bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4488: INK128: An orally active TORC1/2 kinase inhibitor demonstrates potent antitumor activity in preclinical models of renal cell carcinoma
Authors: Wang Shunyou , Kessler Linda , Kucharski Jeff , Lan Lucy , Guo Xin , Staunton Jocelyn , Elia Marikka , Stewart Josh , Brown Jolene , Li Liansheng , Chan Katrina , Martin Mike , Ren Pingda , Jessen Katti , Rommel Christian , Liu Yi 
Published: February 2011

Abstract
Anti-angiogenic agents have demonstrated promising activity in patients with renal cell carcinoma (RCC). Patients with clear cell RCC often have mutations or silencing of the von Hippel-Lindau gene, leading to an accumulation of HIF 1 alpha (HIF1α), a key mediator of hypoxia-triggered neo-angiogenesis. The mammalian target of rapamycin (mTOR) is upstream of HIF1a and downstream of the VEGF pathway. mTOR kinase comprises two distinct multi-protein complexes, TORC1 and TORC2, which together regulate growth, metabolism, angiogenesis and survival. Pharmaceutical derivatives of rapamycin, a partial allosteric inhibitor of TORC1, provide clinical proof of concept for targeting mTOR in RCC as well as insights into how ATP-competitive TORC1/2 inhibitors might provide superior efficacy. Through rational drug design we have discovered INK128, a potent, selective TORC1/2 inhibitor with outstanding drug-like properties. We investigated INK128 in preclinical in vitro and in vivo models of RCC. Interestingly, while both INK128 and rapamycin exhibit comparable anti-angiogenic activity in vitro, INK128 correlated with potent and complete blockade of cell proliferation, while rapamycin failed to establish a dose-dependent maximum inhibition of tumor cell proliferation. A comparison of INK128, rapamycin, Nexavar and Avastin demonstrated that all exhibited potent inhibition of tumor growth, via different molecular mechanisms. INK128 inhibits phosphorylation of AKT, S6 and 4EBP1; rapamycin inhibits only S6 phosphorylation and induces AKT phosphorylation; Nexavar and Avastin have little effect on the PI3K/AKT/mTOR pathway. Only INK128 induced autophagy and decreased expression of cyclin D1. INK128 and rapamycin both inhibit expression of HIF-1α and VEGF, which contributes to their anti-angiogenic activity. We conclude that, although Nexavar, Avastin and rapamycin exert their activity primarily through effects on the tumor microenvironment, the anti-tumor activity of INK128 is derived from direct inhibition of tumor cell growth as well as anti-angiogenic activities. In summary, targeting TORC1/2 signaling with INK128 offers a compelling approach to the treatment of RCC.
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 4488.
Abstract 449: Hypoxia induces tumor aggressiveness by an acquired stem-like phenotype in pancreatic cancer through HIF-1α signaling
Authors: Hashimoto Okito , Semba Syuho , Shimizu Kazuya , Yonson Ku , Yokozaki Hiroshi , Hori Yuichi 
Published: February 2011

Abstract
Background: Intratumoral hypoxia is a negative prognostic indicator, as it has been associated with increased aggressiveness and distant metastasis. Although hypoxia can drive the metastatic phenotype secondary to genetic instability and clonal selection of aggressive tumor cells, the interplay underlying them is to be unanswered. We hypothesized that mature cancer cells might acquire the stem-like phenotype under hypoxia, consequently leading to aggressive phenotype.
Methods: Under normoxia (20% O2) or hypoxia (1% O2) condition, the expression of CD133 (cancer stem cell marker), CXCR4 (chemokine receptor), HIF-1α, and pimonidazole (hypoxic probe) were examined by quantitative RT-PCR and imuunohistochemistry using human pancreatic cancer cell lines. Moreover, we evaluated the expression of CD133 and hypoxia markers (pimonidazole, HIF-1α, and CA) in xenograft and human pancreatic cancer specimen. Furthermore, we transfected dominant active HIF-1α (HIF-1α ΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo.
Results: We demonstrated that hypoxia induces tumor aggressive phenotype in pancreatic cancer, including invasiveness and CXCR4 expression. Furthermore, this phenotype is followed distinctively by the subpopulation of CD133+ pancreatic cancer cells, which themselves show hypoxic and invasive properties, indicating that mature cancer cells might reacquire an undifferentiated stem-like phenotype. In addition, both acquired stem-like phenotype and invasiveness under hypoxia are predominantly in a HIF-1α/CXCR4-dependent manner, and dominant active HIF-1αΔODD transfected cells promoted their tumorigenic ability. Surprisingly, orthotopic engraftment of these cells showed liver metastasis, while the engraftment of mock transfected cells did not occur any liver metastasis.
Conclusion: We demonstrated that mature cancer cells acquired the stem-like phenotype under hypoxia and showed aggressive phenotype including invasiveness and metastasis through HIF-1α signaling.
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 449.
Abstract 4491: Novel multiplex PI3-kinase inhibitors potently inhibit Ras-mutated tumors via suppression of eIF-4E-mediated protein translation
Authors: Hamilton Mark , Bernardino Alexandra K. , Liu Yan , Provoncha Kathleen , Paul Dorothy , Rotshteyn Yakov , Han Amy , Qian Dapeng 
Published: February 2011

