bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL05-01: An overview of the global tobacco epidemic
Authors: Bloch Michele 
Published: June 2012

Abstract
Tobacco use is a leading cause of preventable death, including cancer death, worldwide. The World Health Organization has estimated that, globally, smoking is responsible for 12% of male deaths and 6% of female deaths and that the total number of tobacco-attributable deaths will rise from 5.4 million in 2005, to 8.3 million in 2030. Increasingly, the burden of tobacco mortality is shifting from high-income countries to low- and middle-income countries; between 2002 and 2030, tobacco-attributable deaths in low- and middle-income countries are projected to double from 3.4 million to 6.8 million, while deaths in high-income countries are projected to decline by 9%. In many countries, including the U.S., tobacco use is stratified by socioeconomic status and other demographic variables, and is an important contributor to disparities in health outcomes, including cancer health outcomes. The Framework Convention for Tobacco Control (FCTC), the first treaty ever negotiated under the auspices of the WHO, aims to “protect present and future generations from the devastating health, social and environmental and economic consequences of tobacco consumption and exposure to tobacco smoke by providing a framework for tobacco control measures.” As of January 2011, 172 countries are parties to the FCTC, which has become a crucial force spurring the development of evidence-based tobacco control policies around the world. This presentation will provide a broad overview of the global tobacco epidemic, and its impact on global cancer mortality. It will make use of the traditional epidemiologic model which posits that the agent (diverse tobacco products and secondhand smoke), host (individual user), and vector (tobacco manufacturers), interact in an environment that is shaped by familial, social, cultural, historical, legal, regulatory, economic, media, and other forces.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL05-01.
Abstract A13: Reduction of tumor invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184
Authors: Sennino Barbara , Naylor Ryan M. , Tabruyn Sebastien P. , You Weon-Kyoo , Aftab Dana T. , McDonald Donald M. 
Published: June 2012

Abstract
Inhibition of vascular endothelial growth factor receptor (VEGFR) signaling can slow tumor growth and prolong host survival but can also promote invasiveness and metastasis in some preclinical models. Although the mechanisms involved are unclear, hypoxia-induced activation of pro-invasive pathways involving hepatocyte growth factor and its receptor c-Met may be a factor. We sought to address this mechanism by determining whether inhibition of VEGFR together with c-Met can reduce tumor invasiveness and improve host survival as well as reduce tumor growth. Our approach was to compare the effects of a tyrosine kinase inhibitor, XL184, that blocks VEGFR and c-Met with the effects of an antibody that selectively blocks mouse VEGF in 14-week-old RIP-Tag2 transgenic mice, a model of pancreatic neuroendocrine carcinoma. In this model, tumors arise from pancreatic islet beta cells in their natural microenvironment, and the effects of inhibitors can be tested at multiple stages of tumorigenesis. After treatment with anti-mouse VEGF antibody for 3 weeks, the tumors were smaller than vehicle-treated tumors (tumor area 4.3 ± 0.8 mm2 in antibody group versus 17.3 ± 6.5 mm2 in vehicle group; P &lt; 0.05) but had greater expression of c-Met and had more irregular borders. After the anti-VEGF antibody, irregularity of the tumor perimeter indicative of invasion of the surrounding acinar pancreas was increased (invasion index 18.9 versus 12.7 in vehicle group; P &lt; 0.05), and liver metastases were more numerous (metastases 2.73 ± 1.83 /mm2 versus 0.45 ± 0.12 /mm2 in vehicle group; P &lt; 0.05). By comparison, tumors treated with XL184 not only were smaller (tumor area 0.7 ± 0.1 mm2; P &lt; 0.05) than in the vehicle or anti-VEGF antibody group but also were less invasive (invasion index 4.5; P &lt; 0.05) and had no liver metastases. All mice treated from 14 weeks of age with XL184 (n = 6) survived until 20 weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached that end point. These results show that selective inactivation of VEGF reduces tumor growth but leads to greater invasiveness and metastasis in the RIP-Tag2 model. However, inhibition of VEGFR together with c-Met not only slows tumor growth but also decreases tumor invasiveness and liver metastases and prolongs host survival.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A13.
Abstract B120: Designing potent antibody-drug conjugates: The impact of lysosomal processing efficiency and conjugate linker selection on anticancer activity
Authors: Maloney Erin , Fishkin Nathan , Chari Ravi , Singh Rajeeva 
Published: June 2012

