bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B109: AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors
Authors: Hyman David M. , Smyth Lillian , Bedard Philippe L. , Oza Amit , Dean Emma , Armstrong Anne , Lima Joao , Bando Hideaki , Kabos Peter , Perez-Fidalgo J. Alejandro , Moore Kathleen , Westin Shannon N. , You Benoit , Chandarlapaty Sarat , Alland Leila , Ambrose Helen , Foxley Andrew , Lindemann Justin , Pass Martin , Rugman Paul , Salim Shaista , Schiavon Gaia , Tamura Kenji , Baselga Jose , Banerji Udai 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7.
Citation Format: David M. Hyman, Lillian Smyth, Philippe L. Bedard, Amit Oza, Emma Dean, Anne Armstrong, Joao Lima, Hideaki Bando, Peter Kabos, J. Alejandro Perez-Fidalgo, Kathleen Moore, Shannon N. Westin, Benoit You, Sarat Chandarlapaty, Leila Alland, Helen Ambrose, Andrew Foxley, Justin Lindemann, Martin Pass, Paul Rugman, Shaista Salim, Gaia Schiavon, Kenji Tamura, Jose Baselga, Udai Banerji. AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B109.
Abstract B139: Determination of the plasma inhibitory activity of drugs using cellular kinase assays
Authors: Boehmer Kira E. , Weber Holger , Feger Daniel , Birkle Marianne , Siedentopf Oliver , Mueller Melanie , Umber Sarah , Ehlert Jan E. 
Published: May 2016

Abstract
Anticipation of the in vivo activity of new investigational drugs is challenging. In the context of the living body, compounds are subjected to degradation, modification or binding to plasma proteins - mechanisms that may compromise the activity predicted from target-specific in vitro assays. As such assays are performed in artificial cell-culture media it was our aim to measure the activity directly in human plasma, as initially described by Levis et al.1. We hence established a method to analyze the activity of kinase inhibitors in human or rodent plasma (plasma inhibitory activity, PIA) in high throughput compatible ELISA-based cellular kinase assays for e.g. FLT-3 or BCR-Abl. Testing reference compounds such as Sunitinib or Sorafenib, we could confirm the expected correlation between the plasma binding of a compound and the loss of its activity in this assay setup compared to the activity in serum free medium. Furthermore we observed a donor dependent interference of the plasma with assay performance. This issue was solved by appropriate plasma heat-inactivation which made confirmation of compound stability to heat treatment mandatory before generating pharmacokinetic data using this methodology. Our aim is to establish the PIA assay for our panel of more than 30 kinases and analyze the activity of important reference kinase inhibitors spiked in human plasma. In the next step samples from mice treated with reference compounds shall be tested. This way, we want to compile reliable in vitro PIA assays to better predict the in vivo effect of kinase-directed drugs and to determine the amount of freely available active test substance in the blood of treated patients.
1 = Levis et al.; Blood, 2006; 108:3477
Citation Format: Kira E. Boehmer, Holger Weber, Daniel Feger, Marianne Birkle, Oliver Siedentopf, Melanie Mueller, Sarah Umber, Jan E. Ehlert. Determination of the plasma inhibitory activity of drugs using cellular kinase assays. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B139.
Abstract B14: ALT specific C-circle detection in a whole blood of cancer patients using qPCR assay
Authors: Malykh Andrei , Doyle Jonathan 
Published: May 2016