Abstract
Background: The PI3K pathway is a target of significant interest for cancer drug development due to its prominent role in cancer cell growth and survival. However, PI3K pathway inhibition alone has limited efficacy in the presence of oncogenic Ras mutations, which are found in approximately one-third of all human tumors. In preclinical models, efficacy in Ras-mutated tumors has required the inhibition of both PI3K and other Ras-activated pathways. One key function of these pathways is to regulate eIF-4E, a central factor in cap-dependent translation of critical proteins involved in growth and survival (e.g., c-myc and Mcl-1), and anti-tumor activity has been associated with the selective inhibition of translation of these proteins. Simultaneous inhibition of PI3K and other Ras-activated pathways that converge on eIF-4E-mediated protein translation represents an attractive strategy for oncology drug development.
Methods and Results: Using rational drug design, we identified a novel chemical series of small molecules that possess potent activity against PI3K and additional Ras-regulated kinases implicated in protein translation. The anti-tumor activity of these multiplex PI3K inhibitors was assessed against a panel of 30 human tumor cell lines comprised of various genetic backgrounds and histotypes. Multiplex PI3K inhibitors demonstrated broad and potent anti-proliferative activity in all cell lines tested (EC50: 10 nM - 500 nM) and induced cell death in Ras-mutated cell lines (e.g., PANC-1, HCT116 and A549). Mechanistically, these multiplex PI3K inhibitors induced caspase activity, inhibited the phosphorylation of AKT, 4E-BP1, ribosomal S6 and eIF-4E, and inhibited the expression of c-myc and Mcl-1 proteins. In contrast, PI3K-selective inhibitors were partially cytostatic in Ras-mutated tumor cell lines, inhibiting cell proliferation by at most 60-90%. PI3K-selective inhibitors also failed to induce significant increases in caspase activity, inhibit eIF-4E phosphorylation, or inhibit c-myc and Mcl-1 expression.
Conclusion: We have discovered novel multiplex PI3K inhibitors that demonstrate potent anti-tumor activity in Ras-mutant tumors via inhibition of eIF-4E-mediated protein translation.
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 4491.
Abstract 4493: Rapamycin enhanced in vitro and in vivo activity of dexamethasone against acute lymphoblastic leukemia and lymphoma preclincal models via inhibition of p70S6 kinase activity
Authors: Ryu YongKu , Zhang Chong , Chen Taylor , Kang Min H. 
Published: February 2011

