bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-99: Identification and characterization of small molecule thieno[3,2-d]pyrimidine inhibitors of Protein Kinase C iota (PKCι)
Authors: Soudy Christelle , Stanway Emma , Patel Bhavisha , Barton Caroline , Barnard Michelle , Pang Leon , Owen Paul , Turnbull Andrew , Ruggeri Bruce A. , Dorsey Bruce D. , Ator Mark A. , Ott Greg R. , Linch Mark , Riou Philippe , Parker Peter J. , Kjaer Sven , Dillon Christian , McDonald Neil Q. , Roffey Jon 
Published: May 2015

Abstract
We describe a novel series of small molecule ATP-competitive inhibitors of the atypical class of Protein Kinase C (PKC). The PKC family of serine/threonine kinases are divided into four structurally and functionally distinct sub-types: classic (PKCα, PKCβ, PKCγ); novel (PKCδ, PKCε, PKCη, PKCθ); atypical (PKCι,PKCζ); and PKNs (PKN1, PKN2, PKN3). The PKCs have been defined as key regulators in a multitude of signal transduction pathways that impinge on diverse cellular processes such as proliferation, differentiation, and survival. The regulation and functions of the atypical PKCs are distinct from the classic and novel PKCs.Both atypical isoforms have been implicated in various models of cancer, and PKCι in particular has been described as a potential oncogene. Its abundance is frequently increased, primarily through PKCι gene amplification, in many epithelial tumours including: subsets of squamous non-small cell lung carcinoma, serous ovarian carcinoma, and squamous esophageal carcinoma. It has been widely demonstrated that deregulation of PKCι signalling leads to unconstrained cell growth, increased migratory and invasive behaviour, and aberrant cellular polarity, which is a hallmark of aggressive cancers. Together, these data make a strong case for the inhibition of PKCι as a novel therapeutic strategy. We have discovered a series of ATP-competitive thieno[3,2-d]pyrimidine- based PKCι inhibitors from a high throughput screen. Using structure-based design we have optimized the series and demonstrated potent and selective inhibition of PKCι in biochemical and cellular models. The biochemical, structural, and cellular characterization of these compounds will be described herein.
Citation Format: Christelle Soudy, Emma Stanway, Bhavisha Patel, Caroline Barton, Michelle Barnard, Leon Pang, Paul Owen, Andrew Turnbull, Bruce A. Ruggeri, Bruce D. Dorsey, Mark A. Ator, Greg R. Ott, Mark Linch, Philippe Riou, Peter J. Parker, Sven Kjaer, Christian Dillon, Neil Q. McDonald, Jon Roffey. Identification and characterization of small molecule thieno[3,2-d]pyrimidine inhibitors of Protein Kinase C iota (PKCι). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-99. doi:10.1158/1538-7445.AM2014-LB-99
Abstract SY05-02: Targeting kinases with reversible covalent fragments
Authors: Taunton Jack 
Published: May 2015

Abstract
The clinical utility of targeting kinases with covalent drugs has been firmly established, culminating in the recent FDA approval of afatinib and ibrutinib, which irreversibly inhibit the tyrosine kinases, EGFR and BTK. More broadly, chemical probes that form a covalent bond with a nonconserved, noncatalytic cysteine often show enhanced potency, selectivity, and utility in biological studies. Despite these advantages, protein-reactive compounds are usually avoided in high-throughput screening campaigns. Motivated by a desire to explore the chemistry of reactive electrophiles and thiols under physiological conditions, we initiated a study of Michael acceptors bearing substituents with increasing electron withdrawing capacity. We hypothesized that the intrinsically labile nature of the cysteine/cyanoacrylamide bond could be exploited to yield cysteine-targeted, reversible covalent inhibitors. These concepts led to the design of ultra-selective cyanoacrylamide-based RSK inhibitors with picomolar affinity and slow dissociation kinetics, the structural basis of which was revealed by x-ray crystallography. The intrinsically reversible, yet thermodynamically favorable nature of the cysteine/cyanoacrylamide bond suggested that this ‘sweet spot’ in electrophile space could form the basis of a fragment-based approach to ligand discovery. Screening a collection of cyanoacrylamide fragments against three kinases (RSK2, NEK2, and PLK1) containing a structurally equivalent cysteine delivered unique inhibitors for all three kinases with potencies in the submicromolar range. Optimization guided by x-ray crystallography rapidly led to the first dual inhibitor of MSK and RSK, with subnanomolar affinity and &gt;500-fold selectivity over NEK2 and PLK1. In close collaboration with Brian Shoichet and Nir London, we have employed covalent docking methods to screen large virtual libraries of electrophilic fragments. We designed a pilot virtual library of 13,000 cyanoacrylamide fragments that can be synthesized in one simple step from commercially available aldehydes. A virtual screen of this library rapidly led to novel inhibitors of NEK2, PLK-, and MSK/RSK-family kinases. Finally, I will discuss our efforts to discover and design new electrophilic chemotypes that form reversible covalent bonds with cysteine residues.
Citation Format: Jack Taunton. Targeting kinases with reversible covalent fragments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY05-02. doi:10.1158/1538-7445.AM2014-SY05-02
Abstract SY05-03: Natural product-inspired peptide drug discovery accelerated by the RaPID system
Authors: Suga Hiroaki 
Published: May 2015

