bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 676: Dinitroazetidines are a novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from highly energetic materials
Authors: Ning Shoucheng , Bednarski Mark , Oronsky Bryan , Scicinski Jan , Saul Gordon , Knox Susan J. 
Published: June 2012

Abstract
Here we report the first biologic studies of a unique class of potentially clinically useful compounds, derived from highly energetic materials. In an effort to develop unique targeted cancer therapies which maximize cytotoxicity to cancer cells while minimizing unwanted side effects to normal tissue, we have studied a series of novel, non-explosive compounds, based on the highly energetic dinitroazetidine scaffold. ABDNAZ, 1-acetylbromo-3,3-dinitroazetidine is a lead compound for clinical development both as a stand-alone chemotherapeutic drug and as a radiation sensitizer. In vitro studies demonstrated that ABDNAZ generated reactive oxygen species (ROS) in a concentration- and time-dependent manner. Modulation of intracellular redox status by buthionine-(S,R)-sulfoxime or N-acetylcysteine significantly affected ABDNAZ-induced apoptosis of tumor cells. ABDNAZ administered as a single agent was as cytotoxic to tumor cells as cisplatin with IC50s of 2.6 ± 1.6uM and 4.4 ± 2.2uM for ABDNAZ and cisplatin, respectively. ABDNAZ was more cytotoxic to tumor cells than cisplatin or tirapazamine under hypoxic conditions. ABDNAZ and cisplatin had similar effects on well established SCC VII tumors in mice, but unlike cisplatin, ABDNAZ at well-tolerated sub-maximum tolerated doses (MTD) significantly inhibited tumor growth without systemic toxicity. When combined with local tumor radiation therapy, ABDNAZ significantly enhanced the efficacy of the radiation and improved the therapeutic index of radiation therapy. Toxicity studies demonstrated that ABDNAZ was not myelosuppressive and had no apparent dose limiting toxicity when administered at sub-MTD dose daily for 14 days. These data demonstrate that ABDNAZ is a promising novel anticancer drug with a very favorable toxicity profile at therapeutic doses with activity in preclinical tumor models as both a stand-alone chemotherapeutic agent and as a radiosensitizer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 676. doi:10.1158/1538-7445.AM2011-676
Abstract 770: Lorvotuzumab mertansine (IMGN901) immune effector activity and its effect on human NK cells
Authors: Skaletskaya Anna , Setiady Yulius Y. , Park Peter U. , Lutz Robert J. 
Published: June 2012

Abstract
Lorvotuzumab mertansine, or IMGN901, is a conjugate consisting of the cytotoxic maytansinoid, DM1, covalently linked to the monoclonal antibody, lorvotuzumab, which selectively targets CD56 (also called neural cell adhesion molecule or NCAM). This conjugate is currently being evaluated in clinical trials for the treatment of CD56+ solid tumors and multiple myeloma. It is able to inhibit tumor cell growth by disruption of microtubule dynamics through delivery of its cytotoxic DM1 payload; however, other potential cell killing mechanisms, such as the immune effector activity of its antibody component, have not been fully investigated.
Herein, we report on the immune effector activity of the lorvotuzumab antibody and the lorvotuzumab mertansine conjugate and their effect on the function of CD56+ human primary NK cells in vitro. To investigate the effector activity of the antibody, lorvotuzumab was incubated with CD56+ tumor target cells in the presence of rabbit complement or purified human primary NK cells. The results show that this antibody fails to mediate complement dependent cytotoxicity (CDC) but induces antibody-dependent NK cell-mediated cytotoxity (ADCC) in dose-dependent manner. The complete conjugate showed ADCC activity comparable to lorvotuzumab alone, suggesting that DM1 conjugation did not alter the interaction between the Fc domain of the antibody and NK cell's Fc receptor. Since human primary NK cells express CD56, albeit at a low level, we tested whether lorvotuzumab mertansine or its antibody component could negatively impact the function of NK cells. The results demonstrate that incubation with this antibody or with this conjugate has no effect on rituximab-mediated ADCC activity of the NK cells. Furthermore, overnight exposure of human primary NK cells with lorvotuzumab mertansine did not change rituximab-mediated ADCC activity.
In conclusion, the lorvotuzumab antibody has ADCC activity that is retained after DM1 conjugation. Furthermore, neither lorvotuzumab nor its DM1 conjugate, appear to affect the ability of NK cells (which are CD56+) to mediate ADCC through another antibody.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 770. doi:10.1158/1538-7445.AM2011-770
Abstract 910: High dietary fat promotes inflammation and intestinal neoplasia, independently of diet-induced obesity, in B6.ApcMin/+ congenic-consomic mouse strains
Authors: Doerner Stephanie K. , Leung Elaine S. , Berger Nathan A. , Nadeau Joseph H. 
Published: June 2012