Abstract
Six different ADCs are in clinical testing that contain the maytansinoid agent DM1 or DM4. The two most advanced of these, trastuzumab-DM1 (T-DM1) and IMGN901, have demonstrated encouraging activity and tolerability. These conjugates differ in the linker used to keep the maytansinoid agent (DMx) attached to the antibody until target-cell entry and activation. T-DM1 employs a non-reducible thioether linker and IMGN901 employs a disulfide linker that is reducible intracellularly. Our findings support that the best linker choice can depend on the nature of the target cancer.
We tested conjugates consisting of an anti-EGF receptor antibody (anti-EGFR Ab) attached to DMx using either a reducible disulfide linker or a non-reducible thioether linker. In our initial cytotoxicity survey, we observed that anti-EGFR-DMx conjugates made with either type of linker were potent in vitro (IC50 = 0.07 nM) against MDA-MB-468 breast cancer cells, a cell line with high EGFR expression. In contrast, the reducible, disulfide-linked conjugate was 15-fold more potent (IC50 = 0.2 nM) than the non-reducible thioether-linked conjugate (IC50 = 3 nM) against the A431 epidermoid cell line, which also has high EGFR expression. The greater cytotoxicity of conjugate containing the disulfide linker over conjugate containing the non-cleavable linker against A431 cells was observed using two different disulfide linkers and two different anti-EGFR Abs. Use of fluorescently-labeled anti-EGFR Ab identified that trafficking to lysosomes was delayed in A431 cells, in contrast to the rapid lysosomal localization found in MDA-MB-468 cells. This observation of poor lysosomal processing in A431 cells was corroborated by a cellular metabolism study. Lower amounts of active metabolites were formed in A431 cells treated with the non-reducible linker conjugate than with the disulfide linker design. The disulfide linker conjugate also showed early DMx metabolite release (8 h) due to disulfide cleavage before any lysine-linker DMx metabolite (24 h) was produced by lysosomal degradation. The non-reducible linker conjugate showed only the lysine-linker DMx metabolite at 24 h. Making the disulfide linkage more prone to intracellular reduction (by chemical design) increased the amount of intracellular DMx thiol present and also improved the cytotoxicity of the conjugate. We previously have proposed a model for conjugate activation where lysosomal degradation precedes disulfide linker reduction. The data reported here support an additional pathway of conjugate activation for designs using disulfide linkers (intracellular disulfide cleavage prior to deficient lysosomal proteolysis), which can be beneficial for ADCs targeting cancer cells that have inefficient lysosomal processing or targeting tumor antigens that are, by their nature, inefficiently processed in lysosomes.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B120.
Abstract B148: INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity
Authors: Jessen Katayoun , Wang Shunyou , Kessler Linda , Guo Xin , Kucharski Jeff , Staunton Jocelyn , Lan Lucy , Elia Marikka , Stewart Josh , Brown Jolene , Li Liansheng , Chan Katrina , Martin Michael , Ren Pingda , Rommel Christian , Liu Yi 
Published: June 2012