Abstract
Despite the fact that natural products are attractive resources for the discovery of drug candidates, the screening processes often not only time-consuming and labor-intensive but also high risk to obtain potent molecules. We have previously devised a new means to reprogram the genetic code, which allows us to express macrocyclic peptides using a custom-made in-vitro translation system. Its integration with the mRNA display technique has also led to the development of a means of selecting bioactive macrocyclic peptides, referred to as RaPID (Random non-standard Peptide Integrated Discovery) system. This lecture will describe some of recent examples for the discovery of such natural product-inspired macrocycles and pseudo-natural products with their therapeutic applications.
Citation Format: Hiroaki Suga. Natural product-inspired peptide drug discovery accelerated by the RaPID system. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY05-03. doi:10.1158/1538-7445.AM2014-SY05-03
Abstract SY05-04: Biological discovery and therapeutic insight from DNA-templated macrocycle libraries
Authors: Liu David R. 
Published: May 2015

Abstract
DNA-templated organic synthesis enables the translation of libraries of DNA templates into corresponding libraries of synthetic small molecules. The in vitro selection of a library of DNA-templated small-molecule macrocycles has resulted in the discovery of unusually selective and potent inhibitors of kinase, protease, and protein-protein interface targets. Using this approach, we recently discovered the first physiologically active inhibitor of an enzyme implicated in type-2 diabetes. In a series of biochemical, structural biological, and in vivo physiology experiments, we elucidated the molecular basis of target inhibition by this macrocycle, validated a new target for the potential treatment of type-2 diabetes, and discovered previously unknown and therapeutically relevant physiological roles for this enzyme.
Citation Format: David R. Liu. Biological discovery and therapeutic insight from DNA-templated macrocycle libraries. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY05-04. doi:10.1158/1538-7445.AM2014-SY05-04
Abstract SY06-02: Revisiting the STATs of cancer: Emergence of stem-like cancer cells
Authors: Jove Richard 
Published: May 2015

Abstract
Activation of the STAT3 signaling pathway is now well established as an important factor in cancer progression and as a promising molecular target for cancer therapy. Persistent STAT3 activation in tumor cells prevents apoptosis and promotes cell proliferation. In the tumor microenvironment, STAT3 activation enhances angiogenesis and suppresses anti-tumor immune responses. Communication between tumor cells and stromal cells in the tumor microenvironment, by inflammatory cytokines like interleukin (IL)-6, results in a feed-forward loop that enhances cancer progression and confers resistance to therapy. Recently, we have uncovered another critical role for STAT3 in cancer progression and resistance to therapy. We now show that activation of STAT3 signaling promotes a stem-like cell phenotype in prostate cancer, concomitant with loss of androgen receptor (AR) expression. AR is important for prostate cancer progression, and androgen deprivation often leads to drug resistance and eventual cancer recurrence. We demonstrate that loss of AR expression as a consequence of androgen ablation results in STAT3 activation in prostate cancer cells. This STAT3 activation in turn leads to development of prostate cancer stem-like cells. AR downregulation-induced STAT3 activation is mediated through increased IL-6 expression in the tumor microenvironment. Elevated stem-like cell markers in human prostate tumor specimens coincides with high STAT3 activity and low AR expression. Treatment of mice with soluble IL-6 receptor or silencing STAT3 in tumor cells suppresses prostate tumor growth and inhibits development of stem-like cancer cells. In sum, our results demonstrate that blockade of AR mediates activation of STAT3 signaling through up-regulation of IL-6, which is associated with development of a stem-like cancer cell phenotype. Conversely, inhibition of the IL-6/STAT3 pathway diminishes the stem-like cancer cell population, and results in reduced tumor growth. Our findings provide new mechanistic insights into the role of STAT3 activation upon AR blockade on prostate cancer relapse and drug resistance. We further propose inhibition of STAT3 signaling in combination with anti-androgens as a potential strategy to prevent emergence of drug-resistant recurrent prostate cancer.
Citation Format: Richard Jove. Revisiting the STATs of cancer: Emergence of stem-like cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY06-02. doi:10.1158/1538-7445.AM2014-SY06-02
Abstract SY13-04: Stem cell self-renewal and cancer
Authors: Morrison Sean J. 
Published: May 2015

