bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A85: Peptides specific for chronic lymphocytic leukemic cells: Characterization and use in targeted drug delivery.
Authors: Firer Michael A. , Lubin Bat-Chen , Cohen Sharon , Luboshits Galia 
Published: August 2014

Abstract
The ability to selectively target drugs to Chronic Lymphocytic Leukemia (CLL) cells may significantly improve the efficacy of current chemotherapy protocols for this disease. Our studies in model leukemic systems have already demonstrated that a strategy involving Peptide-Drug Conjugates (PDCs) may achieve this goal. In a previous preliminary study, we used a phage display peptide library to isolate a series of peptides that bind CLL cells. The current research has expanded on this work and began by absorbing a 7-mer linear and 7-mer cyclic phage display peptide libraries on a series of normal human or murine primary cells. Rigorous pre-absorption reduces the original vast phage library population (1011 clones) and enhances the ability to select peptides specific for the target CLL cells. The cells used included endothelial, heart, kidney, lung, liver, skin, fibroblasts and several subpopulations of blood cells. These absorptions resulted in a 7-log reduction in the size of the phage libraries. The stock libraries were also injected into mice. Recovery of blood circulating phage 24hrs later showed that in vivo absorption reduced the pool size of viable phage by approximately 8-logs. These "absorbed" libraries now form the basis for isolating CLL cell-bound and cell-internalizing phage. Target cells include murine cell lines derived from spontaneously-developed aggressive CLL (BCL-1 and A20) and human patient CLL cells. Analysis of peptide sequences of A-20 binding or internalizing phage clones revealed overlap in amino acid usage but not one consistent consensus sequence, suggesting that these peptides target different CLL-specific membrane components, some of which can induce phage internalization and should be applicable for PDCs. Using a similar approach, we are isolating peptides for BCL-1 cells as well as peptides to cells from an initial cohort of CLL patients. The bioinformatic and biochemical results for all these peptides will be presented. Peptides selected on the basis of uptake kinetics will be conjugated to cytotoxic drugs using our dendrimer technology. This technology has already allowed us to demonstrate improved efficacy of known CLL drugs. Progress on this stage of the project will also be presented.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A85.
Citation Format: Michael A. Firer, Bat-Chen Lubin, Sharon Cohen, Galia Luboshits. Peptides specific for chronic lymphocytic leukemic cells: Characterization and use in targeted drug delivery. [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 A85.
Abstract A95: Intermittent, but not chronic, hypoxia increased chromosomal copy number variations of prostate cancer cells.
Authors: Zhang Jingsong , Wang Xue 
Published: August 2014

Abstract
Background: Intra-tumoral hypoxia as a potential mechanism for therapy resistance has been well documented in prostate cancer. Screening drugs under hypoxic conditions, however, has not been adopted for drug discovery. Part of this is due to the difficulty to recapitulate the heterogeneity of intra-tumoral hypoxia in vitro. Indeed, a spatio-temporal irregularity of the microvascular network of a growing tumor creates regions that are either chronically (diffusion-limited) or intermittently (perfusion-limited) hypoxic. If genomic instability is the fundamental driving force for development of therapy resistance, the hypoxic culture condition with the most genomic instability would serve as an alternative in vitro model for drug testing. We therefore accessed chromosomal copy number variations (CCNV) in prostate cancer cells grew under intermittent as well as chronic hypoxia.
Method: Metastatic prostate cancer cell lines, PC3 and DU145, were grown under normoxia (21% oxygen), chronic hypoxia (0.2% oxygen), or intermittent hypoxia (16 hours of 0.2% oxygen alternating with 8 hours of 21% oxygen) for total of 3 weeks. PC3 cells were also treated with the 1 µM poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib under intermittent or chronic hypoxia conditions for 3 weeks. Genomic DNA was extracted for molecular karyotyping with the nanoString nCounter human karotyping platform, which covers 24 human chromosomes with 338 probes. DNA from human foreskin fibroblast (HFF) grew under normal culture condition (21% oxygen) was used as a reference.
Results: Both PC3 and DU145 cells continue to proliferate under intermittent as well as chronic hypoxia. Compared to untreated PC3 cells, daily treatment with PARP inhibitor under chronic or intermitent hypoxia for 3 weeks did not affect the proliferation or survival of the PC3 cells. Compared to HFF, frequent CCNVs were observed in PC3 and DU145 cells. This is consistent with the known complicated karyotype of these 2 cell lines. When compared to PC3 or DU145 cells cultured under normoxia, CCNVs were enhanced under intermittent hypoxia, but not chronic hypoxia. Daily treatment with PARP inhibitor did not alter CCNVs under either chronic hypoxia or intermittent hypoxia.
Conclusions: Intermittent hypoxia is probably a more relevant model to study genomic instability and drug resistance than chronic hypoxia. Neither chronic hypoxia nor intermittent hypoxia sensitizes prostate cancer cells to PARP inhibitor, veliparib.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A95.
Citation Format: Jingsong Zhang, Xue Wang. Intermittent, but not chronic, hypoxia increased chromosomal copy number variations of prostate 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 A95.
Abstract B101: Design and optimization of a new series of HSP70 inhibitors for use in the treatment of pancreatic cancer.
Authors: Maxwell David S. , Sun Duoli , Peng Zhenghong , Qi Wei , McConkey David , Abbruzzese James L. , Bornmann William G. 
Published: August 2014

