bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1793: Platelet-derived growth factor receptor alpha blockade significantly enhances sensitization to docetaxel in ovarian carcinoma
Authors: Matsuo Koji , Stone Rebecca L. , Shahzad Mian , Carroll Amy R. , Han Hee-Dong , Lee Sun-Joo , Nishimura Masato , Mora Edna , Lu Chunhua , Loizos Nick , Sood Anil K. 
Published: February 2011

Abstract
Objective: Platelet-derived growth factor receptor alpha (PDGFRα) is a member of class III receptor tyrosine kinase and is associated with cell survival. Here, we examined whether PDGFRα blockade enhances the anti-tumor activity of taxanes in ovarian carcinoma.
Methods: PDGFRα expression was evaluated with RT-PCR and Western blot in multiple ovarian cancer cell lines. Human-specific monoclonal antibody to PDGFRα (IMC-3G3, ImClone Systems, NJ, USA) was used for in-vitro (cell viability assay, apoptosis assay) and in-vivo experiments with or without docetaxel.
Results: All eleven tested ovarian cancer cell lines had variable expression of PDGFRα. OVCA433 cell line had the highest level of expression of PDGFRα. IMC-3G3 blocked PDGFRα phosphorylation in response to PDGF-AA stimulation. IMC-3G3 alone had no affect on cell viability in all tested cell lines. However, IMC-3G3 significantly enhanced sensitization to docetaxel: IC50 reduction rate, SKOV3-ip1, 25.5%; HeyA8-parental, 31.7%; OVCA433, 35.3%; and HeyA8-MDR, 44.2% (all, p&lt;0.05). While treatment with IMC-3G3 alone did not increase apoptosis, concurrent use with docetaxel significantly enhanced docetaxel-mediated apoptosis (mean percentage of total apoptotic cells in SKOV3-ip1, untreated vs IMC-3G3 alone vs docetaxel alone vs docetaxel with IMC-3G3, 7.3% vs 7.1% vs 15.4% vs 22.2%, p&lt;0.001). In the in-vivo experiment with SKOV3-ip1 bearing mice, administration of IMC-3G3 monotherapy had no significant anti-tumor effects compared to the control group (mean tumor weight, 2.5 ± 0.32 vs 2.9 ± 0.51 grams, p&gt;0.05). Concurrent use of IMC-3G3 with docetaxel significantly reduced tumor weight compared to docetaxel alone (mean tumor weight, 0.22 ± 0.07 vs 0.63 ± 0.14 grams, tumor reduction rate 65.1%, p&lt;0.05).
Conclusion: IMC-3G3 significantly enhances the anti-tumor effects of docetaxel. Therefore, targeting PDGFRα may be an attractive approach for increasing the cytotoxic effects of chemotherapy.
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 1793.
Abstract 1798: TORC1/2 inhibitors have more potent anti-leukemic efficacy and are less immunosuppressive than rapamycin
Authors: Fruman David A. , Janes Matthew R. , Limon Jose J. , So Lomon , Chen Jing , Martin Michael B. , Ren Pingda , Liu Yi , Rommel Christian 
Published: February 2011