Abstract
Haematopoietic stem cell self-renewal and leukemogenesis
“Pre-leukemic” mutations are thought to promote clonal expansion of haematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness; however, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative neoplasms and leukemia. We found that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukemia initiation. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed cell cycle kinetics using H2B-GFP label retention and BrdU incorporation. NrasG12D had a bimodal effect on HSCs, increasing the rate at which some HSCs divide and reducing the rate at which others divide. This mirrored bimodal effects on reconstituting potential as rarely dividing NrasG12D HSCs outcompeted wild-type HSCs while frequently dividing NrasG12D HSCs did not. NrasG12D had these effects by promoting STAT5 signaling, inducing different transcriptional responses in different subsets of HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through bimodal effects on HSC gene expression, cycling, and reconstituting potential.
We have also developed methods for studying protein synthesis by individual stem cells in vivo. Currently, there are almost no data on protein synthesis in any somatic stem cell. We found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other haematopoietic cells, even if we controlled for differences in cell cycle status or forced HSCs to undergo self-renewing divisions. Reduced ribosomal function in Rpl24Bst/+ mice further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24Bst/+ cell-autonomously rescued the effects of Pten deletion in HSCs, blocking the increase in protein synthesis, restoring HSC function, and delaying leukemogenesis. Pten deficiency thus depletes HSCs and promotes leukemia partly by increasing protein synthesis. Increased or decreased protein synthesis impairs HSC function.
Citation Format: Sean J. Morrison. Stem cell self-renewal and cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-04. doi:10.1158/1538-7445.AM2014-SY13-04
Abstract SY20-03: Nuclear-mitochondrial cross-talk: A key determinant of cancer metastasis
Authors: Welch Danny R. , Liu Wen , Feeley Kyle P. , Ballinger Scott W. 
Published: May 2015

Abstract
Despite the well known energy requirements and stresses of metastasis, the relationships between metabolism, mitochondrial genetics and metastasis are still underdeveloped. Two lines of investigation point to more intimate involvement of mtDNA than is widely appreciated. First, recent data demonstrate that the metastasis suppressor KISS1 essentially reverses the so-called Warburg Effect by regulating mitochondrial biogenesis. KISS1 re-expression results in higher pH[Ex] due to reduced lactate secretion concomitant with reduced glycolysis and a shift toward oxidative phosphorylation. KISS1-expressing cells have 30-50% more mitochondrial mass, which appears to be due to higher expression of PPARγ co-activator 1α (PGC1α), a master regulator of mitochondrial biogenesis. shRNA-mediated knockdown of KISS1 and PGC1α establish a pathway between these molecules, mitochondrial biogenesis and metastatic potential. Second, genetic crosses with a newly described MNX (mitochondrial-nuclear exchange) mice suggest that mitochondrial polymorphisms (haplotypes) may control susceptibility to metastasis. Transgenic FVB/N-tg:MMTV-PyMT which spontaneously develop mammary tumors and lung metastasis with high penetrance were crossed with female MNX mice having the same nuclear background (FVB - wild-type) but with C57BL/6 and BALB/c mitochondrial backgrounds. Using this strategy, the mtDNA contributions to metastasis can be discriminated. Results demonstrate that tumor and metastasis incidence do not appear to be significantly different. However, metastasis size is greatly affected. Taken together, these data strongly support the concept that mitochondrial-nuclear cross-talk is a more significant determinant of metastasis than generally appreciated. SUPPORT: NCI-CA134981; Natl Fndn Cancer Res, Susan G. Komen SAC11037, Hall Family Fndn, KS Bioscience Auth.
Citation Format: Danny R. Welch, Wen Liu, Kyle P. Feeley, Scott W. Ballinger. Nuclear-mitochondrial cross-talk: A key determinant of cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY20-03. doi:10.1158/1538-7445.AM2014-SY20-03
Abstract SY28-03: Whole genome pictures of live cancers and personalized medicine
Authors: Nakagawa Hidewaki 
Published: May 2015

