bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3614: In vivo efficacy of the carbonic anhydrase IX (CA9)-targeted antibody-drug conjugate BAY 79-4620 is superior to that of microtubule inhibitors in preclinical models of NSCLC, gastric and colorectal cancer
Authors: Petrul Heike , Kopitz Charlotte , Schatz Christoph , Beier Rudolf , Zatovicova Miriam , Pastorekova Silvia , Kreft Bertolt , Ziegelbauer Karl 
Published: June 2012

Abstract
BAY 79-4620 is a novel antibody drug conjugate (ADC) consisting of a fully human monoclonal antibody directed against carbonic anhydrase IX (CA9) conjugated to the auristatin derivative monomethyl auristatin E (MMAE) and is currently in Phase I clinical testing. CA9 is overexpressed in a range of tumor types, including gastric cancer, non-small cell lung cancer (NSCLC), pancreatic cancer and colorectal cancer. CA9 is a hypoxia-inducible protein regulated by HIF-1α, and its expression has been linked to higher aggressiveness of tumors and is predictive of poor prognosis in several cancers.
In this study, we first compared the internalization rates of the ADC BAY 79-4620 and of the naked antibody, which were found to be similar in several cell lines, indicating that CA9 internalization in vitro is not affected by the conjugated toxophore. It has previously been shown that the cytotoxicity of BAY 79-4620 depends on both CA9 expression and sensitivity of tumor cells to tubulin inhibitors. The anti-tumor efficacy of BAY 79-4620 was therefore compared to that of free toxophore MMAE as well as paclitaxel. At cumulative doses corresponding to a fraction of that of paclitaxel (calculated as toxophore equivalents), BAY 79-4620 showed equivalent or superior efficacy to paclitaxel and MMAE in xenograft models of human NSCLC and gastric carcinoma. Cumulative BAY 79-4620 doses corresponding to only 30% of the highest dose of free MMAE given showed equivalent or superior efficacy in xenograft models of non-small cell lung carcinoma. Moreover, BAY 79-4620 also showed efficacy in patient-derived NSCLC models that are resistant to paclitaxel and/or cisplatin.
Finally, regrowing CRC tumors after an initial response to BAY 79-4620 responded well to a second cycle of BAY 79-4620 treatment. This indicates that no resistance through clonal selection of CA9 negative tumor cells was induced and that repeated treatment cycles should be possible for cancer patients.
These results show the superiority of the CA9-targeted approach over the systemic administration of tubulin inhibitors, component of treatment regimens commonly used for the treatment of NSCLC and gastric cancer. Efficacy of BAY 79-4620 was particularly high in models expressing high levels of CA9, making BAY 79-4620 a promising agent for the treatment of CA9-positive NSCLC and gastric 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 3614. doi:10.1158/1538-7445.AM2011-3614
Abstract 362: Comparison of Mig-6 and hormone receptor expression to BMI as predictors of responsiveness to progestin therapy for endometrial hyperplasia and cancer
Authors: Poisson Jessica , Rossi Emma , Young Steven , Gehrig Paola A. , Bae-Jump Victoria L. 
Published: June 2012

