bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 348: Extracellular heat shock protein 90 (eHsp90) initiates EMT events and enhances cell motility in prostate cancer
Authors: Hance Michael W. , Gopal Udhayakumar , Bohonowych Jessica , Isaacs Jennifer S.
Published: August 2012

Prostate Cancer (PCa) is the most commonly diagnosed malignancy in men, responsible for the second highest lethality. Although early cancer detection and treatment is often curative, subsequent metastatic spread of tumor cells renders the disease incurable. Activation of the epithelial to mesenchymal transition (EMT) genetic program is considered a key event contributing to metastatic potential and subsequent lethality. Although targeting EMT may be a promising approach for improving treatment outcome, the main, potentially druggable, targets driving this pathway in PCa remain poorly defined. Multiple reports indicate that extracellular Hsp90 (eHsp90) promotes cell motility, invasion, and metastasis in a number of cancer cell types. Intriguingly, eHsp90 has been preferentially detected in the serum or plasma from aggressive cancers. Its presence in the serum of metastatic PCa patients implicates a potential causative role in PCa. Therefore, our objective was to investigate whether eHsp90 may influence EMT events, thereby influencing the metastatic potential of PCa. We now report that paired sets of differentially aggressive PCa tumor cell lines exhibited higher expression of eHsp90. Functionally, exposure of PCa cells to eHsp90 elicted a significant increase in cell motility. Inversely, blockade of eHsp90 attenuated the activation of several pro-motility effectors, concomitant with the significant suppression of cell migration. These events were associated with a profound alteration of cellular morphology towards a mesenchymal phenotype. Changes in cell phenotype were coupled with a loss and redistribution of the EMT suppressive gatekeeper protein E-cadherin. eHsp90 was also found to impact on the localization of other junctional proteins known to maintain a cuboidal epithelial phenotype. Finally, eHsp90 was found to transcriptionally upregulate several of the established transcriptional factors known to initiate EMT events. Confirmation of the EMT inducing ability of eHsp90 was determined by focused quantitative real time EMT PCR arrays. Our results therefore highlight a novel role for eHsp90 as a central regulator of EMT events in PCa. Our findings further support the premise that therapeutic targeting of eHsp90 may have the potential to suppress EMT activation and diminish the dissemination and metastatic propensity of PCa tumor cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 348. doi:1538-7445.AM2012-348
Abstract 3484: Distinct cancer cell with stem cell like properties contribute to doxorubicin and paclitaxel resistance
Authors: Sharma Bhawna , Varney Michelle L. , Singh Rakesh K.
Published: August 2012

Resistance to therapy and disease relapse is major concerns in the field of breast cancer management. Accumulating evidence suggests the existence of breast cancer stem cells and it has been proposed that their induction after chemotherapy could be contributing to therapy resistance and relapse. Our preliminary data demonstrate that expression of CXCL1 and CXCL8 (CXCR1/2 ligands) increases after chemotherapy. We also observed that expression of RANKL (ligand of RANK) goes up in a dose dependent manner in both Cl66 and 4T1 cells after treatment with paclitaxel and doxorubicin. Recently, the involvement of RANK/RANKL signaling in mammary tumorigenesis by maintaining the stem cell pool has been elucidated. Given that RANK-RANKL signaling and CXCR1/2 signaling share the common mediator, NFkB, our working hypothesis is that chemotherapy-induced expression of CXCR1/2 ligands and the RANK/RANKL signaling axis plays an important role in selecting a subset of mammary tumor cells with stem cell-like characteristics. We selected Cl66, mammary tumor cells against doxorubicin and paclitaxel. We observed that cells selected against these drugs express higher levels of CXCR1/2 ligands at both the mRNA and protein level. Moreover, 4T1 (6-thioguanine resistant cells) and Cl66 Dox 500 (cells resistant to doxorubicin) express RANK whereas Cl66-parent and Cl66 Pac 400 (cells resistant to paclitaxel) do not. This suggests that doxorubicin specifically selects RANK expressing cancer cells and 4T1 inherently express this receptor. Cl66 resistant cells injected in BALB/c mice grew slower than parent cells. Furthermore, the extent of neovascularization in doxorubicin resistant Cl66 tumors was significantly higher as compared to parent Cl66 tumors and paclitaxel resistant Cl66 tumors. As a result of their slow growth and difference in neovascularization, we analyzed the expression of stem cell markers in these cells. We observed that both Cl66-parent and paclitaxel resistant cells express ALDH1, but the expression was higher in paclitaxel resistant cells. Moreover, resistant cells showed enhanced expression of the mesenchymal marker, vimentin in comparison to parent cells. Overall, our results suggest that use of a particular chemotherapeutic agent may influence the selection of different sub-type of cancer cells with stem cell-like properties. This data also proposes the importance of a chemotherapy-induced cytokine-chemokine axis in maintaining the cancer stem cell pool.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3484. doi:1538-7445.AM2012-3484
Abstract 3490: Targeting E3 ligases in liver cancer stem cells with disruption of TGF-β signaling
Authors: Chen Jian , Zhixing Yao , Saha Tapas , Piao Hai-Long , Song Shumei , Jogunoori Wilma , Mishra Bibhuti , Mishra Lopa
Published: August 2012