Abstract
Through a combination of structure-based design and similarity methods, we have identified a novel series of HSP70 inhibitors that are directed towards the ATPase domain. The structural core was identified through a multi-stage docking and similarity search of screening compounds available from multiple commercial sources. Upon selection of the core, a virtual library was constructed, pre-filtered, and screened in two docking packages. By combining the resulting scores with those from a docking decoy library, workflow software was used to calculate a Z-score, which has recently been shown to assist with separating actives from in-actives. ADME predicted values were also calculated for each structure in the virtual library. Filters were applied in the workflow at several points to focus on the best compounds, thirty of which were ranked and considered for synthesis. The compounds were synthesized in five steps using commercially available starting materials. At present, six compounds from the series have been synthesized and four of those were tested alone and in combination with a known proteasome inhibitor, bortezomib. The third highest ranked compound showed the most potent effect on pancreatic cancer cell death in multiple cell lines. We will report on the design, synthesis, and biological characterization of this new class of HSP70 inhibitors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B101.
Citation Format: David S. Maxwell, Duoli Sun, Zhenghong Peng, Wei Qi, David McConkey, James L. Abbruzzese, William G. Bornmann. Design and optimization of a new series of HSP70 inhibitors for use in the treatment of pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B101.
Abstract B103: Inhibitors of S100B (SBiXs) in malignant melanoma.
Authors: Cavalier Michael , Wilder Paul T. , Coop Andrew , MacKerell Alexander , Weber David J. 
Published: August 2014

Abstract
Summary: In malignant melanoma (MM), elevated levels of the tumor marker, S100B, binds directly to wild-type (wt) p53, dissociates the p53 tetramer, and down-regulates p53-dependent tumor suppression functions; therefore, it is the goal to develop S100B inhibitors (SBiXs; X=compound number) to restore active p53 in this deadly cancer. As a proof of principle for a drug design project, inhibiting S100B with small interfering antisense RNA (siRNAS100B) and several SBiXs was shown to restore wild-type p53 levels and its downstream gene products, as necessary to induce cell growth arrest and apoptosis in malignant melanoma.
Purpose: It is our purpose to discover/synthesize and/or to improve existing inhibitors of S100B to restore p53 activity in human malignant melanoma. Such compounds can then be examined for in vivo efficacy.
Results and conclusions: Development of S100B inhibitors (SBiXs) is ongoing at the University of Maryland Schools of Pharmacy and Medicine with the goal of obtaining higher affinity and better specificity towards inhibiting S100B. Computer aided drug design (CADD) followed by synthesis and experimental assays (i.e. NMR, binding, and cellular assays) have identified compounds that bind S100B and inhibit melanoma cell growth. Available binding data, IC50 data, and 3D structures of S100B-SBiX complexes will be presented that will act as the basis for the design of improved SBiXs. SBiXs may also have therapeutic value for treating other cancers with elevated S100B and wt p53 such as astrocytoma, renal tumors, and some forms of leukemia.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B103.
Citation Format: Michael Cavalier, Paul T. Wilder, Andrew Coop, Alexander MacKerell, David J. Weber. Inhibitors of S100B (SBiXs) in malignant melanoma. [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 B103.
Abstract B118: Histone demethylase inhibitor, trans-2-phenylcyclopropylamine hydrochloride inhibits KDM3A and KDM5A activities, resulting in overcoming resistance against bortezomib.
Authors: Terui Yasuhito , Kuniyoshi Ryoko , Tomida Akihiro , Hatake Kiyohiko 
Published: August 2014

