bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3622: Novel SMAC-mimetic birinapant demonstrates antitumor activity in human head and neck cancer models exhibiting alterations in cell death pathways
Authors: Carlson Sophie , Eytan Danielle , Snow Grace , Schiltz Stephen , Mohan Suresh , Saleh Anthony , Cornelius Shaleeka , Coupar Jamie , Van Waes Carter , Chen Zhong 
Published: August 2015

Abstract
The Cancer Genome Atlas (TCGA) uncovered frequent and prognostically important genomic alterations of cell death signaling molecules, including chromosome 11q13/22 FADD and/or BIRC2 (cIAP1) amplifications, or CASP8 mutations, in distinct head and neck squamous cell carcinoma (HNSCC) subtypes. Consistent with TCGA, we found increased FADD and/or cIAP1 expression in a panel of 11 HNSCC cell lines. Overexpression of cIAP1 has been implicated in resistance to standard of care therapies that act through the induction of apoptosis. Birinapant, a novel SMAC-mimetic that targets and promotes degradation of cIAPs, inhibited cell density and sensitized multiple HNSCC lines to death agonists TNF or TRAIL, which was reversible by inhibitors of caspase-dependent apoptosis and/or RIPK1-mediated necroptosis. In vivo, birinapant significantly inhibited tumor growth and prolonged host survival in two FADD/cIAP1-overexpressing xenograft models, UMSCC 46 and 11B. Remarkably, birinapant combined with radiation treatment, an inducer of TNF, cured animals bearing UM-SCC-46 xenografts. These results suggest that birinapant generates strong synergy with radiotherapy in HNSCC harboring cell death pathway genomic alterations linked to worse prognosis.
Citation Format: Sophie Carlson, Danielle Eytan, Grace Snow, Stephen Schiltz, Suresh Mohan, Anthony Saleh, Shaleeka Cornelius, Jamie Coupar, Carter Van Waes, Zhong Chen. Novel SMAC-mimetic birinapant demonstrates antitumor activity in human head and neck cancer models exhibiting alterations in cell death pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3622. doi:10.1158/1538-7445.AM2015-3622
Abstract 3625: Expression of CRBN binding protein AGO2 plays important roles for myeloma cell growth
Authors: Xu Qinqin , Hou Yuexian , Langlais Paul , Erickson Patrick , Zhu James , Shi Changxin , Luo Moulun , Zhu Yuanxiao , Mandarino Lawrence , Stewart Keith , Chang Xiu-Bao 
Published: August 2015

Abstract
Immunomodulatory drugs (IMiDs) are therapeutically active compounds that bind to the E3 ubiquitin ligase substrate recruiter cereblon (CRBN) and induce many cellular responses, including cytotoxicity. We had found that the expression of CRBN in multiple myeloma (MM) cells provided the basis for their responses to IMiDs. In this report, we have identified argonaute 2 (AGO2) as a new member of CRBN-downstream binding protein and found that: 1) the steady-state levels of CRBN in IMiD-sensitive cells are significantly higher than in IMiD-resistant cells; 2) the steady-state levels of AGO2 in IMiD-sensitive cells are significantly less compared to IMiD-resistant cells, suggesting that CRBN plays a role in regulating AGO2. AGO2 is a component of microRNA (miRNA)-induced silencing complexes and plays an important role in miRNA maturation and function. The matured miRNAs are considered as key regulators of almost all cellular pathways. Treatment of IMiD-sensitive MM cells with lenalidomide, an IMiD, significantly increased CRBN, decreased both AGO2 and miRNAs and inhibited cell growth. In contrast, although treatment of IMiD-resistant MM cells with lenalidomide moderately increased CRBN and decreased both AGO2 and miRNAs, this treatment did not significantly inhibit cell growth. However, silencing of AGO2 with small hairpin RNA significantly decreased both AGO2 and miRNAs and inhibited cell growth regardless of whether the cells are sensitive or resistant to IMiDs. Therefore, AGO2 could be considered as a new drug target for overcoming IMiDs resistance in MM cells.
Citation Format: Qinqin Xu, Yuexian Hou, Paul Langlais, Patrick Erickson, James Zhu, Changxin Shi, Moulun Luo, Yuanxiao Zhu, Lawrence Mandarino, Keith Stewart, Xiu-Bao Chang. Expression of CRBN binding protein AGO2 plays important roles for myeloma cell growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3625. doi:10.1158/1538-7445.AM2015-3625
Abstract 3635: Histone demethylase NDY1/KDM2B as a driver of survival and proliferation of normal and neoplastic mast cells
Authors: Foltopoulou Parthena , Pfau Raymond , Betancur-Boissel Monica , AbdelMageed Manar , Tsichlis Philip N. , McNiel Elizabeth A. 
Published: August 2015