Abstract
Obesity and high fat (HF) diet are associated with increased risk of colon cancer. However, assessing their independent contributions to intestinal carcinogenesis is difficult due to their close association in humans. We utilized Chromosome Substitution Strains (CSSs) in combination with the B6.ApcMin/+ mouse model of intestinal cancer to generate Congenic-Consomic Strains (C-CSs). Using C-CSs, we tested whether a HF diet promotes the development of intestinal cancer, independent of obesity, and found that dietary fats are strong and independent determinants of polyp formation.
CSSs, which have contrasting responses to a HF diet, were used to construct C-CSs that were susceptible to intestinal cancer, but were either resistant or susceptible to diet-induced obesity, depending on the substituted A/J chromosome. A2.ApcMin/+ (obese), A7.ApcMin/+ (lean), and A17.ApcMin/+ (lean) mouse strains were maintained on diets high or low in coconut oil (HFCoco and LFCoco, respectively). If obesity is crucial in polyp formation, all obese strains should develop more polyps than the lean strains. In contrast, if diet is important, we expected to find an increase in polyp number in all strains fed the HFCoco diet, independent of their susceptibility to diet-induced obesity.
Polyp numbers were significantly increased in all strains after 60 days exposure to the HFCoco diet, regardless of obese or lean status, suggesting that a HF diet promotes polyp development. Polyp numbers were also significantly higher in B6.ApcMin/+ after similar exposure to a high fat corn oil (HFCorn) diet. We measured levels of circulating inflammatory factors and showed that adiponectin is decreased and leptin, interleukin (IL)-1beta and IL-6 are increased in B6.ApcMin/+ fed either of the HF diets compared to mice fed the corresponding LF control diets, implicating a role of inflammation in diet-induced intestinal neoplasia.
With the novel C-CS systems, we were able to elucidate complex diet-gene interactions involved in intestinal carcinogenesis and provide evidence for a crucial role of a HF diet in the development of intestinal polyps. These dietary studies have implications for both prevention and non-invasive treatment of intestinal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2011-910
Abstract 934: Chromokinesin KIF4 facilitates chromatin organization critical for immunoglobulin class switch recombination and prevents lymphoma formation
Authors: Mazumdar Manjari , Dasari Siddharth , Keen Jennifer 
Published: June 2012

Abstract
Un-repaired DNA damage and chromosomal translocations are the major causes of genomic instability found in various human cancers. We have observed spontaneous B-cell Follicular lymphomas (FL) in a knock-out (KO) mouse model generated by gene trapping of KIF4, a unique DNA-binding, nuclear and chromatin-associated molecular motor. We have previously shown that KIF4 is an important modulator of higher-order chromatin structure and is required for maintaining genomic stability. Since FL often results from altered levels of DNA recombination of the immune system caused by chromosome structural changes, we investigated the contributions of KIF4 in regulating chromatin structure for B cell function. We show that there is an abnormal proliferation of B cells in mice in both bone marrow and spleen of young adult mice lacking KIF4 function. Chromosome spread from young adult knockout and neoplastic splenocytes show abnormal chromosome numbers (aneuploidy) and structure in the absence of KIF4 indicating that KIF4 is critical in maintaining genome integrity in vivo. Maintaining and establishing a stable but dynamic chromatin organization is critical for successful class switch recombination during B cell development. We observed that immunoglobulin (Ig) class switch recombination (CSR) in activated B cells is severely impaired in the absence of KIF4. Moreover, our biochemical and proteomic analysis reveals that repressive chromatin marks such as trimethylation of histone H3 lysine 9 or 27 that regulate global gene expression patterns, are significantly altered in maturing B cells in the absence of KIF4 compared to wild type control cells. This data demonstrates that KIF4 is necessary for modulating dynamic chromatin structure via a remodeling activity that allows or restricts access to the Igh locus for CSR and antibody diversity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 934. doi:10.1158/1538-7445.AM2011-934
Abstract LB-1: An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients.gg
Authors: Tang Jean Y. , Mackay-Wiggan Julian M. , Aszterbaum Michelle , Lindgren Joselyn , Chang Kris , Coppola Carol , Campbell Angela , Chanana Anita , Marji Jackleen , Callahan Chris , Yauch Robert , Bickers David R. , Epstein Ervin H. 
Published: June 2012