Introduction: Hepatocellular Cancer (HCC) remains the 4th common cause of cancer deaths worldwide. Because it is often diagnosed at an advanced stage in a fragile cirrhotic patient, effective therapies whether they are chemotherapy or biologically based are disappointingly few, with a narrow therapeutic index. Recent studies support a key role for TGF-β signaling in suppressing these tumors. We have previously found that deletion of Smad3/4 adaptor β2SP results in a dramatic and spontaneous formation of liver (HCC) with exon 15 mutations in 11% of human HCC. β2SP+/− and β2SP+/−/Smad3+/− mice develop visceromegaly and multiple cancers (70% of mice), including HCC spontaneously presenting a strong model of the hereditary human cancer syndrome, Beckwith-Wiedemann (BWS) as well as the stages of human HCC. High levels of E3 ligases KEAP1 and PRAJA are observed in human HCCs and in tumors of these mutant mice. Our hypothesis is that disruption of the TGF-β tumor suppressor pathway (through β2SP, Smad3 and Smad4) leads to a proliferative potential in cells that then acquire secondary events such as activation of E3 ligases (KEAP 1, PRAJA and others), presenting these as potentially powerful new targets for HCC. Methods & Results: (1) β2SP+/− and β2SP+/−/Smad3+/− mice are ideal models for a human stem cell disorder (BWS) and HCC progression. (2) Inhibition of PRAJA in the developing Zebrafish embryo leads to high levels of apoptosis. (3) PRAJA is a key E3 Ligase that modulates β2SP and Smad3. (4) PRAJA levels markedly over- expressed in human HCC cell lines and tumor tissues and promotes HCC cell growth. (5) KEAP1 levels are raised in β2SP knockout tissues and human HCCs (6) Knocking-down KEAP1 inhibits HCC tumor cell growth. (7) Seven tumor suppressors are discovered to be potential targets of KEAP1 in HCC. (8) Triterpenoid derivates (Oleanolic Acid/RTA 402/RTA 405) inhibit KEAP1/Nrf2 pathway, as well as PRAJA and inhibit HCC tumor cell growth. Conclusions: Our studies demonstrate that E3 Ligases KEAP1 and PRAJA are dramatically raised in human and mouse hepatocellular cancers when TGF-β signaling is inactivated, inhibiting KEAP1 or PRAJA reduces HCC growth. Determining the synergistic therapeutic effects by targeting both KEAP1 and PRAJA will provide us important insights into development of new therapeutic targets for HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3490. doi:1538-7445.AM2012-3490
Abstract 3503: Enhanced delivery of T cells to tumor after chemotherapy using membrane-anchored, apoptosis-targeted peptide
Authors: He Xiaofeng , Lee Eun-Kyu , Kim In-San , Lee Byung-Heon
Published: August 2012

Chemotherapy-induced apoptosis of tumor cells enhances the antigen presentation and sensitizes tumor cells to T cell-mediated cytotoxicity. Here we harnessed the apoptosis of tumor cells as a homing signal for the delivery of T cells to tumor. Jurkat T cells were anchored with ApoPep-1, an apoptosis-targeted peptide ligand, using the biocompatible anchor for membrane (BAM), an oleyl acid derivative. The ApoPep-1-BAM conjugate was efficiently anchored to cell membrane, while little anchoring was obtained with ApoPep-1 alone. The retention period of the ApoPep-1-BAM conjugate on cells was approximately 40 and 20 minutes in the absence and presence of serum, respectively. The apoptosis-targeted T cells that were anchored with the ApoPep-1-BAM preferentially bound to apoptotic tumor cells over living cells. When intravenously injected into tumor-bearing mice, the number of the apoptosis-targeted T cells and in vivo fluorescence signals by the homing of the cells to doxorubicin-treated tumor were higher than those of untargeted T cells. These results suggest that the chemotherapy-induced apoptosis and subsequent enhancement of T cell delivery to tumor by the membrane anchoring of the apoptosis-targeted peptide could be a novel strategy for cancer immunotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3503. doi:1538-7445.AM2012-3503
Abstract 3523: Preclinical characterization of MT114, a novel CD33/CD3-bispecific BiTE antibody for the treatment of acute myeloid leukemia (AML)
Authors: Henn Anja , Friedrich Matthias , Kischel Roman , Lutterbuese Ralf , Schneider Katja , Mueller Peter , Baeuerle Patrick A. , Raum Tobias , Kufer Peter , Rattel Benno
Published: August 2012