Abstract
mTOR Ser/Thr protein kinase operates in two distinct multi-protein complexes, TORC1 and TORC2, which together regulate growth, metabolism, angiogenesis and survival by integrating nutrient and hormonal environmental signals. The activity of mTOR is frequently up-regulated in human cancer by constitutive mitogen stimuli or oncogenic mutations upstream of TORC1 and TORC2. Rapamycin provides mechanistic rationale and clinical proof of concept for the therapeutic value of targeting mTOR in human cancer, but it also provided insights into how ATP-competitive TORC1/2 inhibitors have the potential to demonstrate superior efficacy.
Through rational drug design we have discovered INK128, a potent, selective TORC1/2 inhibitor with excellent drug-like properties. INK128 inhibits mTOR kinase (sub-nanomolar) in an ATP-dependent fashion and demonstrates a high degree of selectivity against closely related kinases as well as against a panel of more than 400 kinases. INK128 inhibits both the phosphorylation of S6 and 4EBP1, the downstream substrates of TORC1, and selectively inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2, in vitro and in vivo. Interestingly, potent inhibition was also observed in cell lines resistant to rapamycin and pan-PI3K inhibitors. Daily, oral administration of INK128 (alone or in combination) inhibited angiogenesis and tumor growth in multiple xenograft models with predicted dose:exposure PK/PD relationship. We attribute the superior activity of INK128 to the fact that it is a more effective inhibitor of TORC1 relative to rapamycin.
We further demonstrated that TORC1/2 inhibitors cause death of murine and human leukemia cells in models of pre-B acute lymphoblastic leukemia. In vivo, oral daily treatment with TORC1/2 inhibitors delayed leukemia onset and augmented the effects of ABL kinase inhibitors. Unexpectedly, these novel TORC1/2 inhibitors had much weaker effects than rapamycin on proliferation and function of normal lymphocytes. These findings establish that transformed lymphocytes are selectively sensitive to active-site TORC1/2 inhibitors and further support the development of such compounds for leukemia therapy in addition to solid tumors.
In summary, INK128 is a potent, selective, and orally active TORC1/2 dual inhibitor positioned to enter clinical development. TORC1/2 inhibitors are mechanistically distinct from rapamycin and offer a compelling approach to the treatment of cancer by targeting translational control, cell metabolism, growth and angiogenesis.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B148.
Abstract B154: Thymoquinone causes mitochondrial membrane disruption and potentiates chemotherapeutic drug- and radiation-induced cytotoxicity in breast cancer cells
Authors: Sutton Kimberly M. , Hoskin David W. 
Published: June 2012

Abstract
Thymoquinone, which is the active constituent of the volatile oil extracted from black caraway seeds (Nigella sativa), has been reported to have antiinflammatory, antioxidant, and antineoplastic activities in vitro and in vivo. In this study we explored the mechanism by which thymoquinone inhibits breast cancer cell growth, as well as the potential of using thymoquinone in combination with conventional chemotherapeutic drugs or radiation therapy. Cytofluorimetric analysis of Oregon Green 488-stained MDA-MB-231 and MDA-MB-468 breast cancer cells following thymoquinone treatment demonstrated inhibition of cell proliferation. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays performed on MDA-MB-231, MDA-MB-468, and T-47D breast cancer cells after 24, 48, and 72 h treatment with thymoquinone (0.5–10 µM) showed a time- and dose-dependent cytotoxic effect, while untransformed human mammary epithelial cells were not adversely affected by thymoquinone. Longer exposure (144 h) to lower doses of thymoquinone (0.25–1 µM) was also cytotoxic for breast carcinoma cells. Importantly, staining of thymoquinone-treated breast cancer cells with annexin-V-FLUOS/propidium iodide indicated that cell death was by apoptosis. Western blot analysis of thymoquinone-treated breast cancer cells revealed increased cytosolic cytochrome c and PARP cleavage, which suggested induction of the mitochondrial pathway of apoptosis. However, broad spectrum caspase inhibitors (Bod-D and z-VAD-fmk) did not prevent thymoquinone-induced cytotoxicity, implying caspase-independent cell death. Thymoquinone treatment also sensitized breast cancer cells to γ-radiation and the conventional chemotherapeutic agents docetaxel and cisplatin. We conclude that thymoquinone caused caspase-independent apoptosis in breast cancer cells that involved the loss of mitochondrial membrane integrity. Furthermore, the ability of thymoquinone to potentiate the cytotoxic effects of chemotherapeutic drugs and -radiation may have application in a clinical setting.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B154.
Abstract B204: Development of ALN-VSP: An RNAi therapeutic for liver malignancies
Authors: Toudjarska Iva , Judge Adam , Buck Tim , McClintock Kevin , de Jong Susan , Ambegia Ellen , Brodsky Joshua , Akinc Akin , Racie Timothy , Jeffs Lloyd , Yaworski Ed , MacLachlan Ian , Sah Dinah W. , Gollob Jared , Bumcrot David A. 
Published: June 2012