Abstract
Purpose: GDC-0449 (Genentech) is a new hedgehog pathway inhibitor that has been shown in a Phase I trial to reduce locally advanced/metastatic BCCs. We tested the efficacy of GDC-0449 for BCC prevention in a randomized, double-blind, placebo-controlled trial in patients with Basal Cell Nevus Syndrome (BCNS).
Methods: We enrolled 41 BCNS patients from 3 clinical centers from September 2009 to January 2011. Subjects were randomized 2:1 to receive once daily oral GDC-0449 (150 mg) or placebo. The primary endpoint was to assess the number of new surgically eligible BCCs per month after 3 months; secondary endpoints included assessment of the change in size of existing BCCs and safety/tolerability.
Results: 36 subjects (24 GDC-0449, 12 placebo) have been enrolled for greater than 1 month. Upon review of results at the interim analysis, the DSMB ended the placebo arm of the trial due to statistically significant differences between the 2 groups. Subjects treated with GDC-0449 developed 0.07 new BCCs per month vs. 1.74 BCCs per month for those receiving placebo (p&lt;0.0001). The change from baseline in the aggregate size of existing BCCs was −24 cm vs. −3 cm for GDC-0449 and placebo, respectively (p=0.006). Some subjects achieved near complete remission with no BCC developing resistance. Common grade 1–2 adverse events (GDC-0449 vs. placebo) included taste loss (83% vs. 8%), muscle cramps (67% vs. 8%), and weight loss (50% vs. 8%). Two GDC-0449 subjects experienced grade 3–4 adverse events (muscle cramp, suicide attempt). Overall 20% of GDC-0449 subjects discontinued drug participation due to adverse events. BCC samples from 23 subjects treated with GDC-0449 or placebo were available for molecular analysis. The anti-BCC efficacy of GDC-0449 was associated with on-target reduction of the Hedgehog pathway as Gli1 mRNA levels were decreased by 200-fold (p&lt;0.001) after 1month in BCCs. Gli1 mRNA levels were not changed in BCCs from placebo subjects. GDC-0449 also decreased tumor proliferation (Ki67) but had no effect on apoptosis (CC3). Biopsies of lesions taken after 3 months of GDC-0449 showed histologic clearance in 7 out of 11 samples.
Conclusion: GDC-0449 has anti-BCC efficacy in BCNS patients and may be a potential new drug for BCC prevention and treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-1. doi:10.1158/1538-7445.AM2011-LB-1
Abstract LB-156: Improved T cell survival, tumor localization and tumor eradication by folate receptor-alpha redirected T cells is achieved by provision of CD137 costimulatory signaling
Authors: Song De-Gang , Canevari Silvana , June Carl , Coukos George , Powell Daniel J. 
Published: June 2012

