patients have been enrolled, 16 are evaluable for response to date. Patients had an ECOG PS 0–1, and normal organ function. Axitinib 5 mg PO bid was taken days 1 − 14 of each 21-day cycle, and carboplatin/paclitaxel was administered on day 21. Biopsy specimens were sequenced for mutations in BRAF, NRAS, c-KIT, GNAQ and G11 and FLT-PET scans were done in selected patients to on days 1, 14, 17, and 20 of cycle 1.
Results: This regimen was well tolerated with adverse events including GI toxicity, musculoskeletal pain, fatigue, hypertension, and mild sensory neuropathy. Grade 3 adverse events have been uncommon, and grade 4 adverse events have not been observed. Four of 13 WT/NRAS patients have had a PR by RECIST, 7/13 have had some shrinkage of tumor while only 2/13 have had PD. Of the 3 patients with BRAF V600 E/K mutations, all have had PD. In the overall study population, median OS and PFS have not been reached.
Conclusions: Striking activity was seen in patients whose tumors are WT for BRAF including those with NRAS mutation. Given the urgent need for effective therapies in this population, this combination warrants further study.
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 A3.
Abstract A32: Novel ceramide analogs induce apoptosis in chemoresistant breast cancer.
Authors: Ponnapakkam Adharsh , Beckman Barbara , Foroozesh Maryam 
Published: June 2012

Abstract
Ceramide, a central molecule in sphingolipid metabolism, has been shown to mediate cell death by both apoptotic and non-apoptotic pathways. However, the use of endogenous ceramides as a pharmacological intervention is limited by the naturally hydrophobic nature of the ceramide molecule, which prevents efficient penetration of the cellular membrane. One novel approach is to synthesize ceramide analogs with a greater efficacy and specificity than endogenous ceramides. Our laboratory has previously shown that ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and -resistant breast cancer. In this study, the effect of 5 novel ceramide analogs (designated 401–406) on cellular viability and clonogenic survival was examined in the chemosensitive MCF-7, endocrine-resistant MDA-MB-231, and chemoresistant MCF-7TN-R breast cancer cell lines, as well as the Human Embryonic Kidney (HEK) cell line. In the viability assay, analogs 401 and 406 showed the greatest efficacy in the MCF7-TNR cell line, with IC50 values of 4.0 μM and 4.2 μM in metastatic MCF-7TN-R cells. In the clonogenic survival assay, analogs 401 and 406 were again the most effective in the MCF7-TNR cell line with IC50 values of 1.9 and 1.8 respectively. Additionally, Analog 406 showed a 3.8 fold increase over control in the induction of apoptosis (p&lt;0.05), and demonstrated a 3.4-fold increase in caspase-9 activity (p&lt;0.05). Because ceramide has been shown to be involved in tumor sensitivity to apoptosis and chemoresistance, we suggest that development of ceramide analogs with increased antitumor activity represents a potential new class of chemotherapeutic agents.
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 A32.
Abstract A40: A novel cMET pharmacodynamic assay using human hair follicles.
Authors: Mo Jan-Rung , Egge Bryan , Sykes Kara , Li Lixia , Ware Chris , Laskey Jason , Wexler Roseanne , Reilly John , Young Jonathan , Marshall Gary , Strack Peter 
Published: June 2012

Abstract
The Receptor Tyrosine Kinase cMET is an oncogenic driver of gastric and lung cancer. Clinical development of cMET inhibitors to treat these cancers would be aided by a robust Pharmacodynamic (PD) marker, as we have observed heterogenous expression of phosphor-cMET (pMET) in these tumor types with limited clinical access. Here we describe the development of a novel cMET PD marker in plucked human hair follicles to address these issues. To evaluate the presence of activated cMET this surrogate tissue, 50 ug of protein extract derived from 25 plucked human hair follicles was analyzed by Receptor Tyrosine Kinase arrays. Active EGFR, HER2, HER3 IGF1R, Insulin receptor, EphA1, EphB2, and ROR1 were observed; however, no active MET was detected. Ex vivo treatment of human hair follicles with the cMET ligand HGF did however induce activation of MET as measured by pMET. A quantitative METpY1349 mesoscale assay demonstrated that HGF activated MET could be detected in a little as 2 human hair follicles or 1 ug of protein. HGF (EC50 22 ng/ml) induced a 22–38 fold time-dependent increase in pMETpY1349 and could be inhibited by the selective cMET inhibitor MK-2461 (IC50 63 nM). Current efforts to translate this assay to preclinical species will be described. These data provide additional evidence for the expression of functional cMET in human hair follicles and assays described may provide alternative means for measuring cMET inhibitor effect in a clinically relevant surrogate tissue.
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 A40.
Abstract A46: A novel immunoassay (ELISA) for quantitative gamma-H2AX detection and pharmacodynamic monitoring of DNA damage induced by chemotherapeutic agents and PARP inhibitors.
Authors: Ji Jay , Zhang Yiping , Kinders Robert , Redon Christophe , Solier Stephanie , Agama Keli , Pommier Yves , Bonner William , Hollingshead Melinda , Rubinstein Larry , Chen Alice , Kummar Shivaani , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H. 
Published: June 2012