Abstract
The purpose of this study was to evaluate the anti-leukemic and immunosuppressive properties of novel, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). The mTOR inhibitors currently in clinical use, exemplified by rapamycin and related analogs (“rapalogs”), have achieved some success as anticancer therapies. However, these agents also suppress proliferation of both B and T lymphocytes. In addition, rapalogs have a mechanistic limitation: not only are they allosteric inhibitors that selectively bind to mTOR complex-1 (TORC1) and not to mTOR complex-2 (TORC2), but they do not fully inhibit TORC1. In contrast, novel ATP-competitive active-site inhibitors of the mTOR kinase overcome these limitations, displaying full inhibitory activity of both TORC1 and TORC2. We compared rapamycin with active-site TORC1/2 inhibitors in models of Philadelphia chromosome-positive pre-B acute lymphoblastic leukemia (Ph+ B-ALL). We find that PP242 and INK128, active-site TORC1/2 inhibitors, but not rapamycin cause death of murine and primary human leukemia cells. These compounds are also more potent than rapamycin in growth assays of solid tumor cell lines. Biochemical assays confirm that PP242 and INK128 inhibit rapamycin-resistant outputs of both TORC1 and TORC2. In vivo, oral administration of PP242 or INK128 delays leukemia onset and augments the effects of tyrosine kinase inhibitors. Surprisingly, active-site TORC1/2 inhibitors have much weaker effects on proliferation and function of normal B and T cells than rapamycin. Selective TORC1/2 inhibitors are also less immunosuppressive than PI-103, a panPI3K-mTORC1/2 inhibitor. These findings establish that transformed lymphocytes are selectively sensitive to TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.
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 1798.
Abstract 18: Targeted epidermal ablation of EGFR causes local and systemic inflammation
Authors: Mascia Francesca , Lam Gary , Threadgill David , Yuspa Stuart H. 
Published: February 2011

Abstract
EGFR is overexpressed or mutated in a variety of malignancies, and it plays a fundamental role in tumor development and progression, in the angiogenetic process and in the metastatic spread of tumors. As a result investigators have developed approaches to inhibit EGFR activation, with the aim of blocking tumor growth and invasion. The most common adverse effect seen with EGFR inhibition therapy is a pronounced skin inflammatory response (papulopustular rash) that can affect different areas of the body with variable severity. Interestingly, in vitro and in vivo experiments demonstrate that the pharmacological blockade of EGFR or ERK1/2, induces chemokine expression in epidermal keratinocytes and in turn leads to worsening of skin inflammatory conditions. Recent findings suggest a link between chemokine expression and EGFR status in the skin lesions of patients undergoing EGFR therapy and during tumor progression in BCC (basal cell carcinoma) and SCC (squamous cell carcinoma) skin lesions. Given these previous findings we believe that the study of the regulatory functions of the EGFR-ERK1/2 pathway on skin inflammatory mediators will help in understanding not only the adverse effect of this broad class of antitumor drugs but will possibly help to understand if and how they can modify the tumor microenvironment. In this study a mouse model was developed to better characterize the role of EGFR in the control of skin inflammation. By crossing Keratin 5 driven Cre recombinase transgenics with EGFR floxed mice, EGFR was ablated in the epidermis. During the first week of life, double transgenics started to display a strong skin phenotype with aberrant hair growth. During the following weeks the skin of these mice became progressively more inflamed with abundant neutrophilic infiltrate, scaly, dry and less elastic and underwent cycles of hair growth and hair loss. Double transgenic mice experienced a strong pruritus through their entire life, and their scratching behavior caused skin erosions. Tissue samples isolated from skin of adult double transgenics contained high levels of CD45 antigen and increased mRNA levels of a subset of inflammatory mediators namely CCL17, CCL20, CCL2, TNF-α, IL-6, IL-17, IL-18, and G-CSF. Targeted knockout mice also displayed hematological abnormalities with a higher number of circulating CD11b/Gr1 positive cells, extramedullary hematopoiesis and higher plasma levels of G-CSF, IL-1ra, IL-17, IL-6 and CCL2. These data indicate that the local absence of EGFR triggers local and systemic inflammatory responses. Therefore, this model represents a valuable tool to further investigate the control of EGFR in the maintenance of a balanced immuno-homeostasis of the skin.
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 18.
Abstract 1801: Predictive diagnostics for the PI3 kinase inhibitor GDC-0941 in breast and ovarian cancer
Authors: O'Brien Carol , Spoerke Jill , Mohan Sankar , Pandita Ajay , Sampath Deepak , Wallin Jeffrey , Lackner Mark 
Published: February 2011