Abstract
Objectives: Mitogen-inducible gene 6 (Mig-6) is an immediate early response gene that can be induced by stressful stimuli and mitogens, including hormones and growth factors. Ablation of Mig-6 leads to epithelial hyperplasia and adenocarcinomas in a variety of organs, including the endometrium. Mig-6 has been identified as a downstream target of the progesterone receptor (PR) in the uterus. Thus, our goal was to compare Mig-6 and hormone receptor expression to BMI as predictors of responsiveness to progestin therapy for endometrial hyperplasia and cancer.
Methods: Women were identified who underwent progestin treatment (oral or IUD) for either endometrial hyperplasia or cancer. Expression of Mig-6 and the hormone receptors, G-protein coupled receptor 30 (GPR30), estrogen receptor (ER) and PR were evaluated by immunohistochemistry (IHC) in 58 paired formalin-fixed, paraffin-embedded endometrial biopsy specimens before and after progestin treatment. Tissue microarrays were constructed, and three cores were analyzed for each patient. IHC staining was scored according to the intensity (1+ to 3+) and qualitative percent cells staining per core. A “histoscore” was calculated, based on multiplying these two determinants ranging from 0 to 300 (i.e. intensity x % labeled). Results were analyzed using the Student t-test and ANOVA.
Results: There were 41 responders to progestin therapy and 17 non-responders. The majority had endometrial hyperplasia (56/58) but 2 women had grade I endometrial carcinomas. The BMI between the two groups was statistically different at 40.2 for the responders and 49.9 for the non-responders (p=0.0008). There was no difference in age or ER/PR status between the two groups. Mig-6 expression prior to treatment did not predict response to progestin therapy (183.5 = responders, 196.6 = non-responders, p=0.47). GPR30 expression prior to progestin treatment was 118.8 for the responders and 68.9 for the non-responders but was not statistically significant (p=0.06). Neither post-treatment Mig-6 (179.1 = responders, 204.0 = non-responders) or GPR30 (103.6 = non-responders, 108.6 = responders) histoscores or change in histoscores pre- and post-treatment predicted response to progestin therapy.
Conclusions: BMI but not Mig-6 expression or hormone receptor expression predicted response to progestin therapy in women with endometrial hyperplasia and cancer. GPR30 may have potential as a biomarker of progestin responsiveness but needs to be evaluated in a larger cohort of women.
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 362. doi:10.1158/1538-7445.AM2011-362
Abstract 3632: Nonclinical pharmacokinetics and safety of Angiocal, the first VEGF-A-specific alternative scaffold protein entering clinical development for cancer
Authors: Gille Hendrik , Christian Jürgen , Hülsmeyer Martin , Meyer Todd , Amirkhosravi Ali , Audoly Laurent P. , Stern Angelika C. , Jensen Kristian , Hohlbaum Andreas M. 
Published: June 2012

Abstract
Anticalins are high affinity scaffold proteins based on human lipocalins and represent a new class of biologics. Although lipocalins share limited sequence identity among each other they are all made up of a single conserved beta-barrel. The four loops protruding from the opening of the calyx contribute to the observed various binding functions of different lipocalins. The loop residues of human tear lipocalin were randomized to generate a combinatorial library and successive rounds of panning and screening were employed to generate an Anticalin with high affinity and specificity for VEGF-A, Angiocal. Angiocal was found to antagonize VEGF-A function by preventing its interaction with cognate membrane receptors. Following the initial characterization in cell-based and in vivo models as communicated previously (AACR 2008 #4077, AACR 2009 #2318) we sought to estimate the human pharmacokinetics of Angiocal by interspecies scaling. Therefore, PK profiles in mice, rats and cynomolgus monkeys were obtained and will be presented.
Therapeutic antibodies such as bevacizumab are usually well tolerated while significant toxicities occur in a subset of patients, for example leading to an enhanced risk for thromboembolic events. It has been demonstrated that bevacizumab forms multimeric immune complexes in vivo which may be a cause for these effects. Furthermore, immune complex deposition in glomeruli of the kidney may cause glomerulosclerosis. With respect to thromboembolic complications of bevacizumab use, these were mirrored in human FcgammaIIa receptor transgenic mice where administration of complexes between heparin, Bevacizumab and heparin-binding isoforms of its VEGF-A target lead to platelet aggregation and thrombosis (Meyer, T. et al. J. Thromb. Haemost. 2009, 7: 171-181). Angiocal was tested in the same model and does not cause any of these adverse effects on platelets in vivo.
GLP toxicology studies with Angiocal were performed in two relevant species to determine the NOAEL. In addition, we did not observe effects on inflammatory cytokines or complement factors in these studies while exaggerated pharmacodynamic effects consistent with potent VEGF neutralization were seen. Angiocal is currently undergoing phase Ib clinical testing in cancer patients to establish Anticalins as novel and safe class of therapeutic molecules.
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 3632. doi:10.1158/1538-7445.AM2011-3632
Abstract 364: Impact of glucocorticoid in patients with locally advanced esophageal cancer treated with concurrent chemoradiotherapy
Authors: Lu Yen-Shen , Lin Chia-Chi , Hsu Chih-Hung , Lien Huang-Chun , Yeh Pei-Yen , Yeh Ling-Chiun , Cheng Ann-Lii 
Published: June 2012

