bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-491: PD-1 expression level on T cell subsets is a crucial factor forming a novel mechanism for designing immune therapeutic approaches using PD-1 binding ligand
Authors: Mkrtichyan Mikayel , Najjar Yana G. , Raulfs Estella C. , Liu Linda , Langerman Solomon , Khleif Samir N.
Published: August 2012

A significant barrier to tumor regression in the setting of a successful immune response is tumor-mediated immunosuppression. Programmed death receptor-1 (PD-1) is an important signaling molecule and in the context of the tumor microenvironment may inhibit T cell immunity when bound to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), by inducing T cell apoptosis and anergy. Recently we demonstrated that combination of anti-PD-1 antibody with vaccine and low-dose of cyclophosphamide (CPM), that reduces the number and function of Treg cells, significantly enhances antigen-specific immune responses, decreases tumor burden and increases survival of treated mice, suggesting that targeting multiple immune checkpoint inhibitors is a promising strategy for tumor immunotherapy. Here we tested the anti-tumor immune effect of B7-DC-Ig, a recombinant protein that binds and target PD-1. It is composed of the extracellular domain of B7-DC, fused to the Fc portion of murine IgG2a. We demonstrated that B7-DC-Ig can enhance the therapeutic efficacy of a peptide based cancer vaccine when combined with CPM. We showed that this combination significantly enhances antigen-specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. Importantly, we found that unlike anti-PD-1 antibody, B7-DC-Ig does not block the suppressive PD-1/PD-L1 interaction as its primary mechanism, and identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect. We demonstrate, for the first time, that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play a critical role in the anti-tumor effects exhibited by B7-DC-Ig through inhibiting proliferation of dysfunctional PD-1high CD4 T cells, for both Treg and FoxP3−T cells, leading to a significant decrease in levels of tumor infiltration by dysfunctional T cells. In addition, we showed that treatment with B7-DC-Ig also leads to a decrease in PD-1highCD8 T cells, tipping the balance towards non-exhausted, functional PD-1lowCD8 T cells. Aside from presenting a promising anti-tumor immunotherapeutic approach, we demonstrated that the level of PD-1 expression on different T cells subsets determines the “effective target zone” of B7-DC-Ig. We believe that this represents an important parameter that needs to be considered to favorably alter the tumor microenvironment when designing PD-1 targeting immune therapies.

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 LB-491. doi:1538-7445.AM2012-LB-491
Abstract LB-492: CD44 binding peptide attached to an engineered matrix prevents the formation of CSC tumorspheres
Authors: Yang Xiaoming , He Xuezhong , Jabbari Esmaiel
Published: August 2012

Objective: Cancer recurrence is related to the existence of cancer stem cells (CSCs) in the tumor tissue that are highly resistant to conventional therapies. Self-renewal and differentiation of CSCs are regulated by tumor microenvironment. Naturally derived matrices have been used for immobilization of cancer stem cells but, due to their many ligand-receptor interactions, those matrices cannot isolate the effect of individual factors in the microenvironment on CSCs. We hypothesized that an inert biodegradable hydrogel, conjugated with bioactive peptides, that allow precise control of mechanical, physiochemical, and biological properties are ideal for investigating the effect of microenvironmental on maintenance of CSCs. The objective of this work was to investigate the effect of CD44 binding peptide RLVSYNGIIFFLK conjugated to an engineered inert but permissive gel (SPELA gel) on viability and maintenance of 4T1 CSCs. Methodology: 4T1 cancer cells were cultured in RPMI 1640 medium supplemented with 10% FBS, 100 U/ml PEN and 100 μg/ml STREP. After 70% confluence, 4T1 tumor cells were suspended in DMEM-F12 medium supplemented with 0.4% BSA, 5 μg/ml insulin, 40 ng/ml bFGF, 20 ng/ml EGF, 5% horse serum (CSC medium). Next, 4T1 cells were seeded in ultra-low attachment plates at a density of 100K cells/mL. After 7-10 days, the cultures were analyzed for tumorsphere formation. The acrylamide-terminated CD44-binding peptide RLVSYNGIIFFLK was synthesized in the solid phase by Fmoc chemistry. 4T1 cell-laden SPELA gels were produced by photopolymerization and cultured in CSCS medium. At each time point, samples were analyzed by fluorescent microscopy and mRNA analysis for the formation of CSCs. Data and Results: The 4T1 CSCs were characterized by inoculation in the back of Balb/c mice. 500 CSCs inoculated in mice formed larger tumors in mice than 50,000 tumor cells after 14 days. When tumor cells were encapsulated in the inert SPELA gel matrix, tumorspheres began to form and continued to grow in size with incubation, but tumorsphere formation strongly depended on the gel modulus. For example, tumorsphere size in gels with moduli in the 5-10 kPa range increased from 25 to 100, and 225 after 2, 6, and 10 days of incubation. Interestingly, the covalent attachment of CD44 ligand to the inert gel prevented the formation of tumorspheres and maintenance of CSCs. Inert engineered matrices are very powerful tools for understanding the effect of tumor microenvironment on maintenance of CSCs and tumorsphere formation.