Abstract
Background: Glucocorticoids are an important part of therapy for lymphoid malignancies and understanding resistance mechanisms may enable designing drug combinations that will improve treatment outcome. We reported that rapamycin (RM) can enhance cytotoxicity of dexamethasone (DM) in cell culture models of lymphoid malignancies (Proc AACR 50: 4062, 2009). In the current study, we examined the mechanisms of synergy as well as in vivo activity of the DM + RM combination. Methods: Cytotoxicity of DM + RM at fixed-ratio concentrations was assessed using the DIMSCAN system in 12 acute lymphoblastic leukemia (ALL) and 3 lymphoma cell lines. Synergy was determined using the multiple drug-effect equation of Chou-Talalay with Calcusyn software. Protein was measured by immunoblotting. Phosphotransferase activity of p70 ribosomal protein S6 kinase (p70S6K) was determined using [γ-32P]ATP. In vivo drug activity was determined in NOD/SCID (ALL intravenous) and nu/nu (lymphoma, subcutaneous) mouse xenograft models. Results: DM + RM achieved cytotoxicty &gt; 90% in 7 of 15 cell lines, and DM + RM was synergistic in 5 lines (combination index &lt; 0.9). Among the phosphoinositide 3-kinase pathway proteins, phosphorylation of p70S6K and ribosomal protein S6 (rpS6) and also p70S6K enzyme activity was inhibited by DM + RM in those cell lines showing DM + RM synergy, but was not inhibited in lines that failed to demonstrate drug synergy. RNAi knockdown of p70S6K also significantly enhanced cytotoxicity of DM + RM in CCRF-CEM cells. In the COG-LL-317x systemic ALL and the GA-10 subcutaneous lymphoma xenograft models, DM + RM significantly (p &lt; 0.01) extended the event-free survival (EFS) of mice compared with DM or RM as single agents. In the RS4;11 systemic ALL model, DM and DM + RM extended EFS (p &lt; 0.01) compared with control or RM alone, although no differences in EFS was observed between DM and DM + RM. Conclusion: Our study showed that RM enhanced activity of DM in ALL and lymphoma cell lines and xenograft models and that inhibition of p70S6K activity is the molecular basis for the synergy between DM + RM in lymphoid malignancies.
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 4493.
Abstract 4496: INK128, an orally active TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances efficacy of cytotoxic as well as targeted agents
Authors: Kessler Linda , Wang Shunyou , Guo Xin , Kucharski Jeff , Staunton Jocelyn , Lan Lucy , Elia Marikka , Stewart Josh , Brown Jolene , Li Liansheng , Chan Katrina , Martin Michael , Ren Pingda , Jessen Katti , Rommel Christian , Liu Yi 
Published: February 2011

Abstract
mTOR kinase operates via two distinct multi-protein complexes, TORC1 and TORC2, which together regulate growth, metabolism, angiogenesis and survival. Because the PI3K/Akt/mTOR pathway integrates nutrient and hormonal signaling and is frequently dysregulated in human cancer, the mTOR kinase has become an important target for oncology drug development. However, multiple genomic and signaling pathways are often simultaneously activated in cancer, and pathway redundancy and compensatory feedback can blunt the activity of even the most potent anticancer agents. Thus, it is important to study the anti-tumor efficacy of potential anticancer agents, both alone and in combination with cytotoxic and targeted agents, to achieve the optimal therapeutic effect. Through rational drug design we have discovered INK128, a potent and selective TORC1/2 inhibitor with outstanding drug-like properties. INK128 inhibits both the phosphorylation of S6 and 4EBP1, downstream substrates of TORC1, and selectively inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2, both in vitro and in vivo. Potent inhibition was also observed in cell lines resistant to rapamycin and PanPI3K inhibitors. Daily, oral administration of INK128 inhibited angiogenesis and tumor growth in multiple xenograft models with predicted PK/PD relationship. We have studied INK128 in combination with chemotherapeutic agents as well as with molecular targeted agents both in vitro and in vivo tumor models. In most cases, INK128 demonstrated a synergistically enhanced inhibition of tumor growth and suppression of respective signaling pathways. Additionally, induction of apoptosis was observed only when INK128 was used in combination, suggesting apoptosis as a potential contributor to the observed synergy. A subset of the agents that displayed synergy when combined with INK128 in vitro were evaluated in a number of xenograft models. The combinations were well-tolerated and displayed both enhanced anti-tumor efficacy and enhanced inhibition of key pharmacodynamic markers. In summary, INK128 offers a compelling approach to the treatment of cancer either as a single agent or in combination with other anti-cancer 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 4496.
Abstract 4501: Development and biological annotation of a novel RAF inhibitor amenable for clinical evaluation against BRAF (V600E)-harboring human tumors
Authors: Chen Chang-Rung , Lapierre Jean-Marc , Szwaya Jeffrey D. , Liu Yanbin , Namdev Nivedita , Lowe Deirdre , Savage Ron E. , Bull Cathy O. , Chan Thomas C K , Ashwell Mark A. , France Dennis S. 
Published: February 2011