Abstract
Purpose: The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the myeloma treatment. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance remain to be understood yet. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To overcome bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant and bortezomib-sensitive IM-9 myeloma cell lines in response to bortezomib, and expressions of KDM3A and 5A genes were significantly incresed.
Methods: The differential gene expression profiles of bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 multiple myeloma cell lines in response to bortezomib was performed using Affymetrix GeneChip. To confirm the results, real-time PCR and Western blot analysis were performed. bortezomib-resistant IM-9 cells were treated with or without bortezomib and/or histone demethylase inhibitor, trans-2-phenylcyclopropylamine hydrochloride (2-PCPA). Moreover, level of histone methylation was examined by western blot analysis. Results: At concentrations that effectively inhibited proteasome activity (maximum dose with 100nM), bortezomib induced cell death in bortezomib-sensitive IM-9 cells, but not in bortezomib-resistant IM-9. In comparison of differential gene expression profiles between bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 cells, we showed overexpression of KDM3A and KDM5A, which are associated with chromatin-mediated reversible drug-tolerant state, Moreover, 2-PCPA overcomes bortezomib resistance in a dose-dependent manner. The histone demethylation at H3K4, H3K9 and H3K27 was suppressed with 2-PCPA.
Conclusion: Histone lysine-specific demethylase inhibitor, 2-PCPA with bortezomib may be useful for overcoming bortezomib-resistance in myeloma cells by suppression of KDM3A and KDM5A activities.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B118.
Citation Format: Yasuhito Terui, Ryoko Kuniyoshi, Akihiro Tomida, Kiyohiko Hatake. Histone demethylase inhibitor, trans-2-phenylcyclopropylamine hydrochloride inhibits KDM3A and KDM5A activities, resulting in overcoming resistance against bortezomib. [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 B118.
Abstract B138: The landscape of targetable master regulators and genomic drivers of glioblastoma.
Authors: Iavarone Antonio 
Published: August 2014

Abstract
We are experiencing the exciting time of the genome era. For our work this means being able to contextualize the alterations of each genetic network in the natural environment of a specific tumor and identify the key driving modules on which specific tumor subgroups rely for growth, survival and progression. With this information in hand, we can target the critical alterations with specific drugs, often already available for other types of diseases. By focusing on one of the most lethal forms of human tumors, the glioblastoma multiforme (GBM), we have been able to make incredible progress along this line in the last two years. Our recent work led to efficient targeting in preclinical mouse models of the most aggressive gene expression signature of high-grade glioma, the mesenchymal signature. We have identified the first examples of highly oncogenic and recurrent gene fusions in GBM, target their dependency in a particular tumor subtype, and observe dramatic anti-tumor effects. Recurrent gene fusions in GBM result in the constitutive activation of receptor tyrosine kinase genes (FGFR, EGFR and NTRK1) that render tumors addicted to the driver events. Both lines of investigation are maturing towards clinical trials. The integrated computational-experimental pipeline that we developed plus our ability to functionalize any genetic brain tumor module was recently applied to the entire landscape of CNVs, somatic mutations and gene fusions of human GBM. This information will advance our ability to quickly translate each new genetic finding into the personalized context of the clinical setting.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B138.
Citation Format: Antonio Iavarone. The landscape of targetable master regulators and genomic drivers of glioblastoma. [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 B138.
Abstract B177: Non-invasive tumor mutation detection of cell-free urinary DNA using massively parallel deep DNA sequencing.
Authors: Poole Jason C. , Janku Filip , Holley Veronica R. , Wheler Jennifer J. , Meric-Bernstam Funda , Luthra Rayjalakshmi , Leppin Lorieta , Hassaine Lafifa , Kosco Karena , Erlander Mark G. 
Published: August 2014