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 LB-492. doi:1538-7445.AM2012-LB-492
Abstract LB-497: Primary tumor localization determines the metastatic immune profile
Authors: Remark Romain , Crozet Lucile , Lupo Audrey , Alifano Marco , Riquet Marc , Cremer Isabelle , Dieu-Nosjean Marie-Caroline , Goc Jeremy , Mlecnik Bernhard , Cazes Aurelie , Fléjou Jean-François , Gibault Laure , Verkarre Virginie , Oudard Stéphane , Pagès Olivier , Régnard Jean-François , Sautès-Fridman Catherine , Fridman Wolf-Herman , Damotte Diane
Published: August 2012

Primary tumor localization determines the metastatic immune profile Background Most cancer patients die from their metastatic disease and not from their primary tumor. However, little is known on the immune microenvironment of metastatic lesions and on its impact on clinical outcome. Indeed, the immune pattern of the tumor microenvironment has been recently identified as being a major prognostic factor in primary tumors. Thus, a high density of memory T cells with a Th1 and CD8 cytotoxic orientation is beneficial in many cancers. However, there are a few exceptions since CD8+ T cells have been reported to be associated with bad prognosis in renal cell carcinoma. The question of the respective roles of the tumor cell and organ microenvironment to explain these differences has not been addressed. Methods We studied the density and organization of tumor-infiltrating immune cells (CD3+, CD8+, Foxp3+, granzyme B+, NK cells and mature DCs) in retrospective cohorts of primary and lung metastases of colorectal cancer (CRC, n=124) and renal cell carcinoma (RCC, n=55) by immunohistochemistry. We investigated by qPCR the gene expression levels related to immune populations and their functions in the lung metastases from 19 CRC and 12 RCC. Biological data's were compared to clinical data's and patient's outcome. Results The cell composition (CD3+, CD4+ and Foxp3+ T cells, mature DCs and NK cells) and organization (tertiary lymphoid structures) of the immune infiltrate in metastases depend on the origin of the primary tumor. In both cases (colorectal cancer and renal cell carcinoma lung metastases), the density of CD8+ T cells and mature DCs appeared to be strongest prognosticator of patient's survival as reported for many primary tumors, but with opposite impact. High densities of mature DCs and CD8+ cells correlate with good overall survival in lung metastases of colorectal cancer and with poor survival in lung metastases of renal cell cancer. In the latter, a strong Th2 and inflammatory context was present associated with a strong Th1 polarization. Conclusions Altogether, our data demonstrate that the immune pattern depends on the tumor origin and has a major prognostic role in advanced cancer stages with an impact on patient therapeutic management. We demonstrated also the complexity of the immune response polarization and its impact upon tumor immune surveillance.

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 LB-497. doi:1538-7445.AM2012-LB-497
Abstract LB-50: Street smarts: cancer education and outreach in the homeless community
Authors: Ryan Cynthia
Published: August 2012

In response to a year-long investigation of cancer among the homeless in Birmingham, AL, this presenter created an education program called “Street Smarts.” Findings from a focus group consisting of homeless women diagnosed with stage IV breast cancer revealed competing values (poor self-esteem and body image, limited health care resources, etc.) preventing individuals in this population from seeking diagnosis or treatment for cancer, even when free-of-charge options are available. Street Smarts brings together members of this underserved community for a day of pampering while educating them about breast cancer screening and health care alternatives. The program is funded in partnership with the North Central Alabama Susan G. Komen Foundation.

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 LB-50. doi:1538-7445.AM2012-LB-50
Abstract LB-500: Genomic and RNAi analyses identify diverse oncogenic interactions between breast cancer cells and stromal fibroblasts
Authors: Rajaram Megha , Powers Scott , Egeblad Mikala , Li Jinyu
Published: August 2012

Although it is well established that fibroblasts in the breast cancer microenvironment can promote tumorigenicity, the scope and functional importance of all molecular interactions remains unclear. Here we've undertaken a systematic, genome-wide approach to identify and test genes that play functional roles in these interactions. We have developed an in vitro and in vivo based model system using human fibroblasts and breast cancer cell lines. Using this system, we first discovered a set of genes that are induced in fibroblasts upon co-culture with breast cancer cells and are also upregulated in the stroma of primary human breast cancer. Several of the upregulated genes encode secreted growth factors or cytokines. Using this approach, we also identified several oncogenic pathways upregulated in our model system as well as primary human breast stroma. We then used RNAi analyses and a co-injection tumorigenicity assay to functionally test these candidate genes for their roles in tumor-fibroblast interactions. We determined that the majority of our candidates play important roles in promoting breast cancer. Interestingly, these genes have significant yet diverse mechanisms through which they act. These results establish a wide range of potential targets for therapeutic inhibition of the ability of fibroblasts to promote breast cancer.

