bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4475: Discovery and characterization of PI3K isoform-selective inhibitors
Authors: Virone-Oddos Angela , Halley Franck , Certal Victor , Carry Jean-Christophe , Thompson Fabienne , Schio Laurent , Debussche Laurent , Bonnevaux Helene , Nicolas Jean-Paul , Delorme Cécile , Karlsson Andreas , Morales Renaud , Abecassis Pierre-Yves , Lejeune Pascale , Benard Tsiala , Michot Nadine , Foster Paul , Bussenius Joerg , Jaeger Chris , Trowe Torsten , Raeber Oliver , Wang Jing , Nguyen Lam , Aoyama Ron , Rice Ken , Matthews David , Lengauer Christoph 
Published: February 2011

Abstract
Abnormal PI3K pathway activation plays a major role in cancer, as a result of either RTK activation or somatic mutations of major components of the pathway, including activating point mutations and amplification of the PIK3CA gene as well as loss of negative regulatory proteins such as PTEN. Most of the ATP-competitive PI3K inhibitors currently in clinical development inhibit all class I PI3K isoforms: however, several recent reports support the development of isoform-specific inhibitors. In particular, while PI3Kα specific inhibitors are predicted to inhibit growth of tumors with PIK3CA mutations, PTEN-deficient tumors have been shown to depend on PI3Kβ. In addition, isoform specific PI3K inhibitors may exhibit better safety profiles compared to pan-selective PI3K inhibitors, and thus may be easier to combine with other targeted or cytotoxic therapies. Here we report the discovery of ATP-competitive inhibitors with selectivity for PI3Kα, PI3Kα/mTOR, or PI3Kβ, which were identified and optimized by means of high-throughput screening and medicinal chemistry. These inhibitors exhibit biochemical IC50 values below 100 nM and good selectivity over other PI3K isoforms and a diverse panel of protein kinases. Cellular assays demonstrate that PI3Kα or PI3Kα/mTOR compounds inhibit phosphorylation of targets downstream of PI3K (Akt) and mTOR (S6 and p70S6 kinase) in the PI3Kα-activated MCF7 cell line, and that effects on PI3K pathway readouts are less pronounced in PC3 cells lacking PTEN. In contrast, PI3Kβ compounds potently inhibit phosphorylation of AKT (cellular IC50s &lt; 200 nM) in the PTEN-deficient PC3 tumor cell line, and the most PI3Kβ-selective inhibitors are inactive on AKT phosphorylation in PI3Kα-activated H460 cells. In vivo pharmacodynamic analyses following oral administration of these isoform-selective inhibitors to mice bearing xenografted tumors demonstrate dose-dependent inhibition of phosphorylation of PI3K and mTOR effectors at well-tolerated doses.
These results strongly argue for the development of isoform-selective PI3K inhibitors for the treatment of cancer patients harboring tumors with PTEN- deficient or PI3Kα-activated specific genotypes.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4475.
Abstract 4477: Dual-targeting of AMPK and PI3K/mTOR in a panel of breast cancer cell lines
Authors: Elizalde Violeta Serra , Russillo Michelangelo , Scaltriti Maurizio , Rodriguez Olga , Guzman Marta , Cosimo Serena Di , Baselga José 
Published: February 2011

Abstract
Several PI3K/AKT/mTOR pathway inhibitors are presently in early clinical trials for the treatment of cancer. Due to their mechanism of action, many of these compounds markedly increase the blood glucose levels. Metformin is an AMPK activator widely used in clinical practice to contrast hyperglycemia and is also known to reduce cancer risk as well as to improve cancer prognosis. The aim of this study is to explore the in vitro anti-tumor effect of metformin alone and in combination with the PI3K/mTOR inhibitor NVP-BEZ235 in a panel of breast cancer cell lines.