Abstract
Human T cells engineered to express a chimeric immune receptor (CIR) specific for folate receptor-alpha (FRα) have shown robust anti-tumor activity against epithelial cancers in vitro but not in the clinic due to their inability to persist and home to tumor in vivo. To address these issues, we constructed CIRs containing an FRα-specific scFv (MOv19) coupled to the T cell receptor CD3ζ chain signaling module alone or in combination with the CD137 (4–1BB) costimulatory motif in tandem. Primary human T cells transduced to express conventional MOv19-ζ or costimulated MOv19-BBζ CIRs secreted various proinflammatory cytokines and exerted cytotoxic function when cocultured with FRα+ tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BBζ CIR mediated tumor regression in immunodeficient mice bearing large, established FRα+ human cancer. MOv19-BBζ CIR T cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BBζ CIR T cells. T cell persistence and anti-tumor activity were primarily antigen-driven, however, antigen-independent CD137 signaling by CIR did improve T cell persistence but not anti-tumor activity in vivo. Our results show that anti-FRα CIR outfitted with CD137 costimulatory signaling in tandem overcome issues of T cell persistence and tumor localization that limit the conventional FRα T cell targeting strategy to provide potent antitumor activity in vivo. Based upon these encouraging findings, we are preparing to open an anti-FRα CIR protocol for ovarian cancer in mid-2011, pending FDA approval.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-156. doi:10.1158/1538-7445.AM2011-LB-156
Abstract LB-230: Enhancing anti-angiogenic therapy by blocking focal adhesion kinase
Authors: Bottsford-Miller Justin , Sanguino Angela , Thanapprapasr Duangmani , Pecot Chad V. , Stone Rebecca L. , Auger Kurt , Nick Alpa M. , Sood Anil K. 
Published: June 2012

Abstract
Focal adhesion kinase (FAK) represents a central point of convergence for many signaling pathways implicated in cancer progression and metastasis. Pazopanib is a pan-VEGFR and PDGFR inhibitor. In the present study, we examined whether pazopanib treatment would result in greater anti-tumor activity in combination with the novel FAK-inhibitor, GSK2256098. The in vitro effects of GSK2256098 on invasion and migration were examined using the HeyA8 and SKOV3-IP1 human ovarian cancer cell lines. In vivo effects of pazopanib with and without GSK2256098 were then assessed using an orthotopic mouse model of human ovarian cancer. GSK2256098 resulted in reduced levels of FAK phosphorylation at Y397 (pFAKY397) at 1μM concentration in SKOV3-IP1 cells. GSK2256098 resulted in a reduced invasion (p&lt;0.001) and decreased migration (p&lt;0.001) in SKOV3-ip1 cells. Dose-finding studies performed in vivo demonstrated that a 75 mg/kg dose resulted in a significant reduction in pFAKY397. Monotherapy with GSK2256098 resulted in a 58% decrease in mean tumor weight compared to control (p = 0.038). The combination of GSK2256098 with pazopanib resulted in a 71% decrease in mean tumor weight compared to pazopanib monotherapy (p = 0.04). We also tested treatment combinations including traditional cytotoxic chemotherapy. The combination of GSK2256098 with docetaxel resulted in a 44% decrease in mean tumor weight compared to docetaxel monotherapy (p = 0.17). The triplet combination of GSK2256098 with pazopanib and docetaxel resulted in the greatest overall decrease mean tumor weight, 99% compared to control and 92% compared to the doublet alone (p = 0.001). Similar trends were noted with mean number of tumor nodules and ascites volume. On the basis of our recent findings that FAK is highly phosphorylated in platelets in cancer-bearing mice, we also examined FAK phosphorylation in the platelets of treated and untreated mice. Phosphorylation of platelet FAK (pFAKY397) was inhibited by 68% at 4 hours after treatment compared to control (p = 0.07). Treatment with pazopanib decreased MVD by 49% (p &lt; 0.01), which was further enhanced in combination with GSK2256098 (p &lt; 0.01). In summary, FAK inhibition results in substantial anti-angiogenic and anti-tumor effects in combination with pazopanib and represents a viable strategy for further development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-230. doi:10.1158/1538-7445.AM2011-LB-230
Abstract LB-248: IRF4 as a critical regulator and potential therapeutic target in ABC type diffuse large B-cell lymphoma
Authors: Tolga Emre N. C. , Shaffer Arthur L. , Wright George W. , Kohlhammer Holger , Staudt Louis M. 
Published: June 2012