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 LB-500. doi:1538-7445.AM2012-LB-500
Abstract LB-503: Pharmacological inhibition of microglia leads to increased survival in a murine model of glioblastoma multiforme in conjunction with ionizing radiation
Authors: Miller Ian S. , Didier Sebastien , Murray David W. , Issaivanan Magimairajan , Coniglio Salvatore J. , Segall Jeffrey E. , Al-Abed Yousef , Symons Marc
Published: August 2012

Glioblastoma multiforme (GBM) is the most malignant and lethal form of astrocytoma. GBM patients have a median survival time of approximately one year and therefore it is essential to identify novel targets and effective therapies. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of GBM tumors. We have established a microglia-glioma cell co-culture system consisting of normal microglia from C57Bl/6J mice and syngeneic GL261 glioma cells. We have demonstrated that microglia strongly stimulate the invasive behavior of GL261 cells in this system. Our preliminary data also indicate that the microglia significantly stimulate GL261 cell proliferation and resistance to ionizing radiation (IR) in these conditions. In a search for small molecule inhibitors that block the stimulatory effects of microglia on glioma cells, we have examined CNI-1493, a drug that is known to selectively interfere with macrophage function. We found that CNI-1493 potently inhibits microglia-stimulated GL261 invasion. We also examined the effect of intracranially administered CNI-1493 on orthotopic GL261 tumors in the presence or absence of fractionated whole brain irradiation (10 Gy total). We found that although CNI-1493 only has a marginal benefit in the absence of IR, it strongly stimulates animal survival in combination with IR: whereas IR treatment increases survival by 10 days, IR in combination with CNI-1493 treatment extends survival beyond 40 days. In conclusion, our observations support the notion that pharmacological targeting of microglia may be beneficial as adjuvant therapy in conjunction with ionizing radiation.

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 LB-503. doi:1538-7445.AM2012-LB-503
Abstract LB-508: A GSA-NMP1 conjugate: An NIR-activatable fluorescence imaging agent to detect peritoneal ovarian cancer metastases
Authors: Alexander Vinita M. , Sano Kohei , Yu Zhanqian , Nakajima Takahito , Choyke Peter L. , Ptaszek Marcin , Kobayashi Hisataka
Published: August 2012

Purpose: There is a need to improve detection of peritoneal ovarian cancer metastases before and during surgery. Previous designs of activatable GSA-fluorophore probes, which target lectin receptors, have used only visible range dyes conjugated to GSA. However, activatable agents emitting fluorescence in the NIR range are advantageous because NIR photons have deeper in vivo tissue penetration and lower background autofluorescence than those emitting in the visible range. An NIR-activatable GSA fluorophore pair can be synthesized using the dye NMP1. This NMP1 dye has two unique absorption peaks (in green and NIR wavelength ranges) with a single NIR emission peak of 780nm. NMP1 thus has two different Stoke's shifts that have the potential to allow separate imaging of tumor nodules both at the surface and at depths below the surface. Experimental Design: GSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (GSA-NMP1). The activation magnitude of GSA-NMP1 was validated by adding 10% SDS. Flow cytometry, fluorescence microscopy, and in vivo spectral fluorescence imaging were carried out to compare GSA-NMP1 with GSA-IR800 (an always on control agent with similar emission to NMP1) in terms of intracellular activation and abilities to allow detection of small ovarian cancer implants in mice models. Sensitivity and specificity of GSA-NMP1 for implant detection were determined by co-localizing NMP1 emission spectra with red fluorescent protein expressed constitutively in SHIN3 tumor implants. Image processing in Java was used to subtract spectral images, with resulting images theorized to show tumor nodules at a depth below the surface. Results: The fluorescence signal of GSA-NMP1 can be activated ∼100-fold and was specifically yielded after internalization into SHIN3 cells 3h after incubation. Submillimeter ovarian cancer implants in the peritoneal cavity were clearly detectable in vivo with spectral fluorescence imaging. Among 555 peritoneal lesions, the sensitivity and specificity for GSA-NMP using NIR and green excitation light, were 75%/92% and 91%/92% for lesions ∼0.8 mm or greater in diameter, respectively. Image processing suggests that nodules at a depth below the small bowel are imaged only with GSA-NMP1 by subtraction of the two excitation images. Conclusions: GSA-NMP1 is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity.