Abstract
The class I phosphatidylinositol 3’ kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting the PI3K pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. GDC-0941 is a pan-inhibitor of all 4 isoforms of class 1 PI3K that is currently undergoing testing in the clinic. The PI3 kinase pathway is generally regarded as the most frequently altered pathway in cancer, and an attractive hypothesis is that these alterations will help identify tumors where the pathway is particularly active and hence patients who are likely to receive benefit from treatment with a PI3 kinase inhibitor.
We used a large panel of breast and ovarian cancer cell lines as well as in vivo xenograft models to evaluate candidate predictive biomarkers for GDC-0941. The approach involved pharmacogenomic profiling as well as analysis of gene expression datasets from tumor cells profiled at baseline or after GDC-0941 treatment. We found that models harboring key pathway alterations were generally sensitive to the anti-tumor effects of GDC-0941. We found that a number of models that do not harbor these alterations also showed sensitivity, suggesting alternative explanations for sensitivity and thus a need to identify additional diagnostic hypotheses. Gene expression studies identified a small number of genes whose expression appears to be intimately linked to pathway activation that may also be useful diagnostic markers.
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 1801.
Abstract 1808: Modulation of the immune cell repertoire and immunogenicity of tumor cells by sorafenib
Authors: Seliger Barbara , Giersberg Corinna , Mueller Anja 
Published: February 2011

Abstract
Recently, tyrosine kinase inhibitors have been successfully implemented in frontline therapy for the treatment of malignant tumors including renal cell carcinoma (RCC). These different substances provide significant objective clinical responses and a longer progression-free survival of patients. This is mainly caused by the inhibition of cell growth, angiogenesis and induction of apoptosis. In addition, an effect of sorafenib on the frequency and function of T subpopulations, dendritic cells as well as myeloid-suppressor cells has been postulated. The aim of this study was to determine the effect of sorafenib on cell growth, apoptosis and immunogenic properties of RCC cells as well as on the composition of immune subpopulations of peripheral blood mononuclear cells and subsequently immune responses. A direct effect of sorafenib on the expression pattern of a number of immune modulatory components including HLA class I antigens and members of the B7-H family as well as on the proliferation of RCC cell lines was detected. In addition, the frequency and function of different immune cell populations, such as regulatory T cells and myeloid-derived suppressor cells, was altered upon sorafenib treatment. These data suggest a novel activity of sorafenib in tumor patients by extending its activity beyond the tumor endothelium as its major target to the modulation of immune cell function and the immunogenicity of RCC cells.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1808.
Abstract 1809: Reversal of Taxol resistance in ovarian cancer cell lines by IGF pathway inhibition
Authors: Brouwer-Visser Jurriaan , Horwitz Susan Band , Huang Gloria S. 
Published: February 2011

Abstract
Our group recently reported increased insulin-like growth factor 2 (IGF2) expression and AKT activation in ovarian cancer cells following treatment with the microtubule-stabilizing agent Taxol. We hypothesized that IGF2 is a modulator of Taxol resistance. Therefore, we developed cell line models of Taxol-resistance in A2780 and HEY, two ovarian cell lines, by repeated treatment with increasing Taxol concentrations, with or without concurrent verapamil, a p-glycoprotein inhibitor. The involvement of IGF2 in drug resistance was evaluated by real time PCR, immunoblotting, siRNA knockdown of IGF2, and small-molecule inhibition of the IGF1 Receptor (IGF1R; which is the major receptor for IGF2). In both of the resistant cell lines (A2780-Tx8Vp, 3-fold Taxol-resistance; and HEY-T30, 40-fold Taxol-resistance), IGF2 mRNA expression, measured by real time PCR, was significantly elevated compared with the parental cell lines, while IGF1R expression, assessed by immunoblotting, was mildly decreased. IGF1R inhibition by the small molecule NVP-AEW541 dramatically re-sensitized both resistant cell lines to Taxol, and cell cycle analysis demonstrated that concurrent NVP-AEW541 and Taxol significantly enhanced G2/M arrest, compared with Taxol alone. While A2780-Tx8Vp cells did not express detectable mdr1/abcb1 (encoding p-glycoprotein), HEY-T30 cells did over-express mdr1 (and were sensitized to Taxol treatment by verapamil). To exclude a possible interaction with p-glycoprotein, we evaluated IGF2 siRNA as an alternate, more specific approach of targeting the IGF pathway in HEY-T30 cells. It was found that IGF2 depletion by siRNA significantly enhanced the antiproliferative effect of Taxol in these cells. In summary, IGF2 modulates Taxol resistance in these ovarian cancer cell lines. IGF pathway inhibition, by IGF2 depletion or by inhibition of its major receptor IGF1R, reverses Taxol resistance in these cells. Such novel findings suggest that IGF2 could be a therapeutic target for ovarian cancer, particularly in the setting of Taxol resistance.
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 1809.
Abstract 1811: Breaking scaffolds: Targeting paxillin in ovarian cancer
Authors: Carroll Amy , Kim Seung Wook , Nick Alpa M. , Stone Rebecca L. , Spannuth Whitney A. , Armaiz-Pena Guillermo N. , Matsuo Koji , Vivas-Mejia Pablo E. , Mangala Selanere , Mora Edna M. , Shahzad Mian , Lopez-Berestein Gabriel , Sood Anil K. 
Published: February 2011