Abstract
The goal of this study was to evaluate a real-time qPCR assay, which can be used in clinical research environments for detection of telomeric C-circle DNA in tumors and peripheral blood of patients with cancers that utilize Alternative Lengthening of Telomeres (ALT) as their Telomere length Maintenance Mechanism (TMM). Telomeric C-circle DNA has been demonstrated to be specific for ALT, thus enabling the first quantitative test for ALT activity. In 85% of cancers, cells maintain telomere length due to increased activity of telomerase, while 5 - 15% of cancers overall rely on the ALT mechanism for continued growth and survival. Initial retrospective analyses showed that ALT ranges from 25% to 60% in sarcomas and 5% to 15% in carcinomas. ALT is also a potential ‘escape route’ for tumor cells to survive under pressure from treatment with anti-telomerase drugs. Results of in vitro and animal model experiments confirm the possibility of such ALT induction.
The existing detection method using a radioactive probe was shown to detect C-circle DNA in osteosarcoma patients' blood and plasma. However, this method requires highly experienced technicians and dedicated laboratory facilities for handling radioisotopes. Here we present data that the qPCR assay is at least 20 times more sensitive than its radioisotope predecessor and detects C-circle DNA in blood of sarcoma patients.
DNA from 20 frozen whole blood and serum samples from patients with adenocarcinoma (10), sarcoma (4), desmoid fibrosarcoma (1) and melanoma (5) was isolated using QIAmp Kit. Rolling circle amplification of telomere C-circle DNA, which is the core of the assay, was done with and without Phi29 polymerase. Half of the reaction was subjected to radioisotope detection and half for qPCR. Positive results in both isotope and qPCR assay have been confirmed for 3 sarcoma samples. Two serum samples (one from adenocarcinoma and one from melanoma patient) were positive in qPCR, while negative in isotope assay.
A clinically applicable qPCR C-circle assay, which can also be used as a noninvasive blood-based test, will be suitable for ALT activity detection in cancer, as a companion diagnostic tool for anti-telomerase therapy and prognosis, and for anti-ALT and anti-telomerase drug development.
This study was partially supported by the NIH SBIR Grant 1R43CA168124-01A1.
Citation Format: Andrei Malykh, Jonathan Doyle. ALT specific C-circle detection in a whole blood of cancer patients using qPCR assay. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B14.
Abstract B191: Preclinical assessment of targeting the PI3K/AKT pathway in combination with other signal transduction pathway inhibitors
Authors: Lee Sang Hyun , Koblish Holly , Liu Xiangdong , Ye Haifen , Li Jun , Liu Xuesong , Diamond Melody , Zhang Yue , Hall Leslie , Dostalik Valerie , Favata Margaret , Behshad Elham , Wynn Richard , Li Yun-long , Combs Andrew , Xue Chu-Bio , Yao Wenqing , Hollis Gregory , Huber Reid , Scherle Peggy 
Published: May 2016

Abstract
Inhibitors targeting the phosphoinositide 3-kinase (PI3K)/serine-threonine protein kinase B (AKT) pathway have been developed and have shown efficacy in inhibiting tumor growth both in preclinical models and in the clinic. The effectiveness of PI3K/AKT inhibitors, however, is attenuated by the activation of alternative signaling pathways. Conversely, the PI3K/AKT pathway is considered to be a resistance mechanism for other therapeutic or cytotoxic agents. Therefore, understanding these mechanisms may help to inform the most optimal combinations for advancement into clinical studies. Here, we explored the potential of targeting the JAK/STAT or PIM signaling pathways in combination with a novel, potent and selective AKT inhibitor, INCB047775. Consistent with published data, pharmacological inhibition of AKT by INCB047775 caused the upregulation of PIM kinases. The combined therapies of PIM inhibition and AKT inhibition exhibited significant synergistic anti-tumor effects. Combination of PIM inhibition with AKT inhibition resulted in synergistic induction of apoptosis in cancer cells. Similarly, the combination of JAK tyrosine kinase inhibition with INCB047775 exerted synergistic inhibition of the proliferation of multiple myeloma cell lines. Similar data were observed with an inhibitor of PI3Kδ in combination with both PIM and JAK inhibition, demonstrating significant crosstalk between the PI3K/AKT pathway and other critical signaling pathways. These data provide the rationale for combinatorial therapies with inhibitors targeting JAK or PIM kinases with PI3K/AKT pathway inhibitors in the clinic.
Citation Format: Sang Hyun Lee, Holly Koblish, Xiangdong Liu, Haifen Ye, Jun Li, Xuesong Liu, Melody Diamond, Yue Zhang, Leslie Hall, Valerie Dostalik, Margaret Favata, Elham Behshad, Richard Wynn, Yun-long Li, Andrew Combs, Chu-Bio Xue, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle. Preclinical assessment of targeting the PI3K/AKT pathway in combination with other signal transduction pathway inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B191.
Abstract B44: Druggability assessment of protein tyrosine phosphatase binding site
Authors: Ghattas Mohammad A. , Raslan Noor , Sadeq Asil , Atatreh Noor 
Published: May 2016

Abstract
Protein tyrosine phosphatases play important roles in the signalling system in our bodies and were observed to be overexpressed in many diseases. For instance, PTP1B, the most famous member of this family, has a well-established role in diabetes mellitus, obesity and cancer. However, no PTP inhibitors have reached the market so far. This raised a question about the druggability of their catalytic site; which appears to be hydrophilic in nature and is believed to favour mainly polar ligands to bind with. In this study, we did an extensive data minding in the protein data bank to obtain all available crystal structures of all members in the PTP family. We analysed these crystal structures using SiteMap/Schrodinger. This software finds cavities in the examined proteins structure and evaluates these pockets according to their suitability for binding with drug-like ligands. Consequently, we classified PTPs according to their druggability scores; a representative of each category is shown and discussed accordingly. The influence of active site flexibility (open or closed) on PTPs druggability was studied. The effect of tight-bound water molecules on active site druggability was also assessed. This analysis can prove useful in the discovery of new PTP inhibitors and can help researchers to save unnecessary cost, money and efforts by prioritizing PTP targets according to which members have the most druggable catalytic pocket.
Citation Format: Mohammad A. Ghattas, Noor Raslan, Asil Sadeq, Noor Atatreh. Druggability assessment of protein tyrosine phosphatase binding site. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B44.
Abstract B47: Potent and selective CK2 kinase inhibitors with effects on Wnt pathway signaling in vivo
Authors: Dowling James E. 
Published: May 2016