Abstract
Proliferative disorders of mast cells exhibit a range of clinical behavior from benign cutaneous forms to aggressive systemic mastocytosis and mast cell leukemia. While these disorders are rare in people, they are among the most common malignancies in the dog, a circumstance that provides a useful model for an orphan disease. Growth of both normal and neoplastic mast cells is driven by c-kit (CD117), a tyrosine kinase receptor for stem cell factor. Ligand-independent, constitutive activation of c-kit via mutation is a common feature of mastocytic neoplasia. Therefore, tyrosine kinase inhibitors (TKIs) that target c-kit have activity in aggressive mastocytosis in people and in dogs. However, resistance to c-kit targeted TKIs is common in both species, highlighting a need for other therapeutic targets.
Our data indicates that chromatin modification may be important in mast cell biology. Specifically, we have shown that the JmjC domain lysine 36 specific histone H3 demethylase, NDY1/KDM2B, supports the proliferation and immortalization of bone-marrow derived mast cells. It is well known that NDY1/KDM2B is a driver of hematopoietic transformation and is associated with malignant progression in certain solid tumors (breast, pancreatic and urothelial carcinoma). Therefore, we investigated the effects of knockdown of NDY1/KDM2B in neoplastic human and canine mast cells in vitro and in xenografts. Our data demonstrate that this knockdown inhibits proliferation and induces apoptosis in vitro and inhibits tumor growth in vivo. Therefore, targeting therapy of NDY1/KDM2B or downstream effectors in mast cell tumors could be a beneficial addition to the existing therapeutic modalities.
Supported by grants from the Morris Animal Foundation (D14CA) and NIH (R01CA109747).
Citation Format: Parthena Foltopoulou, Raymond Pfau, Monica Betancur-Boissel, Manar AbdelMageed, Philip N. Tsichlis, Elizabeth A. McNiel. Histone demethylase NDY1/KDM2B as a driver of survival and proliferation of normal and neoplastic mast cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3635. doi:10.1158/1538-7445.AM2015-3635
Abstract 3639: Design and development of a novel series of orally active, selective PI3K-p110β/δ inhibitors for the treatment of solid and hematological cancers
Authors: Shuttleworth Stephen J. 
Published: August 2015