There has been little improvement of standard of care for AML patients over the past 20 years, creating a large demand for therapies with improved benefit/risk profile and potential to cure. The CD19/CD3-bispecific, T cell-engaging (BiTE) antibody blinatumomab has shown high response rates and durable remissions in patients with acute lymphocytic leukemia and non-Hodgkin lymphoma. In order to employ this novel therapeutic modality for the treatment of patients with CD19-negative AML, we have constructed a panel of CD33/CD3-bispecific BiTE antibodies and selected MT114 as lead candidate for pre-clinical development for its superior pharmacological and pharmaceutical properties. Its target antigen CD33 (SIGLEC-3) is frequently expressed on AML blasts and leukemic stem cells, and extensive clinical experience has been gained by the CD33-targeting antibodies Mylotarg®, lintuzumab and AVE9633. Here, we report on the biological activities of MT114. MT114 recognized epitopes in the V domain of CD33 and of CD3 epsilon that are conserved between human and macaque antigen, allowing pharmacological and nonclinical safety investigations of the BiTE antibody in macaques as a relevant primate species. MT114-induced redirected lysis of 10 human AML cell lines by unstimulated peripheral blood mononuclear cell (PBMC) at half-maximal concentrations of MT114 between 23 and 328 pg/ml (0.4-7 pM). The 10 AML lines expressed CD33 at 20,000-50,000 molecules/cell. Redirected lysis was specific for CD33-expressing cells, reached completion after 28-h of co-culture, and was effective even at PBMC-to-target ratios of α1:2. MT114 induced the expression of activation markers CD69 and CD25 on T cells and the transient release of IFN-γ, TNF-α and IL-2, -6 and -10 by T cells, but only in the presence of CD33+ target cells. Redirected lysis and T cell activation by MT114 was not affected by up to 100 ng/ml of shed CD33, serum levels of which were found to be associated with AML progression. Neoexpression of CD33 on BiTE-activated T cells did not exceed 8% of total activated T cells when tested with 10 human T cell donors. The BiTE antibody significantly delayed growth of the subcutaneously injected human AML cell line HL60, and induced a robust infiltration of T cells into tumor tissue. MT114 is a highly active novel BiTE antibody with promise for the treatment of AML.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3523. doi:1538-7445.AM2012-3523
Abstract 3525: IMCgp100: A novel bi-specific biologic for the treatment of malignant melanoma
Authors: Hassan Namir J. , Adams Katherine , Bossi Giovanna , Harper Jane , Buisson Sandrine , Paston Samantha , Liddy Nathaniel , Ashfield Rebecca , Gavarret Jessie , Bianchi Frayne , Baston Emma , Baker Debbie , Ladell Kristin , Sewell Andrew , Li Yi , Cameron Brian , Johnson Andrew , Vuidepot Annelise , Todorov Penio , Kalos Michael , June Carl , Karakousis Giorgos , Linette Gerry , Price David A. , Williams Daniel , McGrath Yvonne , Jakobsen Bent K.
Published: August 2012

In recent years significant advances in the treatment of metastatic melanoma have emerged. Small molecule drugs provide potent short-term responses for a significant proportion of the patient population; for a minority of patients, immunotherapy has elicited long-term responses with the promise of a cure. Despite these advances, long-term remission for the majority of patients remains elusive and much effort is focussed on combination therapies attempting to bring together the potency of small molecule drugs with the durability of immunotherapy. IMCgp100 is a novel bi-specific immunotherapy comprising a soluble, affinity- enhanced, T cell receptor (TCR) specific for the melanoma-associated antigen gp100, fused to an anti-CD3 specific antibody fragment (scfv). The engineered TCR portion of the drug targets the gp100 peptide 280-288 antigen, which is over- expressed and presented by HLA-A2 on the surface of melanoma cells, thereby effectively coating these cells with CD3-specific antibody fragments. The anti-CD3 scfv portion captures and redirects any T cells in physical contact with the melanoma cell to kill it. In vitro, IMCgp100 potently redirects T cells from the blood of late stage cancer patients to target melanoma cells exhibiting substantial HLA-down regulation, even in the presence of high numbers of regulatory T cells. Target cell killing is observed within hours, and is associated with the release of pro-inflammatory cytokines and dendritic cell cross-presentation of gp100 and other melanoma-specific antigens. Thus, IMCgp100 demonstrates the potential to elicit potent short-term responses and trigger longer-term anti melanoma durability in vivo (ref: paper to be published imminently in Nature Medicine). IMCgp100 is currently under investigation as part of a Phase 1 dose-finding study in patients with unresectable Stage III/Stage IV malignant melanoma. Safety, tolerability, pharmacokinetic, pharmacodynamic, and clinical activity are assessed after intravenous infusion of IMCgp100, and the maximum tolerated dose (MTD) will be established. We also have a Phase 0 trial open, in which IMCgp100 is injected directly into tumours to assess pharmacodynamic activity in human lesions. Both studies are actively enrolling and preliminary clinical data will be presented.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3525. doi:1538-7445.AM2012-3525
Abstract 3526: Subcutaneous administration of PSMA/CD3-bispecific BiTE antibody MT112/BAY 2010112 leads to complete remission of human prostate cancer xenografts in mice
Authors: Friedrich Matthias , Deegen Petra , Voelkel Markus , Wahl Joachim , Schuhmacher Joachim , Steinke Wolfram , Zopf Dieter , Harris Robert B. , Baeuerle Patrick A. , Kufer Peter , Rattel Benno
Published: August 2012