Abstract
Background: Previous studies have demonstrated the ability to detect tumor DNA mutations by PCR methodologies within cell-free urinary DNA in metastatic cancer patients. This has opened up the possibility to use massively parallel deep sequencing approaches for more global profiling of tumor mutations using cell free urinary DNA from these patients.
Methods: In order to achieve clinical utility the sequencing of cell-free urinary DNA must overcome two technical hurdles: 1) the need for extremely high sensitivity, between 0.01-0.05% and 2) an ultra-short DNA footprint (∼30 bp). Here we report the development of a method using cell free DNA extracted from urine that enriches for extremely low levels of mutated tumor DNA and thereby provides a high detection sensitivity. Detection of the KRAS gene mutations were used as a model system; the developed assay utilizes a 31bp footprint, contains a pre-amplification step that specifically enriches mutated DNA fragments and detects 8 KRAS mutations at the codon 12 and 13 sites. Spiking experiments with DNA derived from cell lines harboring the KRAS G12D mutation were completed to determine the limits of sensitivity of our method.
Results: Mutant DNA input at amounts of 0.2%, 0.05%, 0.01% and 0.0% of the total DNA returned observed detection levels of 18.25%, 4.45%, 1.84% and 0.54% respectively as a percentage of the total sequence reads with the detection of mutant DNA of 0.01% within the theoretical limit of the assay. To test our assay, we sequenced 30 ng of extracted urinary DNA from a stage IV colorectal carcinoma patient with a known mutation at the G12D site. Enrichment of the mutation presented at a level of 13.06% of our total sequence, corresponding to an input amount of approximately 0.14% mutational load in the patient's urine. Ongoing analysis of a larger number of patients will be presented to further evaluate the clinical sensitivity and specificity of KRAS mutations.
Conclusion: Further development of massively parallel DNA sequencing to detect mutations from cell-free urinary DNA has the potential to monitor metastatic patients for response, non-response and the emergence of resistance mechanisms to molecularly targeted therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B177.
Citation Format: Jason C. Poole, Filip Janku, Veronica R. Holley, Jennifer J. Wheler, Funda Meric-Bernstam, Rayjalakshmi Luthra, Lorieta Leppin, Lafifa Hassaine, Karena Kosco, Mark G. Erlander. Non-invasive tumor mutation detection of cell-free urinary DNA using massively parallel deep DNA sequencing. [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 B177.
Abstract B192: Selective induction of apoptosis in TSC2-null cells.
Authors: Alayev Anya , Snyder Rose B. , Holz Marina K. 
Published: August 2014

Abstract
Mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of cell cycle progression and proliferation, and is a target of the inhibitor rapamycin. The mTORC1 pathway is hyperactivated in many types of cancer, as a consequence of inappropriately regulated growth factor signaling pathways, and in diseases with Tuberous Sclerosis Complex (TSC) 1/2 loss, such as TS and lymphangioleiomyomatosis (LAM). Thus, use of rapamycin analogs has emerged as a viable therapeutic option in treatment of these diseases. However, rapamycin is not an effective monotherapy agent because it is cytostatic, and promotes autophagy induction and Akt reactivation, which may contribute to malignant cell survival, impeding tumor regression. We have observed that the combination of rapamycin with the plant-derived polyphenol resveratrol prevents rapamycin-induced autophagy and Akt activation, and selectively promotes apoptosis of TSC2-null cells, such as TSC2-/- MEFs and LAM-derived cells. This combination may be an effective option for targeted killing of cells with dysregulated mTORC1 signaling.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B192.
Citation Format: Anya Alayev, Rose B. Snyder, Marina K. Holz. Selective induction of apoptosis in TSC2-null 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 B192.
Abstract B204: Targeting key DNA/RNA heteroduplex of telomerase by small-molecule ligands.
Authors: Islam Mohammad K. , Thurston David E. , Rahman Khondaker M. 
Published: August 2014

Abstract
Small molecules can be designed to target the DNA/RNA hybrid (DRH) duplex that forms during the catalytic cycle of telomerase. Formation of this unique heteroduplex, which is typically between 4-11 base pairs long, is a key step in the mechanism of telomerase extension. Small molecules that bind to this duplex may inhibit telomerase by either stabilizing the structure thereby preventing strand dissociation (a key step in the catalytic cycle of telomerase), or by sufficiently distorting the substrate duplex causing misalignment of key catalytic groups. As telomerase is frequently over-expressed in cancer cells, the DRH duplex is a good therapeutic target. Thus we initiated a screening programme initially based on the National Cancer Institute (NCI) compound libraries which provide a high degree of structural diversity. Three novel scaffolds were identified in a Fluorescent Resonance Energy Transfer (FRET) based assay that showed at least a 5°C selective stabilization of the DNA/RNA hybrid duplex at 5μM ligand concentration. Medicinal chemistry modifications were then employed on these scaffolds to generate focused libraries of analogues with drug like properties. In total, 30 molecules were synthesized based on the identified scaffolds and subsequently screened against seven different DNA sequences including telomeric and promoter G-quadruplexes, and DRH sequences. A number of compounds showed selective DNA/RNA hybrid stabilization potential without significant affinity for G-quadruplex or duplex DNA sequences. These ligands provided hybrid DNA/RNA stabilization in the range of 5.2-9.5°C at 1μM ligand concentration. A second generation molecules where amides have been replaced by secondary amines are currently being synthesized to obtain SAR. Selected analogues from both compounds set are currently being evaluated in a variety of biological assays to confirm selective telomerase inhibition, and in cell based experiments to assess their potential as antitumour agents.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B204.
Citation Format: Mohammad K. Islam, David E. Thurston, Khondaker M. Rahman. Targeting key DNA/RNA heteroduplex of telomerase by small-molecule ligands. [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 B204.