Abstract
Background: Concerns about the effect of glucocorticoids (GC) on tumor growth and chemosensitivity have been raised recently. Our pervious study shows that GC receptor is highly expressed in esophageal squamous cell carcinoma (ESCC) tumor tissues (Histopathology 2008;52:314-324). This study sought to further characterize the GC effect on the efficacy of conventional anti-cancer therapy to ESCC.
Materials and Methods:The in vitro study was performed in 2 esophagus cell lines: KYSE-70 and KYSE-410. The cell viability is determined by MTT assay and clonogenic assay. The effect of GC on cytotoxic treatment -induced apoptotic cell death was determined by flow cytometric and Western blot analysis. Further, we retrospectively analyzed impact of GC usage on the outcomes of 92 patients with locally advanced ESCC who received preoperative concurrent chemoradiotherapy in a prospective clinical trial. Among 92 locally advanced ESCC patients, 39 patients who received GC twice weekly for four to six weeks (a total of eight doses or more) and 53 patients who received GC only two doses in the first week at discretion of individual physicians.
Results: In vitro study showed pretreatment of GC confer resistance to cytotoxic agents including paclitaxel, gemcitabine and 5-FU, and resistance to irradiation. The effect of increase chemo-resistance by GC may be through decrease of the apoptosis according to PI/annexin V staining flow cytometric study and Western blot study. In the retrospective clinical study, the two groups were well balanced with respect to disease stage and other prognostic factors. Multivariate analysis showed that corticosteroid usage and performance status were independently prognostic of survivals. The median overall survivals of the two-dose group the eight-dose-or-more group were 38.4 and 15.1 months, (p = 0.089), respectively. The median progression-free survivals were 27.5 and 9.4 months (p = 0.024), respectively.
Conclusion: This data suggest that GC decrease chemo-sensitivity and radio-sensitivity of ESCC cells. Frequent usage of GC during concurrent chemoradiotherapy may have a detrimental effect on patients with locally advanced ESCC.
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 364. doi:10.1158/1538-7445.AM2011-364
Abstract 3647: Characterization of the relationship between mature neutrophils and tumor associated granulocytic myeloid-derived suppressor cells
Authors: Youn Je-In , Collazo Michelle M. , Gabrilovich Dmitry 
Published: June 2012

Abstract
Myeloid-derived suppressor cells (MDSC) is a group of cells with potent immune suppressive activity that accumulate in many pathologic conditions. In cancer, most of MDSC are represented by cells with granulocytic phenotype, CD11b+Ly6ClowLy6G+, and morphology and are thus called granulocytic MDSC (G-MDSC). This phenotype and morphology are also shared by mature neutrophils (Neu) in naive mice. The relationship, if any, between G-MDSC and Neu remains unclear. In this study, we compared tumor associated G-MDSC and mature Neu. G-MDSC were freshly isolated from spleen of tumor-bearing mice. Because there are no known specific markers that differentiate between Neu and G-MDSC in tumor being mice or Neu and immature myeloid cells in naïve mice; Neu were isolated from naive mice by mobilizing them to the peritoneum (pNeu). We found that in contrast to pNeu, a substantial proportion of G-MDSC express the M-CSF receptor, CD115, CXCR4 and the CD244 molecule, also known as 2B4. pNeu have high amounts of lysosomes, endosomes and proteasomes, which was validated using immunofluorescence microscopy to measure the expression of associated proteins, LAMP2, EEA1, PSMA5, respectively. G-MDSC had significantly lower expression of LAMP2, EEA1, PSMA5. Also, G-MDSC, compared to pNeu, had significantly lower phagocytic activity, as measured by the uptake of latex beads in vitro. On the other hand, G-MDSC, but not pNeu, suppressed T-cell IFN-γ production upon antigen-specific stimulation. Interestingly, pNeu had higher arginase activity and nitric oxide production than G-MDSC, while G-MDSC had a significantly higher increase in reactive oxygen species levels upon PMA stimulation in vitro. This may explain the differences in suppressive activity. G-MDSC survived 3 days in culture, in the presence of GM-CSF. Within 24 hours in culture with GM-CSF, they became phenotypically and functionally similar to pNeu, with increased phagocytic capacity and LAMP2 expression and decreased expression of CD115, CXCR4, and CD244. These data suggest that, in cancer, G-MDSC may represent pathologically activated precursors of neutrophils.
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 3647. doi:10.1158/1538-7445.AM2011-3647
Abstract 3686: Activation of signal transducer and activator of transcription 3 fails to confer resistance against withaferin A-induced apoptosis in human breast cancer cells
Authors: Lee Joomin , Hahm Eun-Ryeong , Singh Shivendra V. 
Published: June 2012