Blinatumomab, a CD19/CD3-bispecific BiTE antibody has shown high response rates and durable remissions in patients with relapsed or refractory acute lymphocytic leukemia and non-Hodgkin's lymphoma. For treatment of patients with prostate cancer (PCa), we have developed a novel BiTE antibody, MT112/BAY2010112, that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. MT112/BAY 2010112 binds PSMA and CD3 of human and macaque origin allowing for assessment of safety, pharmacodynamics and pharmacokinetics in a relevant animal species. PSMA expressing human PCa cell lines VCaP, 22Rv1, MDA PCa 2b, C4-2, PC3-PSMA and LNCaP were lysed by freshly isolated, unstimulated human T cells redirected by MT112/BAY2010112 at EC50 values ranging between 0.1 and 4 ng/ml (1.8-72 pM). Efficacy of lysis correlated with levels of surface expressed PSMA. No lysis was observed in PSMA-negative PCa cell lines PC3 and DU145, showing the target antigen-specific activity of MT112/BAY2010112. The relevance of cynomolgus monkeys for further nonclinical safety evaluation of MT112/BAY 2010112 was demonstrated by in vitro side-by-side comparison of the BiTE antibody's pharmacological characteristics in human and cynomolgus monkey assay systems. For studying the activity of MT112/BAY 2010112 after subcutaneous (s.c.) administration, human 22Rv1 PCa xenografts were grown s.c. in mice to sizes of >200 mm3 in the absence of human T cells. Three days prior to treatment with BiTE, ex-vivo expanded human T cells were intraperitoneally injected. Animals were treated s.c. at 2.5 mg/kg/d or intravenously (i.v.) at 0.5 mg/kg/d for 28 consecutive days. S.c. administration of MT112/BAY 2010112 resulted in a similar drug exposure, rapid shrinkage and complete remission of established PCa xenografts as seen upon i.v. administration of the BiTE antibody. Treatment with human T cells or vehicle alone had no effect on tumor growth. Compared to i.v. administration, the relative bioavailability of the PSMA BiTE in serum after s.c. injection in mice was approximately 18%. Initial results will be presented showing that 14C-labeled MT112/BAY 2010112 accumulates in s.c. implanted LNCaP PCa tumors of mice after tail vein injection. Based on these preclinical in vivo pharmacology results, treatment of PCa patients with s.c. administered MT112/BAY2010112 appears to be justified.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3526. doi:1538-7445.AM2012-3526
Abstract 353: In vivo PET imaging of HER2 expression with GE226: An 18F-labelled affibody molecule
Authors: Hoppmann Susan , Danikas Antonios , Durrant Clare , Iveson Peter , Glaser Matthias , Indrevoll Bård , Hiscock Duncan
Published: August 2012

Background: The assessment of HER2 expression in biopsies from primary lesions of breast cancer patients is a standard procedure to select patients for HER2-targeted therapies. However, in metastatic disease in which HER2 status can change, determination of HER2 expression is not standard procedure, which complicates patient management. Herein we report evidence for GE226 ([18F]FBA-ZHER2:2891), a highly specific HER2 targeted imaging agent that can determine HER2 expression levels in preclinical tumour models. We propose that GE226 can be progressed to clinical development for non-invasive determination of the HER2 status in recurrent breast cancer patients to improve the clinical management and therapy selection. Methods: The highly selective HER2 targeted 18F-labelled Affibody molecule GE226 was characterized in a murine dual tumour breast cancer model bearing NCI-N87 (high HER2 status) and A431 (low HER2 status) xenografts in separate flanks. Tumour-bearing mice were injected with 3 to 10 MBq of GE226, followed by biodistribution or positron emission tomography (PET) imaging analysis. Results: Biodistribution analysis demonstrated good differentiation of GE226 retention between high and low HER2 expressing tumours (8.4% ID/g and 3.4% ID/g respectively, 30 min post injection). GE226 cleared quickly from background tissue, including kidneys, with excellent ratios for tumour-to-muscle (8.9 for high HER2 status tumours and 3.6 for low HER2 status tumours, 30 min post injection) and tumour-to-blood (2.5 for high HER2 status tumours and 1.0 for low HER2 status tumours, 30 min post injection). PET imaging of GE226 in the dual tumour mouse model showed a marked difference in signal intensity between the two tumour types. Conclusions: The highly selective HER2 targeted Affibody molecule GE226 can image different levels of HER2 expression in a dual-tumour preclinical model of breast cancer with good target-to-background ratios. These data compare favourably with previous patient SPECT and PET studies using the 111In- or 68Ga-labelled HER2-binding Affibody molecule ABY-002 (Baum et al., J Nucl Med. 2010;51(6):892-7) which supports the efficacy of this class of Affibody tracer for visualization of HER2 expressing metastases. We plan to progress GE226 further to assess HER2 status in metastatic breast cancer patients in clinical PET studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 353. doi:1538-7445.AM2012-353
Abstract 3564: A Phase II randomized trial of lycopene-rich tomato extract among men with high-grade prostatic intraepithelial neoplasia (HGPIN)
Authors: Gann Peter H. , Deaton Ryan , Enk Erika , van Breemen Richard B. , Han Misop , Lu Yi , Ananthanarayanan Viju
Published: August 2012