Breast cancer cells (BT474, SKBR3, MCF7, MDA-468, MDA-231) were exposed to escalating doses of BEZ235 as single agent and in combination with metformin. Levels of phosphorylated and total AMPK, MAPK, EGFR, HER2 and S6 ribosomal protein were evaluated by western blot. Metformin induced dose-dependent growth inhibition. The combined treatment of NVP-BEZ235 plus metformin resulted in an inhibitory effect on cell proliferation greater than with either treatment alone in EGFR and HER2 positive breast cancer cell lines. At the IC50 of 20 mM we found that metformin activates AMPK reducing mTORC1 activity and, in turn, decreasing the levels of p-S6 ribosomal protein. Metformin treatment was also associated with reduced receptor tyrosine kinases (RTKs) expression (EGFR and HER2) and decreased p-MAPK. The dual PI3K/mTOR inhibitor NVP-BEZ235 potently decreases p-AKT and p-S6. As described for other mTOR inhibitors, NVP-BEZ235 increases MAPK phosphorylation by transactivation of several RTKs of the HER family. Treatment with metformin downregulates these RTKs preventing NVP-BEZ235-dependent MAPK pathway transactivation, providing a possible explanation for the potent anti-proliferative activity of the combination in HER2 positive breast cancer cell lines. The combination of metformin and NVP-BEZ235 significantly inhibits the growth of several breast cancer cell lines. We propose that inhibiting the PI3K/Akt/mTOR pathway in combination with metformin treatment would result in superior antitumor activity. Further studies are warranted to determine the applicability of this approach in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4477.
Abstract 4486: OSI-027, a selective dual mTORC1/TORC2 kinase inhibitor displays broad spectrum anti-tumor activity in preclinical models of human cancer
Authors: Gokhale Prafulla C. , Bhagwat Shripad V. , Crew Andrew P. , Cooke Andrew , Mantis Christine , Workman Jennifer E. , Landfair Darla , Bittner Mark , Epstein David M. , Pachter Jonathan A. , Wild Robert 
Published: February 2011

Abstract
The mammalian target of rapamycin (mTOR) protein kinase plays a central role in regulating cell proliferation and cell survival. The PI3K/AKT signaling pathway that activates mTOR is frequently altered in many human cancers. mTOR exists as multi-protein complexes with distinct signaling functions. Complexes containing mTOR and RAPTOR (mTORC1) phosphorylate S6K and 4E-BP1 and are rapamycin sensitive. Whereas, complexes that contain mTOR and RICTOR (mTORC2) phosphorylate AKT and 4E-BP1 and are insensitive to rapamycin treatment. OSI-027 is a selective small molecule dual inhibitor of both mTORC1 and mTORC2 kinase activity with biochemical IC50 values of 22 nM and 65 nM, respectively. In the MDA-MB 231 breast carcinoma xenograft model, a single 65 mg/kg oral dose of OSI-027 resulted in significant inhibition of 4E-BP1 phosphorylation (&gt;70%) up to 16 h in tumor tissue. At 24 h post-dose, 59% inhibition of phospho-4E-BP1 was observed with a corresponding plasma OSI-027 concentration of 2.2 μM. Consistent with its ability to inhibit mTORC2 in vitro, a single dose of 65 mg/kg also resulted in significant inhibition of phospho-AKT (Ser473) for up to 8 hours with slow recovery thereafter. Such extended target suppression at 65 mg/kg was associated with significant efficacy corresponding to 100% tumor growth inhibition (TGI) with 19% regression in the MDA-MB 231 xenograft model when dosed for 14 consecutive days. In comparison, a lower dose of 25 mg/kg resulted in only 39% TGI which corresponded with a shorter duration of pharmacodynamic effects in vivo. In particular, at the 25 mg/kg dose, inhibition of 4E-BP1 phosphorylation was observed only up to 8 h in tumor tissue with return to predose levels by 16 h which corresponded with plasma drug concentrations of &lt;0.1 µM. These data suggest that maximal anti-tumor efficacy may require plasma levels sufficient to chronically suppress phospho-4E-BP1 in tumor tissue. In addition to significant efficacy in MDA-MB 231 breast carcinoma model, OSI-027 demonstrated robust anti-tumor activity in several different human xenograft models representing different histologies, including colon carcinomas, non-small cell lung carcinomas and ovarian carcinomas. These preclinical studies indicate that OSI-027, a dual mTORC1/2 kinase inhibitor, may show broad spectrum anti-tumor activity, including superior efficacy compared to mTORC1-selective rapalogs against some human cancers. OSI-027 is currently being evaluated in Phase I clinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4486.
