bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B220: Artificially inducing protein-membrane anchorage: Introducing a new therapeutic modality.
Authors: Avadisian Miriam , Fletcher Steven , Liu Baoxu , Zhao Wei , Yue Peibin , Turkson James , Gradinaru Claudiu , Gunning Patrick 
Published: June 2012

Abstract
We aim to develop an innovative therapeutic modality of inhibiting aberrant protein function through suppression of activation and/or nuclear translocation. Nature has developed prenylation, a post-translational modification that covalently attaches a hydrophobic prenyl group to a protein to facilitate protein-membrane association to the plasma membrane. We hypothesize that mimicking Nature by artificially inducing protein-membrane anchorage through the use of a rationally designed protein-membrane anchor (PMA), we can simultaneously inhibit the activation and nuclear translocation of oncogenic proteins. Our aim is to explore the therapeutic potential of the protein-membrane anchor and potentially develop a novel drug modality that can be utilized by cancer patients.
Our proof-of-concept PMA was design to target signal transducer and activator of transcription 3 (Stat3) protein.
Constitutively-active Stat3 directly contributes to the progression of cancer and is present in numerous human cancers. A number of studies have shown that down-regulation of this oncogene via iRNA knockdown induces cellular apoptosis. Thus, Stat3 is an attractive target for the development of potent anti-cancer therapeutics for cancer.
Our proto-type PMA 1 was composed of two binding modules: a recognition motif to bind the protein and an anchor to sequester the protein complex to the membrane. The PMA was comprised of a potent Stat3 recognition sequence GpYLPQTV-NH2 covalently attached to a cholesterol membrane anchor.
We tested the ability of our PMA to anchor Stat3 to the cell membrane in MDA-MB-231 breast cancer cells which are known to have constitutively-active Stat3. We immunostained these cells with membrane stain FM-4–64 (red), anti-Stat3 antibody (green) and DAPI (nucleus, blue). In the absence of PMA 1, there was strong Stat3 nuclear presence. Most excitingly, in the presence of 25 μM concentration PMA 1, we observed complete sequestration of Stat3 to the cell membrane through PMA-Stat3 association. Currently, we are designing and synthesizing more drug-like, nonphosphorylated PMAs that are less prone to metabolic degradation. We will conduct further studies to determine the biochemical and biological utility of these PMAs.
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 B220.
Abstract B238: Novel imidazo[1,2-a]pyridines as inhibitors of the IGF-1R tyrosine kinase.
Authors: Ducray Richard , Simpson Iain , Jones Clifford D. , Curwen Jon , Trigwell Catherine B. , Veldman-Jones Margaret H. , Fitzek Martina , Walker Graeme E. , Ward Lara T. , Hudson Kevin , Pass Martin 
Published: June 2012

Abstract
The Insulin-like Growth Factor-1 Receptor (IGF-1R) is a receptor tyrosine kinase which plays an important role in cancer by promoting proliferation and survival through activation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Deregulation of the IGF-1R axis has been reported in a variety of solid cancers and occurs by overexpression of either the receptor or its ligands (IGF-1 and IGF-2) or by down-regulation of IGF binding proteins (in particular IGFBP3). Therapeutic approaches to inhibit IGF-1R signaling include antibodies targeting the receptor and small molecule inhibitors of the tyrosine kinase. The latter strategy offers a potential advantage by simultaneously inhibiting the closely related Insulin Receptor A (IR-A) tyrosine kinase. Indeed, IR-A can drive tumor growth in some cancer cell lines and has been suggested has a potential escape mechanism for IGF-1R inhibition.
Following a cell based high throughput screening, we have identified a series of imidazo[1,2-a]pyridines inhibiting the IGF-1R kinase. Although hit compounds carried a significant activity against CDK2, modifications of the aniline part has led to more potent and selective inhibitors. We selected 1-[4-[4-[(5-chloro-4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-yl)amino]-3-methoxy-phenyl]piperazin-1-yl]ethanone (5) as a lead compound having good pharmacokinetics in pre-clinical species. Compound (5) displays a dual inhibition of IGF-1R and the insulin receptor tyrosine kinase as measured in biochemical assays as well as in cellular auto-phosphorylation assays. Structure-activity relationship around (5) is described for IGF-1R inhibition as well as for the hERG ion channel.
Compound (5) has been assessed in an in vivo efficacy model based on the NIH 3T3 fibroblast cell line transfected to express human IGF-1R and IGF1 ligand. In contrast to the non-transfected parent line, this cell line rapidly grows as a sub-cutaneous xenograft in nude mouse, thus providing a suitable model to measure anti-IGF-1R pharmacology by tumor growth inhibition. The high expression of IGF-1R also enables the generation of good quality PD data using receptor phosphorylation as an endpoint.
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 B238.
Abstract B239: Inhibition of myeloproliferative neoplasms by combinations of JAK2 and PI3K inhibitors.
Authors: Choong Meng Ling , Pecquet Christian , Tai Shi Jing , Yong Jacklyn Wei Yan , Pendharkar Vishal , Wang SiFang , Defour Jean-Philippe , Diaconu Carmen C. , Sangthongpitag Kanda , Constantinescu Stefan N. , Lee May Ann 
Published: June 2012