Abstract
The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies. For solid tumor therapy, the majority of clinical activity has largely centered on pan-class I (p110α, β, δ and γ) inhibitors with limited selectivity, or pan-class I/mTOR dual inhibitors, whereas targeting p110δ and p110γ has been the main focus for hematological cancer treatment in the clinic. Our research at Karus in the PI3K arena has been based upon the emerging role of p110β and p110δ in PTEN-deficient solid and hematological tumorigenesis, and in the emerging role of individual PI3K isoforms in tumor immunotherapy. We have designed and developed a uniquely-selective series of orally-active molecules that inhibit the p110β/δ isoforms, and which display high degrees of specificity over protein kinases and other lipid kinases. Moreover, a spectrum of p110β/δ selectivity has been achieved in this series, which has facilitated interrogation of preferred isoform inhibition profiles required to confer tumor growth inhibition; additionally, by tuning selectivity over the other class I isoforms, elimination of the mechanism-related toxicities associated with the pan-class I inhibitors currently in the clinic can be realized, making such agents potentially more conducive to combination therapy. In vitro and in vivo therapy data for advanced lead compounds will be disclosed.
Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of orally active, selective PI3K-p110β/δ inhibitors for the treatment of solid and hematological cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3639. doi:10.1158/1538-7445.AM2015-3639
Abstract 3642: Structure enabled design of inhibitors of the mitotic kinase MPS1
Authors: Innocenti Paolo , Woodward Hannah , Cheung Kwai_Ming J. , Naud Sébastien , Solanki Savade , Westwood Isaac M. , Faisal Amir , Hayes Angela , Schmitt Jessica , Baker Ross , Matijssen Berry , Burke Rosemary , Eccles Suzanne A. , Raynaud Florence I. , Linardopoulos Spiros , Blagg Julian , van Montfort Rob L M , Hoelder Swen 
Published: August 2015

Abstract
MPS1 (also known as TTK), is a dual-specificity protein kinase that is essential for the proper attachment of chromosomes to the mitotic spindle. MPS1 expression is elevated in a variety of human cancers and is correlated with higher histological grade, aggressiveness and poor patient survival. It has been also shown that basal, PTEN-deficient and triple negative breast cancers are sensitive to MPS1 inhibition. These data together provide strong support for selective antitumour action of MPS1 inhibitors in human cancers. Here we report the discovery of pyridopyrimidines as a new class of inhibitors of MPS1 exploring a hybridization approach. Rapid structure based optimisation of the initial hits led to highly potent, selective and ligand efficient compounds. We will discuss our initial design approach and the structural features that are critical for potent biochemical and cellular inhibition as derived from SAR and co-crystal structures. Furthermore, we will report pharmacokinetic and in vivo properties of selected compounds and comment on our strategy to optimise this series towards preclinical candidates.
Citation Format: Paolo Innocenti, Hannah Woodward, Kwai_Ming J. Cheung, Sébastien Naud, Savade Solanki, Isaac M. Westwood, Amir Faisal, Angela Hayes, Jessica Schmitt, Ross Baker, Berry Matijssen, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Spiros Linardopoulos, Julian Blagg, Rob L M van Montfort, Swen Hoelder. Structure enabled design of inhibitors of the mitotic kinase MPS1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3642. doi:10.1158/1538-7445.AM2015-3642
Abstract 3644: Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer
Authors: Chong Curtis , Ercan Dalia , Bahcall Magda , Capelletti Marzia , Gray Nathanael , Janne Pasi 
Published: August 2015

Abstract
All patients with oncogenic driver mutations in non-small cell lung cancer (NSCLC) who are treated with a targeted agent will eventually develop resistance. In an effort to identify inhibitors of NTRK1 and ROS1, which are inappropriately activated in NSCLC, we created and screened a library of existing targeted drugs against BaF3 cells transformed with these oncogenes. This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 (IC50 = 9 nM), including the crizotinib-resistant mutants G2032R (IC50 = 26 nM) and L2026M (IC50 = 11 nM), with no inhibition of the parental BaF3 cells (IC50 &gt; 10 μM). AP26113, a dual ALK/EGFR inhibitor undergoing phase I/II clinical trials, also potently inhibited CD74-ROS1 (IC50 = 4 nM), including the crizotinib-resistant mutants G2032R (IC50 = 206 nM) and L2026M (IC50 = 84 nM), with weak inhibition of the parental BaF3 cells (IC50 &gt; 1 μM). Both cabozantinib and AP26113 inhibited ROS1 autophosphorylation and downstream ERK activation in CD74-ROS transformed BaF3 cells and in the ROS1-rearranged NSCLC cell line HCC78. The FGFR3 inhibitor dovitinib, which is in phase III clinical trials for renal cell carcinoma, potently inhibited NTRK1 compared to parental BaF3 cells (IC50 = 69 nM vs &gt; 1 μM), and blocked NTRK1 autophosphorylation and ERK activation. While acquired resistance to targeted therapies is a major clinical problem, this study highlights other existing agents that may overcome resistance, and identifies several promising candidates for clinical trials.
Citation Format: Curtis Chong, Dalia Ercan, Magda Bahcall, Marzia Capelletti, Nathanael Gray, Pasi Janne. Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2015-3644
Abstract 3653: Structure-based study to overcome cross-reactivity of novel androgen receptor inhibitors
Authors: Li Huifang , Lallous Nada , Dalal Kush , Leblanc Eric , Ban Fuqiang , Ciesielski Fabrice , Rennie Paul S. , Cherkasov Artem 
Published: August 2015