Evidence from observational epidemiology, animal models and cell culture experiments suggest that tomato foods or other sources of lycopene might inhibit the development of prostate cancer. Clinical trial data, however, is thus far sparse, especially in relation to effects on benign prostate tissue. We conducted a 6-month repeat biopsy trial in men with HGPIN who were randomly assigned to consume either placebo or capsules of Lyco-Mato®, a tomato oleoresin containing 30 mg/day of lycopene. All participants were encouraged to avoid lycopene containing foods and supplements while on-study. Here we report results for serum lycopene, PSA and IGF proteins, and initial results for immunohistochemical analysis of markers for proliferation (minichromosome maintenance protein 2, MCM-2) and cell cycle inhibition (p27). Biopsy slides were stained using monoclonal antibodies for both markers and scoring was performed using an Aperio whole-slide digital microscope and scoring algorithms plus Genie® pattern recognition software for defining the epithelial compartment. Serum lycopene was determined by LC-MS-MS; PSA, IGF-1 and IGFBP3 were measured by enzyme immunoassay. Primary analyses compared treatment groups using a paired t test for the change in each endpoint. A total of 58 men completed the trial (26 active, 32 placebo); assignment groups were equivalent at baseline in terms of age, race, serum lycopene, PSA, IGF-1 and IGFBP3. Serum lycopene increased by 0.550 μmol/L (77%) in the active treatment group and declined by 0.288 μmol/L (19%) in the placebo group. We observed no meaningful differences in serum PSA, IGF-1 or IGFBP3 concentrations between groups. There were also no differences between groups in the percentages of epithelial nuclei expressing MCM-2 or the scoring index combining percentage with nuclear stain intensity. Similar null results were seen for staining with the CDK2 inhibitor p27. We conclude that despite a large difference in serum lycopene concentrations following intervention, no effects were apparent at 6 months on PSA or IGF proteins. The IHC results, although preliminary, suggest that treatment had no effect on epithelial cell proliferation or cell cycle inhibition via p27. Further analyses, including analysis of additional IHC markers, are currently underway.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3564. doi:1538-7445.AM2012-3564
Abstract 3570: Cervical cancer screening practices among Hispanic migrant and seasonal farmworkers of Michigan
Authors: Knoff Jayne S. , Soliman Amr S. , Harlow Sioban D. , Yassine May , Barnhardt Kelly
Published: August 2012

Cervical cancer incidence among all racial/ethnic groups in the United States is highest among Hispanics. Previous studies have found that migrant and seasonal farmworkers have limited access to health care and may therefore be less likely to follow screening recommendations for early cervical cancer detection. The objective of this study was to describe Pap test utilization and identify barriers, attitudes and knowledge regarding cervical cancer screening among Hispanic migrant and seasonal farmworkers served by Northwest Michigan Health Services, Inc (NMHSI) in Shelby and Traverse City, Michigan. This cross-sectional study surveyed the patient population of NMHSI. A questionnaire addressing knowledge, attitude and practice of cervical cancer screening was administered to 309 participants in NMHSI clinics or in participants’ residences. The Hispanic study population included 184 seasonal and 125 migrant farmworkers. Of all Hispanics surveyed (mean age 38.7), 94.2% had ever received a Pap test. Comparatively, 87.7% had received a Pap test recently (in the last two years for 21-29 year olds, in the last three years for those over 30) and 14.5% had an abnormal Pap test result in the last ten years. There was no significant difference between migrant and seasonal farmworkers in terms of ever having had a Pap test or having had a recent Pap test (p-value 0.88 for both comparisons). Consistent with these findings, participants reported that they understood the benefits of and experienced few barriers to getting Pap tests. These findings suggest that migrant farmworkers may not experience more difficulty in receiving Pap tests than seasonal farmworkers in Michigan. Farmworkers in general recognize the importance of receiving Pap tests even though both groups of women have low levels of acculturation. Furthermore, findings suggest that recent efforts to increase cervical cancer screening have been effective. While cervical cancer screening rates are high, knowledge is low and this continuing research will aid in identifying specific gaps in cervical cancer screening knowledge and attitudes to address in future interventions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3570. doi:1538-7445.AM2012-3570
Abstract 3575: The effects of selection bias by lung cancer screening
Authors: Aerts Joachim
Published: August 2012