Abstract
We have shown previously that withaferin A (WA), a constituent of Indian Ayurvedic medicine plant Withania somnifera that has been used safely for thousands of years for treatment of different ailments, inhibits growth of cultured MDA-MB-231 (an estrogen receptor negative cell line with mutant p53) and MCF-7 (an estrogen-responsive cell line with wild-type p53) human breast cancer cells. Moreover, the WA administration significantly inhibits growth of MDA-MB-231 xenografts in female athymic mice without causing any side effects. The WA-mediated inhibition of breast cancer cell growth in culture and xenografts correlates with apoptosis induction. However, the mechanism underlying proapoptotic effect of WA is not fully understood. The present study was designed to study the role of signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor activated in many human malignancies including breast cancer, in proapoptotic response to WA using MDA-MB-231 and MCF-7 cells. Growth suppressive and proapoptotic concentrations of WA (2 and 4 μM) decreased constitutive (MDA-MB-231) or interleukin-6 (IL-6)-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr705) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (a) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (b) dimerization of STAT3 (MDA-MB-231); and (c) nuclear translocation of Tyr705 phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred only a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. General implication of these findings is that WA can trigger apoptosis and largely inhibit cell migration/invasion of breast cancer cells even after IL-6-induced activation of STAT3, which should be viewed as a therapeutic advantage for this agent. This investigation was supported by the USPHS grant CA142604-01, awarded by the National Cancer Institute.
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 3686. doi:10.1158/1538-7445.AM2011-3686
Abstract 3691: Selective depletion of mutant p53 by isothiocyanates and its structure-activity relationships
Authors: Chung Fung-Lung , Pasqua Anthony Di , Wang Xiantao , Govind Suhda , Hong Charles , Mi Lixin , York Tomita , Woodrick Rebbecca Covington 
Published: June 2012

Abstract
It has been shown that isothiocyanates (ITCs), derived from hydrolysis of glucosinolates in cruciferous vegetables via Lossen rearrangement by myrosinase, induce apoptosis in cancer cells. We here demonstrate that certain naturally-occurring ITCs selectively deplete mutant p53, but not the wild type, and do so via a post-transcriptional mechanism. Direct p53 binding and the sequential conformational changes appears to be one of the mechanisms by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally-occurring and synthetic ITCs show that depletion is influenced by the structure of the ITC side chain moiety. Consistent with the gain of function by mutant p53, we show that cells with p53 mutations are more sensitive to the cytotoxicity of phenethylisothiocyanate (PEITC) than are those with the wild type. Furthermore, 2,2-diphenylethyl ITC, a synthetic ITC and one of the most potent depletors of mutant p53 studied, induces apoptosis to the greatest extent in breast cancer cells with mutant p53 status. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs.
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 3691. doi:10.1158/1538-7445.AM2011-3691
Abstract 3696: Effect of dietary omega-3/omega-6 ratio on mammary carcinogenesis, circulating biomarkers and molecular regulators in rats
Authors: Zhu Zongjian , Jiang Weiqin , McGinley John N. , Manni Andrea , El-Bayoumy Karam , Thompson Henry J. 
Published: June 2012