Abstract
The mutation-driven transformation of clinically used anti-androgens into agonists of human androgen receptor (AR) represents a major challenge in the current treatment of prostate cancer (PCa). To address this problem, we have developed a novel class of AR inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the mutations-prone androgen binding site (ABS) in the ligand-binding domain (LBD) of the AR, targeted by all conventional antiandrogens. While many members of the developed phenyl-thiazol-2-yl-morpholine series demonstrated potent sub-micromolar inhibition of the wild-type AR, some compounds also exhibited an undesired partial agonistic effect toward the T877A mutated form of the receptor, implying their cross-interaction with the AR ABS.
To study the molecular basis of the cross-reactivity, we have solved the T877A mutated form of the AR LBD in complex with one developed compound exhibiting such unwanted partial agonism. Based on the resolved crystal structure, we have identified critical protein-ligand interactions and conformational changes in wild-type and T877A forms of AR that drive observed agonistic effects. The identified structural basis has further been used to modify the scaffold of developed AR DBD binders to eliminate their cross-reactivity toward T877A mutated AR LBD. In particular, the replacement of the phenyl ring with less hydrophobic heterocycles resulted in a series of inhibitors that did not demonstrate affinity toward ABS or exhibit an undesired agonistic effect on AR. This study provides insights into the development of AR inhibitors with high specificity, which may help overcome the mutation-driven resistance of anti-AR drugs in the treatment of PCa.
Citation Format: Huifang Li, Nada Lallous, Kush Dalal, Eric Leblanc, Fuqiang Ban, Fabrice Ciesielski, Paul S. Rennie, Artem Cherkasov. Structure-based study to overcome cross-reactivity of novel androgen receptor inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3653. doi:10.1158/1538-7445.AM2015-3653
Abstract 3656: PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer
Authors: Waddell Ian D. , James Dominic , Smith Kate , Holt Sarah , Acton Ben , Fairweather Emma , Hamilton Niall , Hamilton Nicola , Hitchen James , Huttom Colin , Jordan Allan , McGonagle Alison , Small Helen , Stowell Alex , Waszkowycz Bohdan , Ogilvie Donald 
Published: August 2015