Abstract 4489: The activity of novel, potent, selective PI3K/mTOR pathway inhibitors in B-cell malignancies
Authors: Jueliger Simone , Maharaj Lenushka , Iyengar Sunil , Ghazaly Essam , Cutillas Pedro , Auer Rebecca , Rommel Christian , Li Liansheng , Gribben John , Vanhaesebroeck Bart , Joel Simon P. 
Published: February 2011

Abstract
Background: Activation of the PI3K pathway is implicated in a number of tumour types, including haematological malignancies. Agents that target this pathway at different levels (e.g. RTK, PI3K, mTOR etc) have shown promising activity in preclinical models and in early phase trials. We have therefore investigated the activity of novel, potent, pan- and isoform-selective PI3K pathway inhibitors in lymphoma and myeloma models. Methods: Compounds studied included those with selectivity for mTOR (INK128, mTOR IC50 1.6 nM), PI3Kδ/γ (INK713, INK1048, IC50s &lt;10 nM for δ/γ isoforms, &gt;50 nM for others) and PI3Kδ/γ/β (INK1138, IC50s &lt;10 nM for each isoform). IC87114 (δ- selective), GDC-0941 (α/δ selective), rapamycin and doxorubicin were included as comparators. Agents were studied in a panel of lymphoma and myeloma cell lines, in normal PBMCs and in primary tumours cultured with stromal cells. Effects on cell viability and proliferation were assessed using the Guava Viacount assay, on apoptosis induction by annexin V labelling, and on cell cycle distribution by flow cytometry. PI3K pathway activity and inhibition was determined by Western blotting as well as mass spectrometry. Results: In cell lines, inhibition of mTOR by INK128 resulted in potent inhibition of cell proliferation, in many at concentrations as low as 10 nM. Selective PI3K inhibitors were less potent anti-proliferative agents, although activity was seen in cells with activation of the PI3K pathway as determined by western blot analysis. For all compounds tested, the major impact was on cell proliferation rather than cell viability. PI3K inhibitors showed little effect on cell viability at concentrations &lt; 1µM. The effect of these compounds in primary mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia and myeloma samples was variable, both between and within tumour types, possibly due to differences in basal PI3K pathway activity. Effects in normal PBMCs were markedly different to those seen in tumour cells, with a concentration-dependent increase in cell number with either mTOR or PI3K inhibition. Conclusion: Selective PI3K pathway inhibition, particularly at the level of mTOR, results in cytostatic, and at higher concentrations cytotoxic, responses in haematological malignancies. The variable activity of these compounds between cell lines and primary samples suggests it will be important to characterise the activity of the PI3K pathway in individual tumours to identify patients likely to benefit from such agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4489.
Abstract 4502: Synthesis and evaluation of curcumin-like compounds as inhibitors of the JAK/STAT pathway in cancer
Authors: Abdelhamid Dalia , Corcoran Mike , Etter Jonathan P. , Hu Sheng , Pandit Bulbul , Li Chenglong , Li Pui-Kai , Fuchs James R. 