Abstract
Background
Paxillin is a mediator of many cellular processes important for cancer progression. Here, we characterize the clinical and biologic significance of paxillin in epithelial ovarian cancer.
Methods
Paxillin and phospho-paxillin expression was determined in 93 human epithelial ovarian cancer specimens. Clinical data were extracted and associations tested using univariate and multivariate analyses. The effect of paxillin silencing on ovarian cancer cell migration and invasion was evaluated in vitro. In vivo paxillin silencing was achieved with siRNA incorporated into DOPC nanoliposomes and its effect on tumor growth, angiogenesis, and proliferation were examined.
Results
Examination of 93 epithelial ovarian cancers revealed moderate to high paxillin expression in 84% and high phospho-paxillin expression in 63% of tumors. High paxillin expression correlated with high tumor grade (p=0.02) and advanced stage (p=0.03). Phospho-paxillin expression was associated with high tumor grade (p=0.01), suboptimal cytoreduction (p=0.01), and decreased overall survival (p&lt;0.001). Compared to non-transformed ovarian epithelial cells (HIO-180), paxillin expression was increased in chemosensitive (HeyA8, SKOV3) and chemoresistant (HeyA8-MDR, SKOV3-TR) ovarian cancer cell lines. Paxillin siRNA resulted in &gt;85% reduction in protein expression in these cell lines. In vitro paxillin silencing decreased HeyA8 and HeyA8-MDR cell migration (60% and 75%) and invasion (55% and 47%). In orthotopic mouse models, paxillin siRNA treatment reduced tumor growth in HeyA8 and HeyA8-MDR by 49% and 31%, respectively, compared to non-targeting siRNA controls. The greatest efficacy was observed by combining paxillin siRNA with docetaxel, resulting in a &gt;90% and 45% reduction in tumor burden over non-targeting siRNA in HeyA8 and HeyA8-MDR tumors, respectively. The dramatic in vivo effects of paxillin silencing are due, in part, to its activation of multiple signaling cascades once localized to the focal adhesion complex. Protein complex immunoprecipitation confirms interactions with Src, FAK, and EphA2 tyrosine kinases as well as effector molecules such as Crk. Paxillin silencing resulted in decreased proliferation by 57%, decreased microvessel density by 72%, and increased apoptosis by 140% in HeyA8 tumors.
Conclusion
Paxillin is overexpressed in epithelial ovarian cancer. Paxillin influences several pathways important to cancer progression and represents a novel and attractive treatment target in ovarian 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 1811.
Abstract 1818: Space-time analysis of racial disparities in advanced-stage prostate cancer incidence across Florida
Authors: Goovaerts Pierre , Xiao Hong 
Published: February 2011