Background: Lung cancer is the most common cause of cancer mortality worldwide. The five-year survival rate of lung cancer is still extremely poor: only 16%. This is mainly due to the fact that most patients present with an advanced stage of the disease. Recent studies showed that screening of high risk persons is very effective in reducing the mortality from lung cancer. However, the inclusion criteria for these studies are rather strict. For instance the study by The National Lung Screening Trial Research Team Persons only included people with more than 30 pack-years (PY) and aged between 55 and 74 years at time. Aim: To evaluate the effects of selection bias in lung cancer screenings studies as the The National Lung Screening Trial. Methods: The inclusion criteria of The National Lung Screening Trial were extrapolated to our population based cohort: The Rotterdam Study. The Rotterdam Study is an ongoing prospective cohort study in Rotterdam, the Netherlands, in which all inhabitants of the Rotterdam suburb Ommoord aged ≤ 55 years were invited to participate in the study. A total of 7,983 participants (78%) were included between 1990-1993 in the first cohort. Up to 2009, 208 deaths due to incident lung cancer were found in this cohort. Results: In our cohort, only 62 cases (29.8%) complied with the criteria of the screening trial (persons with unknown smoking history were included in the >30 PY group). 12.5% of the lung cancer cases between 55-74 years of age were never smokers or had a history of <30 PY at baseline and the remaining 57.7% were above 74 years. Consequently, 70.2% of cases would not have been included. A relative reduction in mortality of 20%, as found in the screening trial, would lead to a reduction in mortality in the Rotterdam Study population of lung cancer of 6.0% (i.e. 0.2*62 = 12.4 persons out of the 208 would have been saved from mortality by lung cancer). Conclusion: Screening of lung cancer with the present inclusion criteria reduces lung cancer death rate compared to standard of care, but because only a minority of lung cancer patients comply with these criteria, we should be cautious in generalizing findings to the total population of such patients. In addition, mortality reduction may be different in countries with other demographics and health care systems.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3575. doi:1538-7445.AM2012-3575
Abstract 3579: Prognostic and predictive role of JWA and XRCC1 expression in gastric cancer
Authors: Zhou Jianwei , Wang Shouyu
Published: August 2012

Purpose: Polymorphisms in the DNA repair genes JWA and XRCC1 have recently been reported to increase susceptibility for gastric cancer, but the expression pattern and significance of these genes in gastric cancer is unknown. Experimental Design: Expression of JWA and XRCC1 were assessed by immunohistochemistry in three independent tissue microarray sets of gastric carcinoma (total n=1227), and paired adjacent non-tumoral tissues (n=80) with minimum five years follow-up time. Prognostic value of JWA and XRCC1 and of clinicopathologic factors, were evaluated in patients treated only with surgery. The predictive role of JWA and XRCC1 expression status in cases treated with adjuvant chemotherapy compared with surgery alone was analyzed. Results: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent non-cancerous tissues (P < 0.001 for all correlations). Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expression, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01), however, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI = 0.26-0.73; P = 0.002, and HR = 0.44; 95% CI = 0.26-0.75; P = 0.002, respectively). Conclusions: JWA and XRCC1 protein expression in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant FLO chemotherapy in resectable human gastric carcinoma. Acknowledgements: This study was supported in part by the project funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, the National Natural Science Foundation of China (30930080, 81001231), the Foundation of Cancer Center of Nanjing Medical University (08ZLKF08), and the Postdoctoral Science Foundation of China (20100481165).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3579. doi:1538-7445.AM2012-3579
Abstract 3581: Long-term results of organ sparing surgical treatments of precancerous cervical lesions in Mongolia
Authors: Damdin Avirmed , Jazag Amarsanaa
Published: August 2012

Background: Cervical cancer is the most common cancer in female reproductive system. Since introduction of diagnostic modalities like Pap-tests, the detection pre-cancerous cervical lesions CIN1, CIN2 and CIN3 have increased dramatically. Early detection of pre-cancerous lesions enables performance of organ sparing treatments like LEEP, conization and cryotherapy. Aim: Since there are no studies in the field of organ sparing treatment of cervical cancer, we decided analyze the results of such treatments and calculate the: 1. Five year survival of patients underwent organ sparing surgical procedures 2. Fertility and reproductive function of these patients Method: LEEP (n-63), knife conization (n-22) and trachelectomy (total removal of cervix) (n-15) was performed in women of reproductive age (25-35 years old) at National Cancer Center. The treatment results were followed for 5 years and statistical analysis of survival and reproductive function were analyzed. Results: 87.7% of patients with CINI lesions had LEEP, 12.3 % had knife conization and 0% had trachelectomy. 44.4% of patients with CINI lesions had LEEP, 55.6 % had knife conization and 0% had trachelectomies respectively. For CINIII 6.2% of patients had LEEP, 0% had knife conization and 93% had trachelectomy. We performed organ sparing treatment in 100 patients, out of which 10% had cancer recurrence in LEEP treatment, 9.1% in knife conization and 0% in trachelectomy. Complications of hemorrhage were observed in 14% of patients, cervical tube obstruction in 3% and deterioration of chronic inflammations in 13% respectively. After the organ sparing treatment, menstrual cycle was normal in 75% of the all patients, 65% reached pregnancy. 9.2% of patients who reached pregnancy had stillbirth, 12.3% had abortion, and 78.5% had normal delivery. 80.4% of patients with pregnancy had natural labors, while19.6% of patients had caesarean sections respectively. Conclusion: in Mongolia, LEEP, knife conization and trachelectomy methods are used since 2000. But the treatment results were not reported so far. 10% of patients treated by LEEP and 9.1% of patients treated by knife conization had tumor recurrence. Thus our treatment efficiency is above 90%. Up to 20% of patients had complications ranging from bleeding to cervical tube obstruction. We conclude that organ sparing cancer treatment allows better QOL (quality of life) for the patients and provides opportunity to have children.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3581. doi:1538-7445.AM2012-3581
Abstract 3590: Use of four biomarkers to evaluate survival disparity between black women and white women 35 to 64 years of age at diagnosis with invasive breast cancer
Authors: Ma Huiyan , Lu Yani , Malone Kathleen E. , Strom Brian L. , Simon Michael S. , Deapen Dennis M. , Sullivan-Halley Jane , Press Michael F. , Bernstein Leslie
Published: August 2012