Published: February 2011

Abstract
Curcumin is an attractive lead compound for drug discovery and development. It displays a range of remarkable and diverse biological activities due to its interaction with numerous biological targets including the receptor tyrosine kinase Janus Kinase 2 (JAK2) which transduces cytokine and growth factor mediated signals by activating signal transducer and activator of transcription 3 (STAT3). The significant role of JAK-STAT pathway activation in the development, progression, and survival of cancer has been widely recognized since the 1980s. Based on our interest in developing more potent curcumin analogs which act as inhibitors of the JAK-STAT pathway we synthesized a series of monoketone curcumin analogs that bear a strong structural resemblance to AG490 and WP1066; known synthetic small molecule inhibitors of JAK2. A thorough investigation of the SAR of these compounds was pursued to elucidate which parts of the molecules are essential for the anti-proliferative activity. Thus hybrid molecules containing structural motifs found in all three classes of compounds were synthesized and screened using breast, prostate and colon cancer cell lines. Enzyme-linked immunosorbent assay (ELISA) measuring the relative amount of STAT3 phosphorylation was utilized to determine whether the anti-proliferative activity of these compounds was directly related to inhibition of the JAK-STAT pathway, and therefore whether these three classes of compounds exhibit similar cytotoxic mechanisms of action. Our results showed that although the monoketone curcumin analogs displayed potent cytotoxicity; they failed to inhibit STAT3 phosphorylation. The WP1066 analogs also showed potent cytotoxicity correlating directly to STAT3 inhibition. The pyridine and the halogen at the C3 position of the pyridine ring are essential for activity and appear to have a synergistic effect. Longer aliphatic chains at the benzylic position enhanced the cytotoxic activity and aromatic substitution usually led to a decrease in activity. Different structural modifications of the AG490 analogs by protection of the catechol moiety and/or changing the relative position of the substituents did not result in remarkable change in cytotoxic activity. We concluded that although the monoketone curcumin analogs bear remarkable structural resemblance to WP1066 and AG490, they do not inhibit the JAK-STAT pathway and may have a different anti-proliferative mechanism of action.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4502.
Abstract 4516: A new class of MDM2 inhibitors cause growth inhibition and stabilize wt p53 in lymphoma cells but do not interfere with MDM2 E3 ligase activity
Authors: Sosin Angela M. , Burger Angelika M. , Yang Dajun , Mohammad Ramzi M. , Al-Katib Ayad 
Published: February 2011

Abstract
The p53 tumor suppressor protein function is impaired in over 50% of all cancers via inactivating mutations. However, the frequency of p53 mutations is much lower in hematological malignancies. Most lymphomas have wild-type (wt) p53, mutant (mt) p53 is found in less than 30% of all cases. The ubiquitin E3 ligase MDM2 plays a central role in cancer development and progression and is typically overexpressed in lymphomas. MDM2 expression destabilizes functional wt p53 by causing its polyubiquitination and subsequent degradation in the proteasome. Small-molecule inhibitors (SMI) that can block the MDM2-p53 protein-protein interaction and restore p53 function are a promising therapeutic strategy for the treatment of cancers retaining wt p53 that is degraded by overexpression of MDM2. By utilizing two wt p53 and two mt p53 lymphoma cell lines whose p53 status was confirmed by DNA sequencing, we studied the growth inhibitory potential of two different classes of MDM2 SMIs: Nutlin-3, a cis-imidazoline, and MI-219, a new spiro-oxindole MDM2 SMI. Both trypan blue exclusion and MTT assays demonstrated IC50s between 2 and 4 µM in wt p53 cells in vitro. Mutant p53 cells displayed IC50s greater than 10 µM. Growth inhibition was time- and dose-dependent. Additional flow cytometric analyses empolying Annexin V and propidium iodide staining illustrated increasing apoptosis with cells decreasing in G2/M and S phase that also showed time- and dose-dependency. The MDM2 SMI MI-219 showed a much more prominent cell cycle arrest compared to Nutlin-3. Western blotting demonstrated a stabilization of wt p53 and proapoptotic proteins such as p21, Bcl-2, and Bax. In order to determine whether MDM2 SMIs affect the E3 ligase RING-finger domain of MDM2, in vitro autoubiquitination assays were performed using recombinant MDM2 with various concentration of drug. MDM2 autoubiquitination was not affected, even at a concentration as high as 50 µM. These results show that MDM2 autoubiquitination and thus, its degradation remains unaffected in the presence of MDM2 inhibitors that interfere with the p53-MDM2 binding site. This feature of MDM2 SMI is attractive since inhibition of MDM2 autoubiquitination would lead to its stabilization and could negate effects on p53. Our data suggest that MI-219 would be a useful treatment for lymphomas expressing wt p53 and that this should be explored in further preclinical and future clinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4516.