Abstract
The serine/threonine protein kinase CK2, which exists as a constitutively active, hetero-tetrameric complex consisting of two catalytic (α or α') and two regulatory (β) subunits, has emerged as an attractive drug discovery target in oncology. Among its diverse functions, CK2 modulates cellular signaling pathways that are frequently activated in cancer, including PI3K/AKT, NFκB and Wnt. In order to explore the reported links between CK2 kinase activity and Wnt pathway signaling we sought to identify a potent, selective inhibitor of CK2 kinase with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (1), we identified compound 2, a potent CK2 inhibitor with picomolar affinity (CK2a KD = 10 pM) that is highly selective against other kinase family enzymes and inhibits Wnt pathway signaling (Wnt luciferase reporter IC50 = 50 nM) in DLD-1 cells. Compound 2 has demonstrated good pharmacokinetics in preclinical species, depletes β-catenin in vivo and exhibits a high level of activity (TGI &gt; 90%) as a monotherapy in HCT-116 xenografts at tolerated doses.
Citation Format: James E. Dowling. Potent and selective CK2 kinase inhibitors with effects on Wnt pathway signaling in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B47.
Abstract B62: AKT3 expression modulates chemosensitivity to aurora kinase inhibitors
Authors: Noguchi Kohji , Katayama Kazuhiro , Sugimoto Yoshikazu 
Published: May 2016

Abstract
The aurora kinases in human consist of three members, Aurora A, B and C (AURKA, B and C). They are involved in cell cycle progression, especially in mitosis, and aberrant expressions of them are reported in many cancer tissue types. Therefore, AURKs would serve as useful molecular targets for anti-cancer agents and many investigational drugs are currently under development. To understand pharmacological determinants affecting the chemosensitivity to aurora kinase inhibitors, we have established five resistant cell lines to an aurora kinase inhibitor VX 680 by treating human colon cancer HCT 116 cells in vitro with increasing concentrations of VX 680 (40∼200 nmol/L) over a period of 6 months. These VX 680-resistant clones showed aneuploidy and cross-resistance to other aurora kinase inhibitors AZD1152-HQPA and MLN8237. Regarding drug resistance-associated molecules, P-gp and BCRP overexpression were not common to the VX 680-resistant clones, despite the fact that overexpression of P-gp and BCRP conferred strong resistance to VX 680 and AZD1152-HQPA. Gene expression analysis by cDNA microarray indicated that Akt3 was up-regulated in the VX 680-resistant cells. Transient overexpression of myristylated-Akt3 in Hela cells repressed AZD1152-HQPA-induced cell death and polyploidy induction, and stable expression of myristylated-Akt3 in HCT 116 cells induced resistance to both VX 680 and AZD1152-HQPA. In addition, confocal microscopic study showed that endogenous AKT3 was detected during mitosis. These observations suggest that AKT3 activity can affect the mechanism for the chemosensitivity to aurora kinase inhibitors.
Citation Format: Kohji Noguchi, Kazuhiro Katayama, Yoshikazu Sugimoto. AKT3 expression modulates chemosensitivity to aurora kinase inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B62.
Abstract B81: Analogues of the chromenone namoline as inhibitors of lysine specific demethylase 1 (LSD1)
Authors: Schulz-Fincke Johannes , Schmitt Martin L. , Carlino Luca , Haydn Tinka , Willmann Dominica , Metzger Eric , Fulda Simone , Schüle Roland , Sippl Wolfgang , Jung Manfred 
Published: May 2016