Abstract
This study focuses on three main myeloproliferative neoplasms, namely, polycythaemia vera, essential thrombocytosis, and primary myelofibrosis. The main pathological causes of these three diseases are a mutation in the JAK2 protein or a mutation in the thrombopoietin receptor that arises in the hematopoietic stem/progenitor cells. Both type of mutations lead to constitutive activation of the JAK2 signaling pathways. Current JAK2 inhibitors in clinical trials are not expected to be selective and specific enough to suppress the multiple signaling pathways activated by the aberrant JAK2 signaling. Hence, we are seeking a combination treatment using a specific JAK2 inhibitor with another specific kinase inhibitor to inhibit the multiple signaling pathways activated by the constitutively active JAK2. Mouse Ba/F3 cells were engineered to express either JAK2 WT, or JAK2 V617F, or TpoR W515L, or TpoR JAK2 WT, or TpoR JAK2 V617F, or Bcr-abl. The effect of JAK2 inhibitors in combination with a panel of kinase inhibitors in an 8×8 constant ratio drug combination design were used to test for the inhibition of cell viability in the cell models. Calculation of drug synergism was carried out using the Chou-Talalay method. We found that JAK2 inhibitors synergized with PI3K inhibitors. The JAK2-PI3K inhibitors combination was specific for JAK2 signaling as survival of Ba/F3 cells expressing Bcr-abl was unaffected by this combination treatment. Balb/c mice inoculated with Ba/F3 cells expressing TpoR JAK2 V617F were found to have increased spleen weight. Our combination treatment could drastically reduce spleen weight compared to treatment with individual compound alone. The combination treatment also resulted in significant survival benefit in Balb/c mice inoculated with Ba/F3 cells expressing TpoR JAK2 V617F compared to untreated mice or mice given either compound alone.
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 B239.
Abstract B241: Targeting the mitotic checkpoint with NMS-P153, a novel MPS1 kinase inhibitor.
Authors: Colombo Riccardo , Caldarelli Marina , Giorgini Maria Laura , Sola Francesco , Cappella Paolo , Perrera Claudia , Avanzi Nilla , Berthrand Jay A. , Pesenti Enrico , Isacchi Antonella , Donati Daniele , Moll Jurgen , Galvani Arturo 
Published: June 2012

Abstract
Aneuploidy is one of the major hallmarks of cancer and is a unique property of tumoral cells. Thus, targeting the molecular mechanisms required for the growth of aneuploid cells might be expected to yield more cancer cell specific therapeutic approaches. The Spindle Assembly Checkpoint (SAC) is a mitotic mechanism required for proper chromosomal segregation, ensuring that cells do not divide until all sister chromatids correctly align to the metaphase plate. It is a complex machinery tightly regulated by a number of members which are rarely mutated in tumors. Rather, checkpoint components have been found to be upregulated in aneuploid tumor cells, suggesting a potential tumor “addiction” to SAC functions. MPS1 kinase, (also known as TTK) is an essential SAC enzyme aberrantly overexpressed in a wide range of tumors and necessary for tumor cell proliferation. We previously reported the identification of NMS-P715 as a selective and orally bioavailable MPS1 inhibitor capable of promoting mitotic acceleration, thereby causing aneuploidy and cancer cell death both in vitro and in vivo. Supported by the proof that MPS1 small-molecule inhibitors display the expected mechanism of action and promote tumor growth inhibition in preclinical cancer models, further medicinal chemistry efforts were undertaken and led to the discovery of NMS-P153 as an early candidate product.
NMS-P153 is highly selective, and compared to NMS-P715, shows improved in vitro enzymatic potency on MPS1 (IC50 of 3 nM), 10-fold increased mitotic override activity, longer dissociation half-life and better mouse and rat PK parameters, leading to impressive tumor growth inhibition associated with tumor regression in efficacy studies.
Proliferation data performed on a large panel of cell lines (&gt;100) have been obtained and will be essential to decipher the most sensitive genetic backgrounds to chemical abrogation of MPS1 function. In addition, single and repeated toxicology studies in rat are being carried out to establish therapeutic safety margins. Inhibiting the spindle assembly checkpoint by targeting MPS1 kinase could represent a promising new approach to cancer therapy.
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 B241.
Abstract B28: Organic anion transporting polypeptide 1B3 as a novel biomarker for hypoxia in prostate cancer.
Authors: Pressler Heather M. , Pisle Stephen , Sissung Tristan M. , Cropp Cheryl D. , Price Douglas K. , Figg William D. 
Published: June 2012