Abstract
An activating somatic mutation in BRAF kinase (V600E) is found in approximately 70% of melanomas, 50% of papillary thyroid cancers and 10% of colon cancers, fueling interest in BRAF (V600E) as a therapeutic target for cancer treatment. We have previously described a novel class of RAF inhibitors with initial pre-clinical profiling. This compound class has been optimized for solubility, eADME properties, and oral bioavailability. ARQ 736 has been selected as a candidate to advance into clinical testing. ARQ 736 is a potent RAF inhibitor (IC50 values of 2.6, 2.7, and 7.3 nM against BRAF, BRAF (V600E) and c-Raf-1, respectively) and extremely selective biochemically, with only 11 of 272 human kinases being inhibited within 100-fold of the IC50 against BRAF. Worthy of note, ARQ 736 was also found to be inactive against vascular endothelial growth factor receptor 2 (VEGFR2 or KDR). Despite being a pan-RAF inhibitor, at the cellular level, ARQ 736 showed a high degree of selectivity against cancer cells harboring at least one allele of BRAF (V600E) (IC50 values in cytotoxicity assays of 200-300 nM), while sparing normal cells with wild-type (wt) BRAF and wt ras as well as cancer cells harboring k-ras mutations (IC50 values in cytotoxicity assays ranging from 4 μM to greater than 10 μM). In cellular pharmacodynamic assays, ARQ 736 inhibited the MAPK pathway potently in a rapid and durable fashion (78, 65, and 11 nM respectively for inhibition of ERK phosphorylation in the human melanoma lines A375, SK-MEL-28, and Colo-205). Acute pharmacodynamic studies in vivo showed a nearly complete reduction of phospho-MEK and phospho-ERK in A375 human melanoma tumors grown in athymic xenograft models and significant tumor growth inhibition was shown in the same model with daily dosing of ARQ 736. ARQ 736 was found to be well-tolerated and orally bioavailable in dogs, and has been advanced into full pre-clinical toxicology studies, data from which will be discussed. In summary, ARQ 736 is the advanced candidate of a novel class of BRAF kinase inhibitors with excellent drug-like properties that may have clinical utility for human cancers driven by oncogenic BRAF (V600E).
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 4501.
Abstract 4507: Discovery of a novel single chain ribosome inactivating protein that selectively kills human melanoma cells
Authors: Cheung Melissa , Revers Leigh , Perampalam Subodini , Wei Xin , Kiarash Reza , Green David , Green Erin , Gariepy Jean 
Published: February 2011

Abstract
Few treatment options exist for patients with metastatic melanoma. The standard treatment, dacarbazine (DTIC), shows low response rates ranging from 15% to 25 % with an 8-month median survival time. The development of targeted therapeutics with novel mechanisms of action may improve patient outcome. Ribosome-inactivating proteins (RIPs) such as Shiga-like Toxin 1 (SLT-1) represent powerful scaffolds for developing selective anticancer agents. Here we report the discovery and properties of a single chain, ribosome-inactivating protein (scRIP), termed SLT-1AIYSNKLM that selectively targets and kills human melanoma cells. SLT-1AIYSNKLM was identified following the purification and screening of cytotoxic A chain mutants derived from a combinatorial SLT-1A library This scRIP was shown to selectively kill 7 out of 8 human melanoma cell lines while being ineffective at killing non-melanoma cell lines. Biodistribution and imaging studies of radiolabeled SLT-1AIYSNKLM in SCID mice bearing a human melanoma xenograft indicate that it readily accumulates at the tumor site. Furthermore, the co-administration of SLT-1AIYSNKLM [i.v.] with DTIC [i.p.] resulted in tumor regression and greatly increased animal survival in this mouse xenograft model in comparison to DTIC or SLT-1AIYSNKLM treatments alone. SLT-1AIYSNKLM is stable in serum and binds to human melanoma 518-A2 cells with a dissociation constant of 18 nM. The intravenous administration of SLT-1AIYSNKLM resulted in modest immune responses following repeated i.v. injections in immunocompetent CD1mice. These results suggest that scRIP templates can be evolved to target cancer cells and in the case of SLT-1AIYSNKLM can specifically kill human melanoma cells.
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 4507.
Abstract 451: HIF-1 alpha silencing in MDA-MB-231 human breast cancer cells alters choline phospholipid metabolism
Authors: Shah Tariq , Krishnamachary Balaji , Wildes Flonne , Bhujwalla Zaver M. 
Published: February 2011