Abstract
Since it had been discovered in 2004, lysine-specific-demethylase 1 (LSD1) has been emphasized as a potential target for anticancer drugs. The physiological role of LSD1 is versatile which can be seen in its function in different LSD1-related protein complexes such as CoREST with the androgen receptor. Interacting with those various molecular domains, LSD1 leads to e.g. a regulation of gene expression and control of hematopoietic differentiation. So it is hardly surprising that several LSD1 inhibitors are already in clinical trials.
Namoline has been identified in collaboration with other groups using a bioinformatics approach based on active site similarity and a focused library screen. This hit impairs LSD1 activity in-vitro and in-vivo and is a promising starting compound for further investigations. Our latest developed heterogeneous assay-systems are resistant against auto-fluorescence and maybe will give us further insights into biophysiological interactions between inhibitors and the targeted enzyme. Based upon on this, we report structure-activity studies of namoline and its improved analogues which lead up to a 40-fold increased potency and retained selectivity over MAO-A and B. We show that namoline and its potent analogues have antiproliferative activity in Rhabdomyosarcoma cells with slightly improved efficacy for the new analogues.
Citation Format: Johannes Schulz-Fincke, Martin L. Schmitt, Luca Carlino, Tinka Haydn, Dominica Willmann, Eric Metzger, Simone Fulda, Roland Schüle, Wolfgang Sippl, Manfred Jung. Analogues of the chromenone namoline as inhibitors of lysine specific demethylase 1 (LSD1). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B81.
Abstract C56: Platinum containing anti-cancer agents as targeted therapeutics
Authors: Bruno Peter M. , Park Ga Young , Murai Junko , Liu Yunpeng , Pritchard Justin , Pommier Yves , Lippard Stephen J. , Hemann Michael T. 
Published: May 2016

Abstract
Cisplatin and its analogs are one of the most widely used family of cancer chemotherapeutics. However, despite a diverse array of analogs having been synthesized over the past decades, the underlying assumption has been that they all work similarly by damaging DNA. Utilizing a unique multi-platform genetic approach we show that this is not the case, and that small modifications to the core structure of cisplatin can produce unexpected changes in mechanism of action. Specifically, we found oxaliplatin and a subset of mono-functional cisplatin analogs closely resembled transcription and translation inhibitors. This set of platinum-based agents do not rely on traditional cisplatin repair and tolerance pathways such as nucleotide excision repair, homologous recombination and inter-strand cross-link repair. Instead, we've demonstrated oxaliplatin treatment kills cells by eliciting a ribosome biogenesis stress response. Additionally, across a panel of human cell lines, we've shown that higher expression of ribosomal proteins correlates with resistance to these transcription/translation inhibitor-like platinum agents. From this analysis, and by analyzing and comparing human patient tumor expression data, we've concluded that oxaliplatin treatment is best applied in tumors that have developed a heightened dependence on translation. Thus, while commonly regarded as “blunt weapons”, our current arsenal of genotoxic anti-cancer agents utilizes surprisingly diverse mechanisms that suggest new paradigms for their application in patients.
Citation Format: Peter M. Bruno, Ga Young Park, Junko Murai, Yunpeng Liu, Justin Pritchard, Yves Pommier, Stephen J. Lippard, Michael T. Hemann. Platinum containing anti-cancer agents as targeted therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C56.
Abstract C57: Discovery and development of replication protein A (RPA)-DNA interaction inhibitors for cancer chemotherapy
Authors: Gavande Navnath , VanderVere-Carozza Pamela S. , Mishra Akaash , Turchi John J. 
Published: May 2016

Abstract
Platinum (Pt)-based chemotherapeutics exert their efficacy via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. DNA repair of Pt-DNA adducts via nucleotide excision repair (NER) or homologous recombination repair (HRR) can substantially reduce the effectiveness of the Pt therapy, which is a major contributor for cellular resistance. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt-treatment and increase the clinical efficacy. Replication protein A (RPA) is a single-stranded DNA binding protein that plays a crucial role in the NER and HRR pathways apart from its role in replication and DNA damage checkpoint activation. We have pursued the development of small molecule inhibitors of the RPA-DNA interaction as a mechanism to target RPA activity and increase the efficacy of Pt-based cancer chemotherapy. We have developed an inhibitor, TDRL-551, that targets the central oligonucleotide/oligosaccharide binding folds in DNA binding domains A and B (DBD-A/B) of the 70 kDa RPA subunit. This lead compound shows synergy with cisplatin in tissue culture models of epithelial ovarian cancer (EOC) and in vivo efficacy, as a single agent as well as in a combination with platinum, in a lung cancer xenograft model. We have expanded our synthetic scheme and defined structure-activity relationships (SAR) towards optimization of TRDL-551 as an anticancer therapeutic for the treatment of lung and ovarian cancer.
Supported by NIH grants R01 CA180710 and R41CA162648 to JJT.
Citation Format: Navnath Gavande, Pamela S. VanderVere-Carozza, Akaash Mishra, John J. Turchi. Discovery and development of replication protein A (RPA)-DNA interaction inhibitors for cancer chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C57.