Purpose: To evaluate the extent to which the black-white disparity in mortality following breast cancer diagnosis is explained by the expression status of four biomarkers - estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and p53 protein. Methods: The four biomarkers were assessed in paraffin-embedded breast tumor tissue for 1204 (523 black, 681 white) women, ages 35-64 years at diagnosis, who participated in the Women's CARE Study, a population-based case-control study of newly incident breast cancer, and who accrued a median of 10 years follow-up. The impact of these biomarkers on black-white disparity in breast cancer-specific and all-cause mortality was determined by fitting multivariable Cox proportional hazards regression models. Results: The black-white disparity in breast cancer-specific mortality was 54% in an age- and study site-adjusted model (relative risk [RR], 1.54; 95% confidence interval [CI], 1.21 to 1.97); it declined to a 36% greater risk for black women than white women after additionally controlling the status of the four markers (RR, 1.36; 95% CI, 1.06 to 1.75). Similar results were observed for all cause-mortality. Separate analyses for triple negative (ER-/PR-/HER2-) and luminal A (ER+ and/or PR+ plus HER2-) tumors showed that the black-white differences in mortality were predominately observed for older (50-64 years) women with luminal A tumors (breast cancer-specific RR, 2.07; 95% CI, 1.16 to 3.70; all-cause RR, 2.21; 95% CI, 1.40 to 3.47). For luminal A tumors, the greater mortality risk for older black women was attenuated after adjustment for stage, comorbidities, and education, and was most evident for all-cause mortality. Conclusions: Black-white differences in mortality following breast cancer diagnosis vary by tumor biomarker subtypes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3590. doi:1538-7445.AM2012-3590
Abstract 3600: Comparison of estrogen receptor expression in breast cancer cells by immunohistochemistry using the monoclonal antibodies SP1 and 1D5
Authors: Madeira Klesia P. , Daltoe Renata , Sirtoli Gabriela , Rezende Lucas , Silva Ian , Carvalho Alex , Rangel Leticia
Published: August 2012

Background: Accurate pathological analysis of biopsies is crucial for conclusive and precise disease diagnosis, prognosis and therapeutic guidelines. Evaluation of estrogen receptor (ER) expression in breast cancer (BC) is imperative in determining the disease prognosis, and patients' eligibility for hormonotherapy. Herein, ERα status was evaluated in 61 BC cases using two different anti-ERα monoclonal antibodies, Sp1 (rabbit) and 1D5 (mouse). Methods: Primary BC cases registered in two reference hospitals, with correspondent written informed consent, were used to generate in house tissue microarray platforms. ERα expression was accessed by immunohistochemistry using the monoclonal antibodies anti-ERα, SP1 and 1D5. Staining scoring followed the Allred method (PS, proportion score or percentage of stained cells; IS, intensity score). Concordance and correlation parameters were calculated using Kappa factor; Pearson, Spearman's, or intraclass correlation coefficient (CF). Staining patterns were compared by paired T-Test and Wilcoxon test. Findings: SP1 and 1D5 provided equivalent results (Concordance rate, 96.7%; Kappa factor, 0.921), whereas SP1 was more prone for positive results than 1D5 (2 samples diverged). Total concordance of PS was obtained (Pearson and intraclass CF, 0.7351 and 0.6193, respectively); however, concordance between the antibodies seems more accurate in higher PS values. Excellent SI correlation between antibodies was observed throughout the population (Spearman's CF, α=0.9150). Following the Allred score, 17 out of 42 positive BC samples diverged; always pointing 1D5 to weaker staining than SP1. When calculating Spearman's CF of Total Score (TS) within the population, excellent correlation between both the antibodies (α=0.9238) was noted; nonetheless, results were less concordant result among the BC positive cases (α=0.7743). Indeed, 20 samples were differentially classified using the antibodies (only 3 had higher TS with 1D5). Considering the mean TS of all samples, or of invasive ductal carcinoma, SP1 provided higher scores than 1D5 (p<0.05). Interpretation: Despite the equivalence between the anti-ERα monoclonal antibodies, SP1 and 1D5, the former has proven superior to the latter with respect to the IS and TS. Therefore, we suggest the clinical use of SP1 while diagnosing BC, due to its higher accuracy in examining ER status; thus, enabling more accurate therapeutic decisions to treat the disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3600. doi:1538-7445.AM2012-3600
Abstract 361: PET imaging of antitumor responses with anti-4-1BB (anti-CD137)
Authors: Escuin-Ordinas Helena , Atefi Mohammad , Ng Charles , Sharp Leslie , Ribas Antoni
Published: August 2012