Abstract
Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP) was tested in orthotopic liver tumor models in which human tumor cells are implanted directly into the livers of immunocompromised mice. We show that intravenous administration of ALN-VSP leads to silencing of both KSP and VEGF expression in established liver tumors. This is accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, we demonstrate that ALN-VSP treatment provides a clear survival benefit even when treatment is initiated in animals with a significant tumor burden. A Phase 1 clinical trial of ALN-VSP has recently been initiated.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B204.
Abstract B92: P38 MAPK activation is critical for FGFR3-induced cell transformation in human bladder carcinoma
Authors: Bernard-Pierrot Isabelle , Dunois-Larde Claire , Stransky Nicolas , Herault Aurelie , Lepage May-Linda , Ouerhani Slah , Abbou Claude , Laplanche Agnes , Benhamou Simone , Lebret Thierry , Allory Yves , Radvanyi François 
Published: June 2012

Abstract
Bladder cancer is estimated to be the fifth most prevalent type of cancer in industrialized countries. In most of the cases (more than 90 %), tumors are urothelial cell carcinoma (UCC). Activating mutations of the fibroblast growth factor receptor 3 (FGFR3) are the most frequent genetic alteration in UCC (up to 80% in low grade Ta tumors). We have previously described that the mutated receptor displays oncogenic properties (Bernard-Pierrot et al., 2006). In this study, we aimed to better understand the signaling properties of the oncogenic mutated FGFR3. We performed a systematic analysis of phosphoproteins involved in classical signaling pathways activated by FGFRs coupled to a pharmacological study in NIH-3T3 cells expressing the mutated receptor or not. We identified p38 MAPK as a key down-stream signaling molecule of FGFR3-induced NIH-3T3 cell transformation. We further showed that activation of p38 is also critical for FGFR3-induced tumorigenesis of epithelial cells. Indeed, in vitro, p38- siRNAs and SB203580, a specific p38 MAPK inhibitor, inhibited the transforming properties of MGH-U3 cells derived from a human bladder tumor and expressing mutated FGFR3. Moreover, in vivo, treatment with SB203580, inhibited mutated FGFR3-induced proliferation both in MGH-U3 xenografted tumors and in transgenic mice expressing mutated FGFR3 in the skin (Logié et al.,2005). Finally, we identified p38 activation in all FGFR3 mutated human bladder tumors studied and more generally in all human bladder tumors presenting identified FGFR3 signaling pathway alterations. Taken together, those results suggest that p38 is a key signaling molecule in a high proportion of human bladder tumors and could represent an interesting therapeutic target both in muscle non-invasive and invasive tumors mutated for FGFR3 or more generally in tumors with FGFR3 pathway activation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B92.
Abstract C208: CCT129254 (AT11854) is a well tolerated, orally bioavailable inhibitor of AKT/PKB with pharmacodynamic and antitumor activity in a range of xenograft models
Authors: Davies Barry R. , Dudley Philippa , Cosulich Sabina , Luke Richard , Thompson Neil , Collins Ian , McHardy Tatiana , Garrett Michelle , Ogilvie Donald 
Published: June 2012