Abstract 4531: Anticancer potential of curcurbitacin IIa trough STAT3/JAK2-independent, survivin and PARP mediated apoptosis and disruption of actin cytoskeleton
Authors: Lu Qun , Boykin Christi , Zhang Gen , Chen Yan-Hua , Zhang Ren-wei , Fan XE , Yang Weimin 
Published: February 2011

Abstract
The medicinal plant Hemsleya amalils Diels has been used as a homeopathic treatment for various diseases in China for centuries and has recently been indicated as being effective in inhibiting cancer cell growth. To investigate the molecular mechanisms underlying the anti-cancer activity of Hemsleya family, we purified the active component curcurbitacin IIa. Curcurbitacin IIa inhibited cell growth, induced apoptosis in several cancer cell lines, and reduced tumor growth in vivo. Immunofluorescent light microscopy as well as time-lapse imaging demonstrated the remarkable clustering of filamentous actin and the increases in G2/M populations in cell cycle, indicating the disruption of mitosis as the potential mechanism of inducing apoptosis by curcurbitacin IIa. Flowcytometry confirmed increased cell death while western blots showed reduced phospho-histone H3 immunoreactivity, consistent with reduced mitosis. Cleavage of Poly (ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as a result of caspase activation, was increased dramatically while AKT phosphorylation and the Inhibitor of Apoptosis Protein survivin expression were reduced. Prostate cancer cells stably transfected with oncoprotein δ-catenin in which survivin expression was increased showed reduced efficacy of curcurbitacin IIa to induce cell death. Combined with lack of its effects on STAT3/JAK2 phosphorylation, theses studies highlight curcurbitacin IIa as a new class of anti-cancer drugs in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo apoptosis through inhibition of surviving, AKT, and PARP. Supported by Department of Defense (PC040569) and National Cancer Institute (CA111891).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4531.
Abstract 454: The regulation of tumorigenesis by crosstalk between hypoxia and PPARdelta
Authors: Jeong Eunshil , Kim So Young , Lee Joo Young 
Published: February 2011

Abstract
Hypoxia, insufficient state of oxygen, is a feature of the tumor environment. Upon tumor growing, inside of tumor mass is hypoxic state. Hypoxia promotes tumor progression, expression of angiogenic mediators and tumor resistance to cancer therapy. Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, also play an important role in the regulation of cancer cell growth and angiogenesis. However, it has not been entirely elucidated if hypoxia can regulate PPARdelta activation during tumorigenesis. Therefore, we investigated the relationship between hypoxic stress and PPARdelta activation in tumor cells and the contribution of the crosstalk between these factors to tumor cell growth. Hypoxia (&lt;1% O2) and a hypoxia-mimetic (deferoxamine) increased mRNA levels and protein expression of tumor-promoting mediators such as IL-8, VEGF, and COX-2 in colon cancer cells (HCT116), but not in PPARdelta-knockout HCT116 cells. A synthetic ligand of PPARdelta(GW501516) induced the expression of IL-8, VEGF, and COX-2 in wild-type colon cancer cells but not in PPARdelta-knockout cells. Hypoxia increased both transcriptional activity and mRNA level of PPARdelta in HCT116 cells. In addition, overexpression of HIF-1alpha enhanced transcriptional activity of PPARdelta suggesting that HIF-1alpha regulates the activation of PPARdelta. The proliferation and migration rate of macrophages were enhanced by conditioned media derived from wild-type colon cancer cells but not PPARdelta-knockout cells. These suggest that the expression of IL-8, VEGF, COX-2 induced by hypoxic stress is dependent on PPARdelta activity and that HIF-1alpha and PPARdelta cooperate to promote tumor cell growth. [Supported by a grant from Research Center for Biomolecular Nanotechnology, GIST]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 454.