Agonistic antibodies to 4-1BB (CD137), a member of the tumor necrosis factor family expressed on activated T cells, are being tested for immunotherapy in patients with advanced cancers. Being able to study the mechanism of 4-1BB action in vivo using non-invasive approaches would help guiding its clinical development. We used positron emitting tomography (PET) with [18F]FDG to study how 4-1BB mAb modulates the immune system in a mouse model for cancer treatment. The administration of 1mg/kg of the 4-1BB mAb to Balb/c mice induced reproducible CT26 tumor regressions and improved survival (n=8 mice per group, p = 0.006 for survival by log rank test). The mean tumor size (mm) was also strikingly different (5.8 ± 0.20 4-1BB mAb group vs 8.3 ± 0.19 control, on day 7 after 4-1BB mAb; p < 0.0009). All mice responded to the treatment and complete tumor shrinkage was achieved in 75% of cases, 14 days after 4-1BB mAb administration. Using microPET imaging there was markedly increased mean signal (% ID/g) of [18F]FDG at the tumor site and draining lymph nodes (18.4 ± 1.6 4-1BB mAb group vs. 10.3 ± 0.418 control group). Due to the shrinkage of the tumor in the treated group, we hypothesized this higher PET signal is the result of higher activity of immune cells in the site. In a metabolic probe in vitro uptake assay, there was a 7-fold increase in uptake of [3H]DDG in lymphocytes extracted from tumor-draining lymph nodes and a 2-fold increase in tumor infiltrating lymphocytes (TILS) of mice treated with 4-1BB mAb compared to untreated mice, supporting the in vivo PET data. In conclusion, increased uptake of [18F]FDG by PET scans visualizes 4-1BB mAB-induced anti-tumor immune responses and can be used as a pharmacodynamic readout to guide the development of this class of antibodies in the clinic.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 361. doi:1538-7445.AM2012-361
Abstract 3610: GW182 associates with circulating microvesicles and microRNA in human plasma
Authors: Brown Kirk , Millis Meredith , Smith Shannon E. , Yeatts Kim , Zhong Jason , Stark Adam , Kojima Yuka , Garcia Julie , Spetzler David B.
Published: August 2012

To date, microRNAs (miR) in human plasma have been discovered within circulating microvesicles (cMV), bound to Argonaute 2 and associated with HDL and LDL microvesicles. The protein GW182 shares an association with both multivesicular bodies and the Argonaute family of proteins. GW182 has the capacity to bind all human Argonaute proteins (1-4) and their associated miRs. In the cell, GW182 is associated with the membrane of multivesicular bodies and has the ability to congregate Argonaute-loaded RISC complexes. In addition, GW182 has been observed on the surface of purified exosomes. Here we investigated the relationship of GW182 with Argonaute and cMV in human plasma. A monoclonal antibody directed toward GW182 was used to capture the protein. This isolate also contained Argonaute proteins as determined by Western analysis. The co-precipitation of GW182 and Argonaute suggests that these two proteins retain their functional relationship in plasma. RNA was then isolated from precipitates for miR detection and analysis. The GW182-associated miR profile from human plasma contained individual miRs whose abundance either equaled or surpassed that of their matched Argonaute 2 immuno-precipitated miRs. This implies that GW182 maintains an association with the family of Argonaute proteins and a subset of cMV in human plasma. Phenotypic analysis of GW182-associated human plasma microparticles was performed using flow cytometry with a Beckman Coulter MoFlo XDP. A subpopulation of plasma-derived cMV was observed that co-expressed tetraspanins, GW182 and Argonaute 2. Since tetraspanins are transmembrane proteins highly associated with cMV, these results suggest that both GW182 and Argonaute can associate with cMV in human plasma. Thus, precipitation of GW182 enables the isolation and purification of miRs from human plasma including those bound to Argonaute 1-4 and a subset of cMV.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3610. doi:1538-7445.AM2012-3610
Abstract 3613: Methylated PLK2 predicts response to taxanes
Authors: Coley Helen M. , Chivers Pritlata , Syed Nelofer , Crook Tim
Published: August 2012

Polo-like-kinases (Plk) are a family of mitotic kinases with close structural similarity but showing functional diversity. Plk2 was originally described as an early response gene as is sometimes referred to as Snk. It has been shown to be a transcriptional target of p53 and activates a G2M checkpoint. Following a screening of a number of taxane resistant ovarian cancer cell lines we saw a close association with down-regulation of PLK2 and the extent of taxane resistance. Methylation analysis including methylation specific PCR (MSP) and pyrosequencing showed heavy methylation of CpG islands in the promoter region. We also saw that when sensitivity to paclitaxel is restored by a process of resistance reversal by growing cells in a drug free environment and this corresponded with upregulation of PLK2. We have also then gone on to look at a range of taxane-resistant breast cancer cell lines and have in many cases seen an association of PLK2 down-regulation with the acquisition of resistance. Translational studies using clinical biopsies and matched serum samples from a total of 43 ovarian cancer patients have indicated that the presence of methylated PLK2 in ovarian cancer tissue at first presentation may predict future relapse on platinum and taxane combination therapy. We also saw an association of presence of methylated PLK2 in either serum or tumour tissue with reduced survival. At present we are examining a series of samples from 40 breast cancer patients in the neo-adjuvant setting treated with taxane containing regimens to look for the association of PLK2 methylation with clinical outcome. We propose that methylated PLK2 is a useful marker of chemoresponse in ovarian and breast cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3613. doi:1538-7445.AM2012-3613