Abstract
Prostate cancer is the most frequently diagnosed non-skin cancer and the second leading cause of cancer-related death for American men. Florida ranks second behind California for both incidence and mortality from prostate cancer in 2008. With the wide spread use of prostate specific antigen (PSA) and digital rectal examination (DRE), a larger proportion of prostate cancer cases is now diagnosed at early stages. Yet, striking racial/ethnic differences in incidence and mortality still persist in the United States and Florida. Eliminating such disparities requires a better understanding of factors responsible for the geographic and ethnic differences in prostate cancer late stage incidence and mortality over time.
Percentages of advanced-stage prostate cancer diagnosis were analyzed yearly from 1981 through 2005 for each county of Florida and three ethnic subgroups (white, black, Hispanic). All three ethnic groups experienced a 50% decline in the state-average proportion of late-stage diagnosis. This drop, which started in the early 1990s when PSA became widely available, was the most pronounced for Hispanics whose rates is now similar to white non-Hispanics; black non-Hispanics still have a 25% larger rate compared to the two other ethnic groups. Interestingly, the total number of diagnosed cases kept increasing for black and Hispanics, while it started declining slowly for white in the early 1990s. These temporal trends are however not uniform across Florida; cluster and boundary analysis revealed geographical disparities that were substantial for all ethnic groups before the mid 1990s. The gap among Florida counties is narrowing with time as the percentage of late-stage diagnosis is decreasing. One outlier is the Big Bend region of Florida where the decline in late-stage diagnosis has been the slowest in all Florida for both white and black males.
While this paper focused on the geographic distribution of race-based disparities in advanced-stage prostate cancer diagnosis in Florida, the approach can be easily generalized to other states and cancer sites, with clear applications in (a) monitoring and surveillance of cancer incidence and mortality, (b) the generation of hypotheses for in depth individual studies of risk factors that are causal, or impact survival; and (c) establishing the rationale for targeted cancer control interventions, including consideration of health services needs, and resource allocation for screening and diagnostic testing.
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 1818.
Abstract 1820: Patterns of hematopoietic cancers in Egypt from a population-based registry
Authors: Herzog Catherine M. , Soliman Amr S. , Eldein Ibrahim A. Seif , Hablas Ahmed , Ramadan Mohamed , Wilson Mark 
Published: February 2011

Abstract
Objectives: Rates of lymphoma are rising by 4% annually in the United States. Globally, lymphoma incidence rates are also on the rise with about 342,000 new cases per year. Egypt, where hematopoietic (blood and lymphatic) cancer is considered common, has one of the highest age-standardized incidence rates of lymphoma in the world (16.3/100,000), greater than that of the United States (15.3/100,000). Risk factors for hematopoietic cancers include radiation, viral and bacterial infections, occupational and environmental exposures, family history, and genetic mutations. We evaluated the incidence of these cancers in Egypt and analyzed them in relation to select risk factors to better understand their etiology.
Methods: Hematopoietic cancer case data for 1999-2005 from the Gharbiah Population-Based Cancer Registry in Tanta, Egypt, the only population-based registry in Egypt, were analyzed. Crude and age- and gender-specific rates were calculated for 4,260 cases, and evaluated by REAL Malignancy type, morphology, topology, and stage. Potential risk factor variables included age, gender, date of diagnosis, and district of residence, and urban/rural setting. Descriptive and multivariable statistics were calculated and space-time patterns were investigated.
Results: Overall, incidence was greater among males and among residents of urban areas. More than half of cases were diagnosed at Stage III or IV. Leukemia and Hodgkin lymphoma predominated in cases under 18 years of age whereas mature B-cell neoplasms were the most common in those older than 18. Average annual crude incidence varied by district, ranging from 10.21 to 20.34 per 100,000, and generally rose during the seven year period. This rise was most prominent in the crude incidence of mature B cell neoplasms, mostly due to diffuse B cell lymphoma.
Conclusions: This study provides numerical evidence of the impact of hematopoietic cancer, especially Non-Hodgkin lymphoma, on the Egyptian population. It also appears to follow the rising trend in Non-Hodgkin lymphoma cases seen worldwide. Further comparison of the distribution of incidence and alternative risk factors may lead to a novel understanding of the etiology of hematopoietic cancers and improvements in current treatment.
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 1820.