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 LB-508. doi:1538-7445.AM2012-LB-508
Abstract LB-51: Breast cancer survivorship in women younger than 45 years
Authors: Preusse Courtney
Published: August 2012

Since opening its doors in 1975, the Fred Hutchinson Cancer Research Center has served as a world leader in advancing the prevention, diagnosis and treatment of cancer and related diseases as causes of human suffering and death. Breast cancer has long been a strong focus of the center. Our Consortium Breast Cancer Research Program initiated over 15 years ago, fosters novel and interdisciplinary work amongst world-renowned scientists and the clinical community that examines the physical, psychological, social and economic effects of cancer treatment. Moreover, our survivorship program, as part of the LIVESTRONG Survivorship Center of Excellence Network, promotes health-protective behaviours and helps survivors and doctors understand, prevent and manage these effects. Despite this wealth of knowledge, I submit that there is a sheer lack of credible breast health resources and there are countless missed opportunties to improve upon surveillance of a sizeable yet largely underrepresented population due to perceived rarity of cancer in young women. Breast cancer knows no boundaries; it does not discriminate on the basis of age. Specific, unique and neglected concerns facing young women with breast cancer must be addressed through new directions in research; first, so as to represent the entire population of survivors rather than a subset and, second, to close critical gaps in knowledge.

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 LB-51. doi:1538-7445.AM2012-LB-51
Abstract LB-510: Longitudinal imaging of melanoma cancer cell metastasis in a preclinical model by bioluminescence, PET/CT, and MRI
Authors: Adiseshaiah Pavan P. , Stern Stephan T. , Patel Nimit L. , Ileva Lilia V. , Kalen Joseph D. , Haines Diana C. , McNeil Scott E.
Published: August 2012

Metastasis of cancer cells from the primary tumor are a leading cause of poor prognosis and death from cancer. The lung is the most common organ for metastatic spread of cancer and leads to 20-50% of cancer-related deaths. Early detection of cancer metastasis to the lung and other organs could be beneficial in disease management. In animal studies, most secondary-site disseminated tumors are evaluated by optical imaging, and gross examination at necropsy and subsequent histopathological analysis. These techniques are limited in that they do not offer the ability to monitor animals during the course of tumor development, and optical microscopy may have inadequate field of view (3-D morphometrics) for thorough tumor evaluation. Noninvasive imaging allows for serial imaging of the same animal, with the ability to repeat measurements in real-time to enhance the observation of disease progression and therapeutic response. Here, we compared the multimodal noninvasive whole-body imaging techniques bioluminescence, 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/ computed tomography (CT), and magnetic resonance imaging (MRI) to image lung metastasis development following intravenous injection of melanoma cells (B16-F10 melanoma cell line expressing luciferase gene) in C57BL/6. By bioluminescence imaging, tumor cell localization in the lungs was evident as early as 3 days (1 x 105 photons/sec; total flux) post cancer cell inoculation and steadily increased through the end of week four (1 x 108 photons/sec; total flux). The increase in the lung tumor burden was confirmed by lung histopathology. As it was difficult to de-convolve the effects of photon flux spreading from lungs over other organs, other metastatic sites were not evaluated by bioluminescence. CT and 18F-FDG-PET are used clinically to image lung metastasis and offer excellent resolution of anatomical and metabolic details of cancer cells. We were able to image metastatic nodules in the lung by PET/CT at week four, which showed a strong correlation with histopathology analysis. [18F]FDG-PET/CT also revealed metastasis in the kidney and mesentery and were confirmed by histopathology. T2-weighted MRI at week 4 identified several lung tumors and metastatic cancers in the abdomen. A comparison of [18F]FDG/PET at week 4 to MRI and CT displayed several highly metabolic regions within the tumors. Histopathology confirmed the metastatic spread of the melanoma cells to the lung, mediastinum, kidney, and mesentery. Funded by NCI contract No. HHSN261200800001E.