Abstract
A 96-well plate-based enzyme-linked immunosorbent assay (ELISA) for quantifying gamma-H2AX as a biomarker to monitor DNA damage was developed and compared with gamma-H2AX detection by both Western blot (WB) and quantitative immunofluorescence assay (IFA). Using a pair of high-affinity gamma-H2AX antibodies for protein capture and detection and a synthetic peptide calibrator, this chemiluminescence ELISA can quantify gamma-H2AX concentrations as low as 16 pg/mL in crude extracts from cancer cells and solid tumors. The assay has a lower limit of detection of less than 4 pg/mL, upper limit of quantitation of 2000 pg/mL, and coefficient of variation of 20%. Treatments under evaluation using the gamma-H2AX ELISA include the topoisomerase 1 inhibitors topotecan and irinotecan, the apoptosis-inducing biomolecule TRAIL (TNF-related apoptosis-inducing ligand), and ionizing irradiation. The gamma-H2AX ELISA showed utility for drug discovery screening, molecular pharmacology studies, and pharmacodynamic monitoring. In a mouse xenograft model (A375 melanoma), the assay detected dose- and time-dependent changes in gamma-H2AX in response to treatment with irinotecan administrated alone or in combination with the poly(ADP-ribose) polymerase inhibitors ABT-888 (veliparib), AZD-2281 (olaparib), or MK-4827. Overall quantitative correlation was 0.96 between the ELISA and IFA, and 0.66 between ELISA and WB. This assay format should prove useful in situations when higher throughput and accurate quantitation are needed and gamma-H2AX analysis does not need to be restricted to nuclear foci.
Funded, in part, by NCI Contract No. HHSN261201100001E and by the Center for Cancer Research, Intramural Program of the National Cancer Institute.
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 A46.
Abstract A53: Prostate cancer cell capture using immobilized inhibitors of prostate-specific membrane antigen.
Authors: Wu Lisa Y. , Liu TianCheng , Hopkins Mark R. , Davis Willian C. , Berkman Clifford E. 
Published: June 2012

Abstract
Prostate circulating tumor cells (PCTCs) in the peripheral blood are shed from either a primary tumor or its metastases. These disseminated PCTCs are directly responsible for the most cancer deaths and the major cause of prostate cancer-related mortality. Therefore, elucidating the quantity of the exfoliated PCTCs in blood circulation can serve as an indicator for the clinical management in prostate cancer diseases by providing information on the success/failure of therapy. And the isolation and removal of PCTCs from circulation could potentially reduce prostate cancer metastasis. Furthermore, culturing and characterizing captured PCTCs from a patient is an attractive strategy for developing personalized treatment options. It has been established that prostate-specific membrane antigen (PSMA) is up-regulated and strongly expressed on prostate cancer cells associated with high grade primary, androgen independent, and metastatic tumors. While it is known that PSMA expression is heterogeneous in primary prostate tumors and metastases, completely PSMA negative prostate carcinomas are rare. The present study has outfitted streptavidin coated magnetic beads with a unique irreversible small-molecule PSMA inhibitor, Biotin-PEG12-CTT-54, and demonstrated that they can selectively capture PSMA + cells. The results demonstrated prostate cancer cells capturing is very specific and highly efficient, and high recovery and high viability were obtained. Subsequent in vitro propagation of these viable captured lymph node-based metastatic prostate LnCaP cells is possible without removal of magnetic beads on the cell surface. The results suggested that PCTCs enrichment by streptavidin coated magnetic beads with biotinated PSMA inhibitor has a high PCTC detection rate with an easy manual protocol, and can serve as an additional research tool and clinical assay in PCTC.
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 A53.
Abstract A59: Wnt, Notch, and Hedgehog pathways as potential therapeutic targets in OCT4A expressing cancer stem cells of malignant melanoma.
Authors: Welte Yvonne , Kohlhof Hella , Leban Johann , Regenbrecht Christian RA 
Published: June 2012