Abstract
Background: DNA single strand breaks (SSBs) are the most common type of damage occurring in cells. Poly (ADP ribose) polymerase (PARP) binds to SSBs and auto-ribosylates itself using NAD+ as a substrate. PARG is the only enzyme known to efficiently catalyse the hydrolysis of O-glycosidic linkages of ADP-ribose polymers and exists (unlike PARP) as a single gene. We have developed novel inhibitors of PARG and here we describe our efforts to understand their sensitivity against a range of cell lines
Methods: A robust and detailed screening cascade for small molecule inhibition of PARG has been developed. Active compounds are tested in cells for PAR chain persistence and for cytotoxicity using a 3-day HeLa assay. In addition, suitable compounds were then evaluated for their physico-chemical properties and their in vivo PK profiles determined. Compounds with the desired PK properties are subsequently profiled in tumour bearing mice to determine their pharmacodynamic effect before progressing to efficacy studies.
Results: We have developed nM PARG inhibitors that are highly selective against ARH3 and PARP1and these derivatives show potent activity in cells. We have designed a breast cancer cell panel against which our compounds have been tested. Our initial bioinformatics analysis suggests that deficiency of a known tumour suppressor confers sensitivity to PARG inhibition.
Conclusions: We have developed two drug-like series of PARG inhibitors that block the breakdown of PAR chains in cells after exogenous DNA damage by methylating agents. These tool compounds are potent, selective and have pharmacokinetic and pharmacodynamics properties that have allowed us to explore their anti-tumour potential. The discovery of a tumour suppressor profile indicating cell line sensitivity will aid the about identification of patient populations that will potentially benefit from PARGi therapies.
Citation Format: Ian D. Waddell, Dominic James, Kate Smith, Sarah Holt, Ben Acton, Emma Fairweather, Niall Hamilton, Nicola Hamilton, James Hitchen, Colin Huttom, Allan Jordan, Alison McGonagle, Helen Small, Alex Stowell, Bohdan Waszkowycz, Donald Ogilvie. PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3656. doi:10.1158/1538-7445.AM2015-3656
Abstract 3657: Preclinical evaluation of water-soluble pyrrolo[3,2-d]pyrimidines as single agents with tubulin and multiple receptor tyrosine kinase inhibition and as antitumor agents
Authors: Shah Khushbu , Gangjee Aleem , Pavana Roheeth , Nicholas Dybdal-Hargreaves F. , Mooberry Susuan 
Published: August 2015

Abstract
Multiple classes of microtubule targeting agents have been identified and these include the Vinca alkaloids and colchicine (microtubule-destabilizers) and taxanes (microtubule-stabilizers). Although tubulin targeting agents are some of the most successful drugs used in the treatment of a wide range of malignancies, multidrug resistance due to overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can severely limit their clinical efficacy. Antitubulin agents like paclitaxel and other taxanes, due to poor water solubility, are formulated with polyethoxylated castor oil which can cause hypersensitivity reactions and require prolonged administration time. Recently, we reported water-soluble pyrrolo[3,2-d]pyrimidine analogs acting as antitubulin agents that circumvent these drawbacks. These analogs also exhibit potency comparable to erlotinib in cancer cell lines overexpressing epidermal growth factor receptor (EGFR) and to that of sunitinib in cancer cell lines overexpressing vascular endothelial growth factor receptor-2 (VEGFR2) and platelet derived growth factor receptor-β (PDGFRβ), in addition to inhibiting tubulin. Promising evidence for the clinical success of combination chemotherapy using multiple RTK inhibitors with antitubulin agents suggests that these dual acting compounds would serve as a single entity with both these activities. To explore the activity of these dual RTK/tubulin inhibitors, compound AG165 was evaluated in in vitro and in vivo xenograft models. In vitro AG165 inhibited the growth of MDA-MB-435 cells with an IC50 of 8.8 nM, comparable to paclitaxel. The compound is also active in paclitaxel resistant cancer cells overexpressing βIII-tubulin or Pgp, thus overcoming two important mechanisms associated with clinical resistance to paclitaxel. Compound AG165 (subcutaneous doses of 75 mg/kg x 7, cumulative dose 525 mg) showed significant (p&lt;0.001) inhibition of tumor growth 15 days after treatment initiation. AG165 caused recoverable weight loss without any evidence of adverse effects. In this study, we have identified a water-soluble, dual acting RTK/ tubulin inhibitory agent that address some critical limitations of existing therapies and demonstrates in vivo antitumor effects with an acceptable toxicity profile.
Citation Format: Khushbu Shah, Aleem Gangjee, Roheeth Pavana, Dybdal-Hargreaves F. Nicholas, Susuan Mooberry. Preclinical evaluation of water-soluble pyrrolo[3,2-d]pyrimidines as single agents with tubulin and multiple receptor tyrosine kinase inhibition and as antitumor agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3657. doi:10.1158/1538-7445.AM2015-3657