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 LB-510. doi:1538-7445.AM2012-LB-510
Abstract LB-512: A novel rotational Raman imaging device for early cancer detection
Authors: Garai Ellis , Zavaleta Cristina , Sensarn Steve , Mandella Michael , Gambhir Sanjiv S. , Contag Christopher H.
Published: August 2012

A novel Raman imaging device that is capable of rotationally scanning hollow structures has been developed to be used in conjunction with tumor targeting Surface enhanced Raman scattering (SERS) nanoparticles. SERS nanoparticles can act as excellent contrast agents in that they offer ultra high sensitivity, and multiplexing capabilities due to the unique spectral signatures associated with them. One key advantage of multiplexing includes the ability to utilize several targeted SERS probes to target and localize a multitude of unique biomarkers associated with a specific disease, and effectively increasing cancer specificity. The device can potentially be used to distinguish a variety of tissues of interest in the colon such as: flat lesions, varying types of adenomas and carcinomas. There are also applications beyond the colon, such as the esophagus, stomach, oral cavity and bladder. In addition, multiplexing can allow for real-time functional imaging. A 45-degree scanning mirror, actuated with micro-motor, is used to perform circumferential scans of the lumen of the colon at a rate of 1 revolution per second and a spatial resolution or approximately 1.5 mm. The device is able to be used with currently available endoscopes by inserting it into the working channel of an endoscope. The use of many (36) multi-mode fibers is used to increase the flexibility of the fiber bundle so that it can be inserted and used in a fully articulating endoscope while still being able to collect a sufficient amount scattered Raman light. When in the circumferential scanning mode, American National Standards Institute (ANSI) regulations will allow us to increase the laser illumination power to about 580 mW at a scan rate of 60rpm, resulting in a detection limit of approximately 1 pM of SERS nanoparticles. One of the key features of our Raman device is that it has been designed for efficient use over a wide range of working distances. This is necessary to accommodate for imperfect centering of the device within the colon, as well as variable working distances due to folds and bends within the colon. These techniques could allow endoscopists to distinguish between normal and cancerous tissues instantly, as well as to identify flat lesions that are easily missed during conventional screening endoscopy. After a suspicious region has been identified, the rotating mirror can be held at a certain angle, and used to help guide biopsies or resection of tissues in real-time.

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 LB-512. doi:1538-7445.AM2012-LB-512
Abstract LB-515: Guanine nucleotide exchange factor Dock7 expression is increased in human glioblastoma and mediates tumor cell invasion.
Authors: Murray David W. , Didier Sebastien , Chan Amanda , Paulino Vincent , Tran Nhan , Byrne Annette , Symons Marc
Published: August 2012

Glioblastoma multiforme (GBM), the most common and deadly adult brain malignancy, is an incurable disease with an average life expectancy of 14 months following diagnosis. GBM morbidity is primarily due to its rapid growth, neovascularization and invasion throughout the brain. Recently, anti-VEGF therapies approved in this indication have paradoxically been shown to stimulate the invasive behavior of GBM. Members of the Rho family of small GTPases have been established as important mediators of GBM cell invasion. These proteins are activated by guanine nucleotide exchange factors (GEFs). In the current study, we sought to identify GEFs that are up-regulated in high-grade glioma and which may be of functional importance in human GBM. In this study we have shown that that Dock7, a GEF that can mediate signaling of Rac1 and Cdc42 Rho GTPases is up-regulated in human GBM tissue in comparison with normal brain. We have further demonstrated that Dock7 silencing by RNA-interference inhibits invasion of U87 and SNB19 GBM cells into ex vivo brain slices. Dock7 silencing inhibits Hepatocyte Growth Factor (HGF)-induced cell invasion in a 3D in vitro assay. HGF is known to strongly stimulate GBM cell invasiveness and both HGF and its receptor c-MET have been shown to be up-regulated in high- versus low-grade gliomas. Interestingly, we have also shown that Dock7 binds to c-MET in an HGF-dependent manner and that this interaction requires the GAB1 adaptor protein. Dock7 silencing reduced HGF-induced activation of Rac1 and consistent with this, we have shown that Dock7 silencing results in the inhibition of HGF-induced lamellipodia formation in GBM cells. Finally Dock7 was shown to be activated in an HGF-dependant manner, using Rac1-G15A pull-down assay. In summary, our data suggests a role for Dock7 in GBM cell invasion thus, Dock7 may present a potential therapeutic target in the management of invasive GBM, in particular in the adjuvant setting in combination with anti-VEGF therapies.