Abstract
Recent findings have demonstrated that within tumors a small subpopulation of so called cancer stem cells (CSCs) exists, which exhibits a self-renewing capacity and seems responsible for tumor maintenance and metastasis. But today's methods of isolating CSCs from the bulk of cells are highly inefficient. The most important step in the field of CSC research is to identify markers that represent stem cell criteria like self-renewal and asymmetric cell division. We identified small subpopulations of OCT4A+ cells within patient-derived malignant melanoma cells providing such criteria. To enrich for putative CSCs we sorted these low-passage melanoma cells into CD133+ and CD133− fractions and found the TGF-β signaling cascade only active in CD133+ cells. Furthermore, the self-renewal factor OCT4 is predominantly present in CD133+ but not in CD133− tumor cells. Sequencing and restriction digest confirmed specific expression of OCT4A. OCT4A+ and OCT4A− cells were then transfected with a phOCT4-EGFP reporter construct and FACS sorted into the respective subpopulations. Immunocytological staining with an anti-OCT4A-specific antibody confirmed that OCT4-EGFP+ melanoma cells express nuclear OCT4A. Results showed a strong nuclear staining pattern for OCT4A in OCT4-EGFP+ melanoma cells whereas OCT4-EGFP− melanoma cells were only weakly and unspecifically stained all over the cell body. To further characterize OCT4-EGFP+ and OCT4-EGFP− cells we performed genome-wide expression profiling. KEGG pathway analysis revealed that key developmental pathways such as Wnt, Notch and Hedgehog signaling were amongst the most up-regulated pathways in OCT4-EGFP+ compared to OCT4-EGFP− melanoma cells, thus suggesting that OCT4 expression plays a crucial role in maintaining cancer stem-like properties in melanoma-derived cells. In embryonic stem cells processes that govern development, self-renewal and cell fate are mainly regulated by the Wnt, Notch and Hedgehog pathways. These pathways are also known to be frequently deregulated in many types of cancers. Our data provide evidence that only a small subpopulation of melanoma cells is characterized by aberrant developmental pathways. These OCT4+ cells comprise both, the characteristics of stem-like cells and malignant tumors, thus defining CSCs in melanoma. In conclusion, Notch, Wnt and Hedgehog pathways might be ideal targets to eradicate CSCs from the tumor, thus preventing regrowth and metastasis. In combination with classical chemotherapeutic agents this might be an effective therapeutic strategy to circumvent the failure of conventional 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 A59.
Abstract A63: Targeting cancer stem cells with small molecule inhibitors.
Authors: Kohlhof Hella , Regenbrecht Christian , Welte Yvonne , Zybarth Gabriele , Leban Johann , Zaja Mirko , Kronthaler Kerstin , Schrepfer Sabine , Baumgartner Roland , Vitt Daniel 
Published: June 2012

Abstract
4SC AG develops a mini portfolio of small molecule inhibitors to target cancer stem cells. The portfolio includes a Wnt inhibitor, a class I specific HDAC inhibitor and a specific metabolism inhibiting agent. The Wnt inhibitor targets the self-renewal capacity of cancer stem cells and has been shown to prevent anchorage independent growth of CD133+ and unsorted patient derived melanoma cells and other cell lines. Additionally, it inhibits spheroid formation of colon cancer cells and embryonic carcinoma cells in a low μM range. From gene expression profiling experiments it seems as if the HDAC inhibitor and the metabolism inhibiting agent induce differentiation in cancer stem cells and their inhibitory potency has been shown in CD133+ and unsorted patient derived melanoma cells, respectively. The metabolism inhibiting agent has been shown to reduce the expression of NANOG on the mRNA level. Nanog is one of the core transcription factors that regulate and maintain stemness. Currently a comprehensive characterization of the therapeutic potential especially on cancer stem cells is ongoing. A specific focus of our research is on the mechanisms involved in inhibiting self-renewal or inducing differentiation of cancer stem cells, in vitro and in vivo.
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 A63.
Abstract A65: Targeting the defective decatenation checkpoint in melanoma.
Authors: Brooks Kelly M. , Ranall Max , Pavey Sandra , Mukhopadhyay Pamela , Wigan Matthew , Giles Nicole , Gabrielli Brian 
Published: June 2012

Abstract
In Australia melanomas account for 10% of all reported cancers and 3% of cancer mortalities. Current treatments offer &lt;25% response rate and &lt;8 months improved survival. Cancers frequently demonstrate defects in the cell cycle, particularly the checkpoint mechanisms. Loss of these protective mechanisms may provide opportunities for selectively targeting cancer cells. One G2 phase checkpoint, the decatenation checkpoint, ensures that entangled sister chromatids can be segregated with high fidelity during cellular replication. Topoisomerase II is responsible for resolving these tangles.
Using ICRF-193, an inhibitor of Topoisomerase II, a panel of melanoma cell lines were investigated for decatenation checkpoint function. This analysis revealed that 17/25 melanoma cell lines possessed a defective decatenation checkpoint, suggesting it to be a common defect. Treatment with ICRF-193 caused checkpoint defective cells to undergo an aberrant mitosis, resulting in accumulation of cells exhibiting abnormal nuclear morphologies, while checkpoint functional cells remained relatively unaffected. Comparative gene expression analysis revealed differential expression of cell-division and cell-death associated genes, suggesting adaptive changes compensating for checkpoint failure. A strong gene-expression signature for the checkpoint defect was also observed in this analysis and potential bio-markers are being investigated for use identifying this defect in tumors. A synthetic lethality siRNA screen of the kinome (∼700 genes) was carried out to identify genes/pathways crucial to the viability of cell lines with a defective decatentation checkpoint. This screen identified 10 potential hits, many involved in PI3Kinase signaling. We have validated this pathway as a selective target.
This research has shown that the defective decatenation checkpoint is a viable target in melanoma. Using targets identified by the synthetic lethality screens and bio-markers to the defect in tumors, it should be possible to identify tumors most likely to be sensitive to drugs targeting the checkpoint defect, providing effective and selective therapeutics for the treatment of metastatic melanoma.
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 A65.