Abstract
The organic anion transporting polypeptide 1B3 (OATP1B3) is aberrantly expressed in prostate cancer. We showed that OATP1B3 expression correlated to Gleason score in primary prostate cancer samples. As a transporter, OATP1B3 functions to influx both endogenous small molecules and xenobiotics. We also demonstrated that decreased survival and decreased progression in patients with prostate cancer was associated with a polymorphism in SLCO1B3, the gene encoding OATP1B3. However, OATP1B3 has not been validated as a clinical biomarker and the cause of expression in cancer is unknown. The purpose of this study was to identify a molecular regulation that explains OATP1B3 expression in cancer. In this study, we show that hypoxia increases the transcriptional and translational expression of OATP1B3 in cancer, that hypoxia-inducible factor 1-alpha (HIF1-alpha) binds putative hypoxia response elements in the SLCO1B3 promoter region by chromatin immunoprecipitation, and show co-localization of hypoxia and OATP1B3 by immunohistochemistry in clinical tissue samples. Additionally, cooperation between androgen- and hypoxia-signaling pathways explains the increased expression of OATP1B3 in prostate cancer xenografts under castration conditions. These data provide a foundation for the use of OATP1B3 as a biomarker of cancerous disease.
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 B28.
Abstract B3: Allosteric MEK inhibitor BAY 86-9766 acts synergistically with sorafenib to inhibit tumor growth, angiogenesis, and tumor cell survival in ectopic patient-derived xenograft models of human hepatocellular carcinoma.
Authors: Ong Richard , Puehler Florian , Scholz Arne , Chung Alex , Soo Khee Chee , Hung Huynh T. 
Published: June 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor and the Raf/MEK/ERK pathway is activated in HCC. Sorafenib has been shown to prolong survival of patients with advanced HCC. BAY 86-9766 (RDEA119) is an orally available, potent, allosteric MEK inhibitor currently in Phase I/II trials. A combination therapy of MEK inhibitor BAY 86-9766 with sorafenib might enhance the therapeutic efficacy of sorafenib in HCC. This study aims to investigate the potential of such a combined therapeutic approach in preclinical models of HCC.
Methods: We treated 15 patient-derived HCC xenograft models (Asian origin) with i) sorafenib, ii) BAY 86-9766, and iii) sorafenib plus BAY 86-9766. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to both angiogenesis and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry.
Results: We report here that sorafenib significantly suppressed tumor growth with the T/C ratios ranging from 0.25 to 0.6, angiogenesis and cell proliferation with modest elevation of pERK Thr202/Tyr204. BAY 86-9766 treatment caused a modest tumor growth inhibition (ranging from 30 to 60%) and dephosphorylation of ERK, Bim and p90RSK. The addition of BAY 86-9766 to sorafenib significantly augmented the antitumor activity of sorafenib in 15 models of HCC. The T/C ratios for the sorafenib/BAY 86-9766 ranged from 0.03 to 0.2. Such inhibition led to further increase in Bad, Bim and apoptosis. Profound inhibition of cell proliferation, angiogenesis and inactivation of p90RSK and mTOR targets were also observed in the combined therapy.
Conclusion: We show that sorafenib/BAY 86-9766 treatment is considerably more effective than either single agents in suppressing tumor growth, angiogenesis, cell proliferation and cell survival. Our findings underscore the potential of sorafenib/BAY 86-9766 combination in the treatment of HCC.
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 B3.
Abstract B41: Overcoming chemo/radioresistance of castration-resistant prostate cancer via modulating autophagy.
Authors: Xu Liang 
Published: June 2012