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 LB-515. doi:1538-7445.AM2012-LB-515
Abstract LB-517: EIF5A2, A downstream target of PI3K/Akt pathway, Is an adverse prognostic marker of melanoma patient survival by increasing cell invasion
Authors: Khosravi Shahram , Wong Ronald P.C. , Martinka Magdalena , Li Gang
Published: August 2012

Human cutaneous melanoma is a life-threatening skin cancer due to its invasive nature and high metastatic potential, leading to poor prognosis for melanoma patients. However, the mechanisms for melanoma invasion and metastasis are poorly understood. Human eukaryotic translation initiation factor 5A2 (EIF5A2) has been shown to be associated with tumor progression in multiple types of cancers. We examined EIF5A2 expression in 459 melanocytic lesions at different stages using tissue microarray and immunohistochemistry and analyzed the correlations between EIF5A2 expression and clinicopathologic parameters and patient survival. We found that positive EIF5A2 staining was significantly increased in primary melanomas compared to dysplastic nevi (P=0.002), and further increased in metastatic melanomas (P=0.036). EIF5A2 expression was correlated with melanoma thickness (P=0.0004) and was inversely correlated with overall and disease-specific 5-year survival of primary (P=0.008 and 0.007, respectively), especially low-risk (≤2.0mm) melanoma patients (P=0.026 and 0.044, respectively). We also examined the correlation between EIF5A2 and p-Akt protein expression and their role in regulating melanoma cell invasion. Combining the TMA data sets for EIF5A2 and p-Akt, we found that positive EIF5A2 staining directly correlated with strong p-Akt expression (P=0.026). Additionally, overexpression of PTEN or inhibition of p-Akt or ILK significantly reduced EIF5A2 expression. EIF5A2 overexpression also increased melanoma cell invasion and MMP-2 activity. We for the first time showed that the expression of EIF5A2, a downstream target of PI3K/Akt pathway, is significantly increased during melanoma invasion and is inversely correlated with patient survival, suggesting that EIF5A2 may be used as a potential therapeutic target for melanoma.

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 LB-517. doi:1538-7445.AM2012-LB-517
Abstract LB-52: Relentless in the fight against blood cancer: the Leukemia & Lymphoma Society
Authors: Patterson Harriet A.
Published: August 2012

WHO WE ARE: The Leukemia & Lymphoma Society (LLS) is the world's largest voluntary health organization dedicated to funding blood cancer research and providing education and patient services. Founded in 1949, we are relentless in pursuit of our mission: Cure leukemia, lymphoma, Hodgkin's disease and myeloma, and improve the quality of life of patients and their families. WHAT WE DO: Investing in blood cancer research: LLS has invested more than $814 million in research, approximately $76.6 million in fiscal year 2011 alone. Programs like the Specialized Center of Research (SCOR), and our Translational Research Program have directly contributed to many breakthrough cancer treatments. Research funded by LLS has led or contributed to advances such as chemotherapy, bone marrow and stem cell transplantation and new, targeted oral therapies. Providing critical information and support for patients and their families: We made 7.1 million contacts with patients, caregivers and healthcare professionals in fiscal year 2011, Advocating for issues impacting blood cancer patients: With more than 56,000 advocacy volunteers throughout the country, our voice is being heard by those responsible for legislation to fund blood cancer research and educational programs. WHY: An estimated 1,012,533 people in the United States are living with, or are in remission from, leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma or myeloma.Approximately every four minutes, someone new is diagnosed with blood cancer. Approximately every 10 minutes, someone dies. Leukemia causes more deaths than any other cancer among children, adolescents and young adults under the age of 20. Lymphomas are the most common blood cancers and incidence increases with age. The survival rate for myeloma is only 41.1 percent. Incidence is more than twice as high among African Americans as for all other races. WHO WE SERVE: In addition to our national headquarters in White Plains, NY, we have a network of 59 local chapters across the United States and Canada. Our constituents live in urban, suburban, and rural communities, seek treatment at large comprehensive cancer centers and community clinics, and represent cultures from around the world. We work in partnership with community organizations, treatment centers, and government agencies to deliver quality cancer support services and to reach as many patients as we can in our region. We also work in partnership with other oncology and health organizations to meets the needs of the underserved people within our community.

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 LB-52. doi:1538-7445.AM2012-LB-52
Abstract LB-520: PTPN14 interacts with and negatively regulates the oncogenic function of YAP
Authors: Liu Xiaojun , Yang Nuo , Figel Sheila A. , Wilson Kayla E. , Morrison Carl D. , Gelman Irwin H. , Zhang Jianmin
Published: August 2012

ABSTRACT The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Using IP Mass-spec analysis, we have identified a novel regulatory mechanism for the YAP oncogenic function via direct interaction with non-receptor tyrosine phosphatase 14 (PTPN14). PTPN14 interacts with YAP through PPxY domain, and overexpression of PTPN14 increases the inactive cytoplasmic form of YAP and decreases the transcriptional co-activator activity of YAP. Moreover, knockdown of PTPN14 induces nuclear retention of YAP and increases YAP-dependent cell migration. In summary, our study indicate a potential tumor-suppressor role for PTPN14 in the Hippo pathway and demonstrate a novel mechanism in YAP regulation.