Abstract
Available evidence indicates that diets enriched in the ratio of n-3 to n-6 fatty acids have a broad range of health-related benefit; however, the epidemiological and preclinical data for breast cancer risk are mixed. The majority of animal carcinogenesis experiments have been done using diets that were high in the percent of dietary calories provided from fat (40 to 50%) and few studies have investigated the impact of the n-3/n-6 ratio despite the fact that considerable emphasis has been placed on this ratio in hypothesized mechanisms of action. The objective of this investigation was to determine the effect of a wide range of dietary n-3/n-6 ratios on mammary carcinogenesis, on plasma levels of cancer associated growth factors and cytokines and on molecular regulators in mammary carcinomas using a pre-clinical rat model for breast cancer. Female Sprague Dawley rats were injected with 1-methyl-1-nitrosourea (50 mg/kg) and 7 days thereafter randomized to groups (n=30/group) in which the n-3/n-6 ratio varied widely and diets were fed in the presence or absence of tamoxifen treatment. Rats were fed a modification of the AIN-93G diet formulation that contained 30% of dietary calories from fat (currently recommended in the US Dietary guidelines). It was observed that mammary cancer incidence, cancer multiplicity and tumor burden were reduced when the dietary ratio of n-3/n-6 was &gt; 5:1. Cancer inhibition was observed in both the presence and absence of tamoxifen. The protective dietary n-3/n-6 ratio was associated with significant reductions in plasma IGF-1, insulin, and leptin and increased adiponectin compared to rats fed the control diet (n-3/n-6=1:1, p&lt;0.05), effects that were not modified by tamoxifen treatment. Carcinomas induced in the protected animals were smaller in mass with altered levels of proteins in the PPAR-NFkB pathway. This work was supported by grant KG081632 from the Susan G. Komen Foundation.
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 3696. doi:10.1158/1538-7445.AM2011-3696
Abstract 3702: 2-Hydroxyflavanone inhibits renal cancer growth by inhibiting tumor cell proliferation and angiogenesis
Authors: Nagaprashantha Lokesh Dalasanur , Vatsyayan Rit , Singhal Jyotsana , Lelsani Poorna , Awasthi Yogesh , Awasthi Sanjay , Singhal Sharad S. 
Published: June 2012

Abstract
Renal cell carcinoma (RCC) is one of the top ten cancers prevalent in USA. Loss-of-function mutation in the VHL is an established risk factor for RCC contributing to 75% of total reported cases of RCC. Loss of VHL leads to highly vascularized phenotype of renal tumors. Intake of oranges has been proven to reduce the risk of RCC in multi-center international clinical trials. Hence, we studied effects of 2HF, an active anti-cancer compound of oranges, in VHL- mutant RCC. Our in vitro investigations revealed that 2HF selectively inhibits VHL-mutant RCC by inhibiting EGFR signaling which is increased due to VHL mutations in RCC. Our results also revealed for the first time, that 2HF inhibits GSTπ activity. 2HF inhibited cyclin B1 and CDK4, and induced G2/M phase arrest in VHL-mutant RCC. Importantly, 2HF inhibited the angiogenesis in VHL-mutant RCC by decreasing VEGF expression. Our in vivo studies in mice xenografts confirmed our in vitro results as evident by decreased levels of proliferation marker, Ki67 and angiogenic marker CD31, in 2HF treated (0.01%, w/w) mice xenografts of VHL-mutant RCC. 2HF also increased the expression of E-cadherin in VHL-mutant RCC which would be of significance in restoring the normal epithelial phenotype. Collectively, our in vitro and in vivo results revealed the potent anti-proliferative and anti-angiogenic effects of 2HF in VHL-mutant RCC, sparing normal cells, which could have significant implications not only in the specific management of VHL-mutant RCC but also in treating other VHL syndromes with highly vascularized phenotype.
(Supported in part by NIH grant CA 77495 (SA), CA 155350, Cancer Research Foundation of North Texas, and Institute for Cancer Research & the Joe & Jessie Crump Fund for Medical Education (SSS))
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 3702. doi:10.1158/1538-7445.AM2011-3702