Abstract
Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with crucial roles in the development of lymphocytes and implicated in malignant transformation. Recently, we have demonstrated that cell lines derived from cancers of plasma cell origin (i.e., multiple myeloma) are addicted to an anomalous gene expression program driven by the wild-type IRF4. Here, we show that an aggressive malignancy of mature B-cells, the activated B-cell-like type of diffuse large B-cell lymphoma (ABC-DLBCL), also requires IRF4 for survival. With an integrative analysis of genome-wide IRF4 localization (ChIP-Seq) assays and gene expression profiling, we identify IRF4 target genes in ABC-DLBCL as members of diverse pathways related to B-cell biology and oncogenesis, largely distinct from the IRF4 targets in multiple myeloma cells. For instance, we identify CARD11, an adaptor in the NF-κB pathway, as a target of IRF4 in ABC-DLBCL, and confirm this by cell-based reporter assays. This novel regulatory mechanism complements the established aspects of ABC-DLBCL pathobiology, where NF-κB pathway is constitutively active and indispensable, and drives IRF4 expression. Furthermore, we find enrichment for a composite ETS-IRF DNA motif in IRF4 binding regions in ABC-DLBCL, suggesting cooperative activity between IRF4 and ETS transcription factor(s). Supporting this, we demonstrate through complementation assays that critical amino acids on IRF4 and the ETS factor SPIB, notably those residues important for their interaction, are essential for the survival of ABC-DLBCL, but not multiple myeloma cells. Taken together we show that ABC-DLBCL cells are addicted to the transcription factor IRF4, in part through a positive feedback mechanism involving CARD11, NF-κB, and IRF4. In addition, our results suggest therapeutic potential for targeting the IRF4-ETS interaction interface in ABC-DLBCL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-248. doi:10.1158/1538-7445.AM2011-LB-248
Abstract LB-27: Dissecting signaling transduction network to infer master regulators of non small cell lung cancer
Authors: Bansal Mukesh ,   Dissecting signaling transduction network to infer master regulators of non small cell lung cancer, Bansal Mukesh , Kustagi Manjunath , Lefebvre Celine , Rieckhof Gabrielle , Girard Luc , Merberg David , Rikova Klarisa , Minna John , Comb Michael J. , White Michael , Califano Andrea 
Published: June 2012

Abstract
Abstract
The dissection of signal transduction networks is lagging significantly with respect to their transcriptional and protein-complex counterparts. Innovative use of multiplex and microarray-based approaches, where multiple antibodies can be used to probe an ensemble of phosphoproteins, is starting to become sufficiently mature to allow characterization of small pathways. Yet, this is still far from providing an unbiased, genome-wide view of signal-transduction processes.
Using data from the first genome-wide profiling of phosphopeptide abundance in normal and tumor related lung tissue1, we have designed a novel algorithm, pARACNe, to generate an unbiased, genome-wide network representing tyrosine kinase signal transduction pathways. Specifically, pARACNe was used to infer tyrosine kinase substrates in non-small cell lung cancer (NSCLC) from tandem mass-spec abundance profiling of phosphotyrosine enriched peptides from ∼250 samples derived from primary tumors, cell lines, and normal lung tissue. SILAC validation of EGFR, MET and ALK substrates, confirmed &gt;80% of the pARACNe inferred interactions. Further analysis of large-scale NSCLC microarray expression profile data, using the MINDy algorithm2, showed significant convergence between the signal transduction pathways inferred by proteomics and gene expression based methods.
The availability of an accurate NSCLC Tyrosine Kinase Interaction Network (TKIN) has significant implications for our ability to elucidate master regulators of oncogenesis and tumor progression and for the identification and prioritization of druggable targets. We used the MARINa algorithm and the TKIN to infer a complete repertoire of master regulator (MRs) kinases of 46 cell lines. Initial validation shows that the method could recapitulate both cancer specific MRs, such as EGFR, as well as cell line specific ones, such as ALK and PTK2 in H2228 cells. Follow up experimental assays have shown that the PTK2, which is active in tumor-related but not in normal cells, is required for H2228 cell viability and may constitute a novel oncogene addiction in NSCLC and a candidate therapeutic target. The TKI suggests that current pathway models are incomplete and sets the stage for quantitative, network-based methods to identify key regulators of physiologic and pathologic cell phenotypes.
References
1. Rikova K et al. Cell 2007;131:1190–203.
2. Wang K et al. Nat Biotechnol 2009;27:829–39.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-27. doi:10.1158/1538-7445.AM2011-LB-27