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 LB-520. doi:1538-7445.AM2012-LB-520
Abstract LB-53: Cancer clinical trials: real answers, real options, real miracles, right here in west Michigan
Authors: Gavin Patrick
Published: August 2012

“Cancer survivors sharing clinical trial experiences to increase awareness and knowledge in the search for prevention and cure.” Our goal is to increase the awareness of cancer clinical trials available in West Michigan. The Patient Advisory Board for Clinical Research was formed to capture the passion that clinical trial participants possess in searching for a cure for a disease that has personally affected them. Fear often accompanies a cancer diagnosis. The vision is to replace fear with the knowledge that is brought through clinical trials. The Patient Advisory Board for Clinical Research's objective is to make cancer clinical trials information available and increase general public awareness of this treatment option.

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 LB-53. doi:1538-7445.AM2012-LB-53
Abstract LB-56: My journey as a breast cancer survivor, from diagnosis to advocate
Authors: Morrow Jeannette
Published: August 2012

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 LB-56. doi:1538-7445.AM2012-LB-56
Abstract LB-58: Advocacy within the PS-OC: Evolution of the program
Authors: Baas Carole L. , Samson Susan
Published: August 2012

The National Cancer Institute (NCI) has emphasized the importance of innovation and creativity in exploring strategies to control and eradicate cancer. This effort resulted in the formation of the Physical Sciences in Oncology program (PS-OC), which utilizes the fields of mathematics, physics, chemistry and engineering to address cancer. The NCI has sponsored a network of twelve PS-OC centers across the U.S. in an effort to have a cross-sectional evaluation of the physical principles used to study cancer. The PS-OC program aims to advance cancer research and move the research closer to practical application. A key instrument to move the research into clinical practice is the voice of patient advocates on the PS-OC research team. Patient advocacy has traditionally been focused on providing support and education for patients and stimulating research for better understanding of diseases and their treatment. The inclusion of patient advocates in the physical sciences is rare as the majority of advocates work in clinically-focused research and researchers in these fields seldom interact with advocates and patients. The PS-OC program has expanded the role of patient advocates to include involvement in basic and translational research in the physical sciences. The PS-OC advocacy program is a cooperative effort between the Centers and advocate advisors, who serve as liaisons between the patient and scientific communities. Each Center is developing an advocacy program unique to its research focus and the skills and interests of the advocate community. Advocates are an integral part of the scientific team, providing insight into clinical aspects of cancer; communicating research findings to the public through public lectures, lay articles and social media; presenting the patient perspective in university courses as guest speakers; and participating in legislative advocacy. However, the most important role of advocates is to provide the human element and perspective to the research.

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 LB-58. doi:1538-7445.AM2012-LB-58
Abstract LB-59: Progressing Forward in Timely Fashion
Authors: Ford Peg
Published: August 2012

Peg Ford, Chair, and Kathy Hagan, Co-Chair, caregiver who lost her mother to ovarian cancer, formalized Peg's advocacy efforts in launching the Ovarian Cancer Advocacy Alliance (OCAA) of San Diego in May 2011. OCAA's Mission was formulated in three aspects of Advocacy: 1) Affect change in the way medical doctors approach diagnosis and treatment of ovarian cancer by education of the medical community, patient organizations, and the community at large to achieve early diagnosis and improved treatment options; 2) advance ovarian cancer research toward early diagnosis and improved quality of care; and 3) Address legislative issues that affect ovarian cancer care and research. From becoming a proud partner of the Ovarian Cancer National Alliance (OCNA); successfully expanding OCNA's “Survivors Teaching Students: Saving Women's Lives®” Program to Schools of Nursing; publishing articles; and actively participation in legislative actions, 2011 was a banner year. The poster reflects the continued outstanding success of the STS Program, and Peg Ford, OCAA Chair's, commitment to pursue her initiative to blossom into a voice as a Research Advocate for the ovarian cancer community on a local, state, national and international level, as a guest speaker, facilitator, or writer for community outreach efforts. Progressing forward in a timely fashion will continue to set the initiatives to strengthen Ovarian Cancer Advocacy Alliance's (OCAA) vision of patient advocates as the bridge between the patient community and the scientific/medical world, working hand-in-hand to advance research and impact changes to better serve both communities.