Abstract
Chemo/radioresistance markedly impair the efficacy of prostate cancer therapy. Anti-apoptotic Bcl-2 family proteins such as Bcl-xL, Bcl-2 and Mcl-1 are overexpressed in castration-resistant prostate cancer (CRPC) and contribute to prostate tumor initiation, progression and resistance to radiotherapy. A natural BH3-mimetic, small molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1, (−)-gossypol, shows promise in multiple Phase I-II clinical trials for human prostate cancer. We have recently shown that (−)-gossypol preferentially induces autophagy in CRPC cells that have high levels of Bcl-2/Bcl-xL/Mcl-1 and are resistant to apoptosis, both in vitro and in vivo, but not in androgen-dependent cells with low Bcl-2 and sensitive to apoptosis (Cell Death Diff 2011, 18(1):60–71). Our results demonstrate for the first time that (−)-gossypol can interrupt the interaction between Beclin1 and Bcl-2/Bcl-xL at the endoplasmic reticulum, thus releasing the BH3-only pro-autophagic protein Beclin1, which in turn triggers the autophagic cascade. (−)-Gossypol-induced autophagy is Beclin1- and Atg5-dependent, together with Bcl-2 downregulation and Beclin1 upregulation. (−)-Gossypol increased autophagic cell death induced by either X-ray radiation or chemotherapeutics in the CRPC cells. Orally administered (−)-gossypol achieved a much greater efficacy with long-term tumor regression when used in combination with ionizing radiation or first-line chemotherapy. We have also explored a series of gossypol derivatives and identified two novel BH3-mimetic lead compounds that are more potent than the parental compound in inducing autophagic cell death in CRPC. Taken together, (−)-gossypol significantly enhances the anti-tumor activity of chemo/radiotherapy in vitro and in vivo, and represents a promising new regime for treatment of castration-resistant human prostate cancer with overexpression of Bcl-2. Our data provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which would facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy.
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 B41.
Abstract B59: Polycomb group ring finger protein plays a role in gamma ionizing radiation-induced DNA damage response in MCF7 cell line.
Authors: Lee Chang Se , Kim Karam , Yoon Young A , Hwang Chang Sun , Jang Sungjae , Park In-chul , An Sungkwan , Jin Young Woo , Kim Tae Jin , Lee Jae Ho 
Published: June 2012

Abstract
Polycomb group (PcG) gene product is a family of proteins that were accumulated with complexes in nuclear and plays an important role in development and maintaining stem cell population of hematopoietic and neuronal cell lineages. PcG complexes can regulate the transcriptional activity of many genes by epigenetic silencing involved in embryogenesis. Recent reports showed the overexpressions of PcG proteins were correlated with the severity of many cancers. To investigate the underlying mechanisms of PcG ubiquitin ligase (PCGF1-6) on DNA damage response after exposure to gamma ionizing radiation, we generated the stable knockdown MCF7 breast cancer cell lines capable of silencing each of PcG ubiquitin ligase genes. Cell survival and proliferation analysis in stable PcG ubiquitin ligase knockdown MCF7 cell lines was compared to the analysis in control MCF7 cell lines after treatment of gamma ionizing radiation using MTT and colony forming assay. Furthermore, we found that loss of several PcG ubiquitin ligases sensitizes MCF7 cell lines to gamma ionizing radiation-mediated growth inhibition. We further demonstrate that several PCGF PcG ubiquitin ligases are localized at γ-H2AX foci after treatment of gamma ionizing radiation. These results demonstrate that PCGF family can coordinately regulate the cell resistance mechanism in DNA damage response.
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 B59.
Abstract B61: Targeting the ATM pathway through histone deacetylase inhibition.
Authors: Thurn K. Ted E. , Thomas Scott , Raha Paromita , Munster Pamela N. 
Published: June 2012

Abstract
Ataxia telangiectasia mutated (ATM) is a major regulator of DNA double strand break repair. It is a member of the phosphatidyl inositol 3' kinase-related (PIKK) family of serine/threonine kinases, whose activation is promoted by the MRN complex (MRE11, Rad50, NBS1) in the presence of DNA damage. Mutations in ATM lead to increased susceptibility to developing lymphoid and breast cancers. Cells with mutated ATM often demonstrate enhanced chromatin decondensation, increased genomic instability, and greater sensitivity to DNA damaging agents. Interestingly, pharmacological inhibition of histone deacetylases (HDACs) often results in many of these same traits. Inhibitors of histone deacetylases (HDACs) have been demonstrated to potentiate the effects of various DNA damaging therapies through regulation of chromatin structure and down-regulating DNA repair. The contribution of HDAC proteins to DNA repair have yet to be fully understood. Therefore, we examined the effect of HDACs on DNA damage signaling and repair.
Treatment of cancer cells with HDAC inhibitors led to a significant decrease in ATM mRNA and protein levels. This caused attenuated induction of the DNA damage response signaling downstream of ATM in the presence of DNA damage. HDAC inhibition led ultimately to reduced DNA repair after therapeutic induction of DNA damage, and decreased overall cell survival. Select depletion of HDAC1 and HDAC2 was sufficient to reduce ATM expression, and potentiate the effects of DNA damaging agents. These results were recapitulated in vivo and demonstrated that pharmacological inhibition of HDACs significantly reduced the activation of the ATM pathway in response to chemotherapeutic induction of DNA damage. Specifically, HDAC inhibition significantly reduced the levels of ATM and down-stream stabilized p53 after treatment of tumors with therapeutic DNA damaging agents. Taken together, these results suggest a contribution of histone deacetylase enzymes in regulating the ATM pathway in response to DNA damage.
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 B61.