Abstract
Primary liver cancer is one of the most common and deadly cancers worldwide, especially in Asia, and has no effective treatment, yet its molecular mechanism remains largely unknown. Although virus-related HCC is a major form of primary liver cancer in Asia, their etiology and phenotype are very heterogeneous (HBV-infected, HCV-infected, or non-viral, and HCC or biliary phenotype). To explore whole genomic alterations and diversity of liver cancers, we performed whole genome sequencing (WGS) analysis integrated with RNA-seq on ∼270 liver cancers, demonstrating comprehensive landscape of diverse phenotypes of liver cancers with multiple etiological backgrounds for point mutations, short indels, copy-number alterations, structural variations, and HBV integrations. On average, approximately 10,000 somatic alterations per one tumor were identified by WGS, and our study indicated the genomic heterogeneity of liver cancer genomes as well as their etiological heterogeneity and that somatic substitution patterns of cancer genomes could be determined by their etiological backgrounds such as carcinogen exposure and cell origins. Understanding of liver cancer genome heterogeneity underlying its biological phenotype and interpreting its genomic data could facilitate cancer biomarkers discovery and personalized medicine, where we can select old and new drugs to each of cancer patients by using their diverse genome information.
Citation Format: Hidewaki Nakagawa. Whole genome pictures of live cancers and personalized medicine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY28-03. doi:10.1158/1538-7445.AM2014-SY28-03
Abstract SY29-04: Beyond necroptosis - regulated necrosis in the kidney
Authors: Linkermann Andreas 
Published: May 2015

Abstract
Regulated necrosis (RN) may result from cyclophilin D (CypD)-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase 1 (RIPK1)- mediated necroptosis, ferroptosis, pyroptosis, NADPH-oxidase (NOX) mediated necrosis and other pathways, but it is currently unclear to what extent these signaling pathways are independent from each other. Especially MPT and necroptosis have been described to contribute to necrotic cell death in kidney ischemia reperfusion injury (IRI). We demonstrate that necroptosis in IRI occurs in mice as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI and the level of protection was significantly stronger than of CypD-deficient mice. Several lines of evidence in vitro and in vivo, including the analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. In addition, we found necroptosis to be completely independent of mitochondria in vitro and therefore generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 (Nec-1) and the MPT inhibitor sanglifehrin A (SfA) confirmed the results with mutant mice. The data demonstrate the pathophysiological co-existence and co-relevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.
Citation Format: Andreas Linkermann. Beyond necroptosis - regulated necrosis in the kidney. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY29-04. doi:10.1158/1538-7445.AM2014-SY29-04
Abstract SY31-02: Building highly effective anti-tumor T cells
Authors: Restifo Nicholas P. 
Published: May 2015

Abstract
Many tumors contain relatively undifferentiated transformed progenitors termed ‘cancer stem cells’ (CSC). Stem cells are defined by the ability to self-renew and generate differentiated progeny, qualities maintained by evolutionarily conserved pathways that can lead to cancer when deregulated. The existence of stem cells has been documented across multiple tissues both during development on into adulthood including the hematopoietic and central nervous systems, intestine, skin, cardiac muscle and lung. All of these sites employ the presence of limited numbers of stem cells in tissues enable a few daughter cells to retain a regenerative potential while the majority of daughter cells enter an irreversible process of differentiation culminating in the generation of specialized cell types. Recently, we have found evidence supporting the existence and function of stem cells within the adaptive immune system in both the CD8+ and CD4+ T cell lineages. This stem cell-like population has been termed ‘T memory stem cells’ (TSCM). In preclinical models using both mouse and human cells, TSCM can overcome many limitations of currently employed T cell-based immunotherapies, especially in the setting of adoptive T cell transfer, including inefficient T cell engraftment, persistence, and ability to mediate prolonged immune attack. Conferring stemness to anti-tumour T cells might unleash the full potential of cellular therapies. Our goal is to trigger stem cell-like pathways in tumor-reactive T cells or to reprogram terminally differentiated tumor-infiltrating lymphocytes (TILs) to confer stem cell-like properties to augment immunotherapies against cancer and CSC, akin to fighting ‘fire with fire.’ In new work from our laboratory (1) as well as unpublished experiments, we have identified several candidate transcription factors that are differentially expressed in stem cell-like T cells. In addition, new experiments have shed significant light on the metabolic properties of highly effective stem cell-like T cell subsets.
Reference
1. Roychoudhuri, R, et al, Nature, 2013.
Citation Format: Nicholas P. Restifo. Building highly effective anti-tumor T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY31-02. doi:10.1158/1538-7445.AM2014-SY31-02