Abstract
Hypoxia-inducible factor-1 (HIF-1) over-expression has been associated with an increased patient mortality rate in many cancer types including breast cancer. Suppression of HIF-1 gene expression has been shown to inhibit tumor growth. Here we have studied the effect of HIF-1 silencing on the metabolism of MDA-MB-231 cells using a magnetic resonance (MR)- compatible cell perfusion assay. Previous studies have identified choline kinase (Chk), the enzyme that converts choline to phosphocholine (PC), and the resulting increase of PC and total choline (tCho) as markers of an aggressive phenotype. We found that HIF-1 silencing resulted in significantly reduced Chk expression together with reduced tCho and PC, compared to parental cells.
The sequence for shRNA against HIF-1α was cloned into a lentivirus vector with a green fluorescent protein (GFP) reporter construct (pRRL-pGK-GFP). Viral supernatant preparation and transduction of MDA-MB-231 breast cancer cells was performed following standard protocol. Transduced cells were validated for HIF-1α knock-down by western blots and by quantitative real-time polymerase chain reaction (q RT-PCR). Cell perfusion studies were performed using an MR-compatible perfusion assay to determine intracellular levels of metabolites using 1H and 31P MR spectroscopy (MRS). Experiments were performed in triplicates. The Mann Whitney-U test was used to determine statistical significance (p &lt;0.05).
HIF-1α protein expression increased following treatment with 200μM of the hypoxia mimetic CoCl2 in parental MDA-MB-231 cells but not in cells transduced with HIF-1α shRNA. Reduced expression of Chk in HIF-1α silenced cells was observed following CoCl2 treatment, while its expression was induced in parental cells. Quantitative data from 1H and 31P MRS showed significantly reduced levels of tCho (p &lt;0.05) and PC (p &lt; 0.01) in HIF-1α silenced cells compared to parental MDA-MB-231 cells, confirming that silencing of HIF-1α reduced levels of choline containing metabolites by reducing Chk expression. We previously observed that Chk is up regulated under hypoxia and have established a HIF-1 binding site on the Chk promoter. The reduction of choline metabolites in HIF-1α silenced cells further confirms the role of HIF-1α in the regulation of Chk. The reduction of Chk, total choline and PC levels in HIF-1α silenced cells are also typical of a less aggressive metabolic phenotype.
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 451.
Abstract 4511: LY2801653 treatment increases survival of mice bearing H441 orthotopic lung tumors
Authors: Wu Wenjuan , Bi Chen , Uhlik Mark T. , Pomeroy Julie A. , Gao Hong , Credille Kelly M. , Walgren Richard A. , Shih Chuan , Yingling Jonathan M. , Yang Wei 
Published: February 2011

Abstract
Lung cancer is the leading cause of cancer-related death for both men and women in the world. c-Met receptor tyrosine kinase (RTK) signaling pathway has been implicated in tumor growth, angiogenesis, and metastasis. Sustained activation, over-expression, or mutation of c-Met is associated with poor prognosis in several tumors, including NSCLC. Therefore, c-Met is emerging as a novel target of therapeutic potential for lung cancer. We have discovered and developed a novel, ATP competitive, and orally active small molecule inhibitor of c-Met, LY 2801653. It is a potent inhibitor of c-Met phosphorylation in vivo, and demonstrated anti-tumor activity in several xenograft tumor models. In the current study, we evaluated the efficacy of LY2801653 in both c-Met dependant and c-Met independent NSCLC cells in vitro and in vivo orthotopic lung models that recapitulated the local and regional growth pattern seen in lung cancer patients. In c-Met dependant H441 model, LY2801653 demonstrated the significant inhibition of both primary tumor (90% inhibition) and metastasis (65% inhibition of lymph node and 70% inhibition of chest wall); whereas in c-Met independent H1299 model, LY281653 only inhibited primary tumor growth (70% inhibition). The benefit of LY2801653 treatment was further demonstrated in the survival of mice bearing H441 lung tumors. Treatment with LY2801653 significantly increased the survival of mice to 192% compared to that in the vehicle treated mice. The anti-tumor and/or anti-metastasis mechanism of LY2801653 was also investigated. These results demonstrated therapeutic potential of LY2801653 in the treatment of lung cancer.
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 4511.