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 LB-59. doi:1538-7445.AM2012-LB-59
Abstract LB-64: Selective estrogen receptor modulators (SERMs) act as breast cancer chemopreventive agents by attenuating oxidative estrogen metabolism
Authors: Hemachandra L P Madhubhani P. , Choi Jaewoo , Bolotn Judy , Thatcher Gregory
Published: August 2012

Possibility of developing hormone dependent cancer in women will increase with long term exposure to endogenous estrogens. Estrogen induced, estrogen receptor (ER) mediated cell proliferation (hormonal pathway) and formation of reactive estrogen metabolites (chemical pathway) are believed to contribute to estrogen carcinogenesis. Estrogens are oxidized to the catechols, 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2) by P450 1A1/1A2 and P450 1B1 respectively. Both catechols are further oxidized to form electrophilic o-quinones which can react with DNA and proteins, while 4 hydroxyestradiol O-quinone (4-OHE2-Q) is considered as the ultimate carcinogen. Selective Estrogen Receptor Modulators (SERMs) are used in cancer chemoprevention and in the treatment of post menopausal osteoporosis. The current study focuses on elucidating the influence of clinical and pre clinical benzothiophene SERMs on oxidative estrogen metabolism in ER negative non tumerigenic human breast epithelial cells (MCF-10A). Upon exposure to 17β-estradiol (E2), MCF-10A cells transformed into a malignant phenotype and showed anchorage independent colony growth in soft agar. After treatment of MCF-10A cells with E2 and SERMs, estrogen metabolites were analyzed using a sensitive LC-MS/MS method. Among the SERMs tested, raloxifene and desmethylarzoxifen (DMA) showed a significant reduction in catechol estrogen formation whereas 4′F-DMA had little effect. Furthermore, raloxifene and DMA significantly inhibited E2 induced malignant transformation and reactive oxygen species formation in MCF-10A cells. These data suggest that raloxifene and DMA possess chemopreventive activity through inhibition of genotoxic estrogen quinone formation, in addition to their action via estrogen receptors.

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 LB-64. doi:1538-7445.AM2012-LB-64
Abstract LB-65: Protein kinase Cε, which is linked to development of squamous cell carcinomas, potentiates ultraviolet radiation-induced expression of novel transcription factors GATA and PAX, which regulates expression of cell survival genes
Authors: Jamal Mohammad S. , Hafeez Bilal B. , Verma Ajit K.
Published: August 2012

Protein kinase C epsilon (PKCε) is among the six PKC isoforms (α, δ, ε, η, μ, ξ) expressed in both mouse and human skin. We have reported that epidermal PKCε levels dictate the susceptibility of PKCε transgenic mice (TG) to the development of squamous cell carcinomas (SCC) elicited by repeated exposures to ultraviolet radiation (UVR). Histologically, SCC in TG mice, like human SCC, is poorly differentiated and metastatic. To find clues about the mechanism by which PKCε may impart susceptibility to UVR-induced development of SCC, we compared the effects of UVR treatment of TG mice with their wildtype (WT) littermates on global transcription factors (TFs) activation profile. In this experiment, mice were exposed to UVR (2kj/m2) four times (Monday, Wednesday, Friday and Monday). At 1hr and 3hrs post last UVR exposure, these mice were sacrificed. Nuclear lysates were prepared from the scraped epidermis of these mice. To screen for unknown TFs, we employed the Panomics Combo Protein array, which contains consensus complimentary sequences of 345 TFs binding sites. Array results from samples of UVR exposed mice were directly compared to the unexposed mice. TFs that had increased over 2-fold in the UVR exposure experiments were scored as positive for activation. We observed (>2-fold) activation of 70 TFs as early as 1hr post UVR exposure. Among all seventy TFs, highly activated TFs were GATA-1, GATA-2, PAX-4, PAX-6, PAX-8, Thy-1BP, HFH-2, HFH-3, HIF-1, CEA, HOXD8/9/10, AhR/Amt, and MUSF. We performed the validation of various activated TFs and among them we found that GATA and PAX families of transcription factors were found activated. UVR-induced expression level of GATA-1, GATA-2, PAX-4 was enhanced in PKCε over-expressing transgenic mice as compared to wild-type littermates. We employed the Genego program and found that VEGFR-2, CyclinD1, Bcl-2, c-Myc, BMP-4, WT1 and survivin are the downstream target genes of GATA1 and GATA-2. All of these genes are known to play role in the cell survival pathway. We have previously shown that PKCε overexpressing transgenic mice also exhibit constitutive activation of Stat3. Taken together, we conclude that PKCε-mediated activation of Stat-3, GATA-1, GATA-2 and PAX-4 may contribute to the susceptibility of PKCε transgenic mice to UVR-induced development of SCC. (Support: NIH Grant CA 35368)

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 LB-65. doi:1538-7445.AM2012-LB-65