Abstract
The PI3K/AKT/mTOR pathway is the most frequently deregulated pathway in human cancer. The serine/threonine kinase AKT (PKB), a member of the AGC family of protein kinases, is central to this pathway and is considered an important target for cancer therapy. However, the development of well tolerated, orally bioavailable inhibitors of catalysis targeting this enzyme has proved challenging and there are currently no such agents that have progressed to phase II clinical studies. We have characterised the pharmacodynamic and anti-tumor activity of CCT129254, a small molecule inhibitor of AKT. CCT129254 was well tolerated when dosed chronically at up to 200 mg/kg qd in nude mice. Acute doses of 100–200 mg/kg CCT129254 caused dose-dependent transient elevations of blood glucose concentration and inhibition of AKT substrate phosphorylation in xenografts. An acute dose of 200 mg/kg qd CCT129254 significantly reduced pGSK3 for &gt;6h in U87-MG xenografts, and this pharmacodynamic activity correlated with plasma drug concentration. Moreover, chronic dosing of CCT129254 caused a dose-dependent inhibition of tumor growth in this model. Chronic once daily dosing of CCT129254 significantly inhibited tumor growth in 14 of 16 other xenograft models, including breast, prostate, lung, ovarian, kidney and colon. The highest single agent activity was seen in two breast cancer xenografts (BT474c and HCC-1954). Significant activity was also seen in the gefitinib-resistant NCI-H1975 NSCLC model with respectively activating and resistance L858R and T790M mutations in EGFR. Increased efficacy is also seen when CCT129254 is combined with the cytotoxic agents cisplatin, doxorubicin and taxotere in xenograft models. CCT129254 exemplifies an oral, well tolerated inhibitor of AKT catalysis with the potential to inhibit the growth of a wide range of solid tumors both as monotherapy and in combination with cytotoxic agents.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C208.
Abstract B111: Targeting of calreticulin exposure for optical imaging of etoposide-induced immunogenic tumor cell death.
Authors: Jung Kyung-Ho , Paik Jin-Young , Park Jinwon , Quach Cung , Lee Eun Jeong , Choe Yearn Seong , Lee Kyung-Han 
Published: June 2012

Abstract
Objective: There is growing interest in reinforcing response to anticancer therapies by promoting immunogenic cell death. This mode of cell death induces surface exposure of calreticulin (CRT) in a manner that precedes apoptosis. In this study, we explored whether CRT-targeted optical imaging may have potential as a biomarker of immunogenic cell death.
Methods: We used a monoclonal antibody against human CRT (FMC 75) conjugated with a phycoerythrin label as a fluorescent imaging probe for CRT. Human CT-26 colon cancer cells were used for in vitro studies, and immunogenic cell death was induced by treatment with 25 M etoposide. Targeting of the probe to CRT exposed on the surface of etoposide-treated cells was verified by confocal microscopy and fluorescence-activated cell sorting (FACS) analysis. In vivo imaging was performed in tumor bearing Balb/C nude mice xenografted by subcutaneous injection of MDA-MB-468 human breast cancer cells. Tumors approximately 1 cm in diameter were treated with 100 μM etoposide intra-tumorally injected in 100 μl PBS. Phycoerythrin labeled anti-CRT antibody was injected into the tail vein 3 hr later. Optical imaging of fluorescent signals was performed on an IVIS® Spectrum system (Xenogen) at 4 and 21 hr post-injection using an excitation filter of 570 nm and emission filter of 620 nm.
Results: Confocal microscopy displayed specific binding of phycoerythrin anti-CRT antibodies to the surface of etoposide-treated CT-26 cancer cells. FACS analysis with the probe showed a right-shift of fluorescent signals in cells treated with etoposide. Hence, signal-positive cells were increased from 1.83 ± 0.1% to 5.81 ± 0.5% by 4 and 24 hr of treatment, respectively. In vivo optical imaging following intra-tumoral etoposide injection demonstrated clear tumor uptake of phycoerythrin anti-CRT antibody from 4 hr post-injection. Tumor contrast was substantially enhanced at 21 hr post-injection owing to reduction of background activity, which resulted in high tumor-to-muscle signal ratios.
Conclusion: This study provides the first evidence that targeted imaging of cell surface-exposed CRT may be useful for noninvasive monitoring of immunogenic cell death during anticancer 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 B111.