bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5496: Cetuximab induces synthetic lethality with the poly (ADP-Ribose) polymerase (PARP) inhibitor ABT-888 in head and neck cancer
Authors: Whitley Alexander C. , Nowsheen Somaira , Trummell Hoa , LoBuglio Albert , Bonner James A. , Yang Eddy S. 
Published: June 2012

Abstract
Purpose: Overexpression/amplification of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab, almost half of treated patients fail this therapy. PARP inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing homologous recombination (HR)-deficient tumors while maintaining minimal toxicity in normal tissues. As EGFR inhibition has been reported to alter cellular DNA repair capacity, we investigated whether cetuximab could induce a transient DNA repair deficit and subsequently induce a synthetic lethality with the PARPi ABT-888 in head and neck cancer cells.
Methods: The head and neck cancer cell lines UM-SCC1, UM-SCC6, and FaDu were used in this study. Kinetics of DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci at various time points following irradiation (IR). Cell viability was determined via the ATPlite as well as colony formation assays. Apoptosis was evaluated by Annexin V staining as well as cleaved caspase 3 and 9 levels. Cell cycle analysis was performed via flow cytometry.
Results: Cetuximab increases γ-H2AX foci, which are well established markers of DNA double strand breaks (DSBs), in head and neck tumor cells. This coincides with reduced DSB-repair as indicated by attenuation of IR-induced Rad51 and DNA-Pk foci, which are well characterized in situ markers of the homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair pathways, respectively. Importantly, cetuximab induces synthetic lethality with the PARPi ABT-888 through a mechanism involving persistent DNA damage and subsequent activation of the intrinsic pathway of apoptosis. The observed effects are not due to cell cycle redistribution.
Conclusions: By generating a DSB repair deficiency, cetuximab can render head and neck tumor cells susceptible to PARP inhibition. The combination of cetuximab and the PARPi ABT-888 can thus be an innovative treatment strategy to enhance therapeutic ratio and improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2011-5496
Abstract 5517: Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-α signal transduction in CD4+ T cells from patients with gastrointestinal malignancy
Authors: Mundy Bethany L. , Young Gregory S. , Bauer Todd , Binkley Elaine , Bloomston Mark , Bill Matthew A. , Bekaii-Saab Tanios , Carson William E. , Lesinski Gregory B. 
Published: June 2012

Abstract
Interferon-alpha (IFNα) can promote anti-tumor immunity through its actions on immune cells. We have shown in murine models that a class of immune suppressor cells known as myeloid-derived suppressor cells (MDSC) have inhibitory effects on IFN signal transduction and gene regulation. Interleukin (IL)-6 and IL-10 are produced by tumor cells in cancer patients and can regulate the survival and function of MDSC. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets and IFNα-induced signal transduction in 40 patients with gastrointestinal (GI) malignancies. Plasma IL-6 and IL-10 levels were significantly higher in patients versus normal donors. CD33+HLADR−CD11b+CD15+ and CD33+HLADR−/lowCD14+ MDSC were also elevated in patients versus normal donors (p&lt;0.0001). Prior studies suggest that CD15 divides human MDSC into granulocytic (CD15+) and monocytic (CD15−) subsets. Therefore relationships between CD15 expression on MDSC and cytokines elevated in GI patients were examined. A significant correlation between plasma IL-6 with CD33+HLADRCD15+ MDSC (p=0.008) and IL10 with CD33+HLADR−CD15− MDSC (p=0.002) was observed. The level of CD15+ and CD15− but not CD14+ MDSC subsets were inversely correlated with IFNα-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFNα-responsiveness in PBMC from normal donors. In a multivariable Cox proportional hazards model, an increased percentage of the CD33+HLADR−CD15− MDSC subset was associated with reduced overall survival (hazard ratio = 1.43; p = 0.049) while an increased percentage of the CD33+HLADR−/lowCD14+ subset was associated with greater overall survival (hazard ratio = 0.69, p=0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets and IFNα responsiveness in patients with GI malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2011-5517
Abstract 5519: Vaccination of melanoma patients with CD40L/IFN-γ activated dendritic cells reveals a correlation between IL-12p70 production and CD8+ T cell priming to the melanoma differentiation antigen gp100
Authors: Carreno Beatriz M. , Becker-Hapak Michelle , Chan Megan , Lie Wen-Rong , Linette Gerald P. 
Published: June 2012

Abstract
Ex-vivo generated dendritic cells (DC) have been used as therapeutic vaccines for the treatment of patients with metastatic cancer. However, these first-generation vaccines consist of DC activated to up-regulate costimulatory molecules with minimal to absent IL-12p70 production. Inflammatory cytokines, primarily IL-12p70 and interferons, provide a critical third signal along with antigen (signal 1) and costimulation (signal 2) for optimal effector CD8 T cell expansion/differentiation and memory formation. In order to generate IL-12p70-producing DC, a GMP-grade cell line expressing CD40L was developed and used in conjunction with IFN-γ to activate monocyte-derived DC. Stage IV melanoma patients (n=6) received an initial priming dose of CD40L/IFN-γ activated DC pulsed with 3 gp100 melanoma peptides (G154, G209-2M, G280-9V), followed by additional DC doses every 3 weeks for a total of 6 immunizations. Peripheral blood mononuclear cells isolated weekly during the course of immunizations were used to evaluate the kinetics and magnitude of vaccine-induced gp100-T cell responses. In all but one patient CD8+ T cell responses to all 3 gp100 peptides were detected, with strongest proliferative responses observed after 2 DC immunizations. Magnitude of responses was not heightened with further immunizations. Antigen-specific frequencies to the high affinity G154 peptide were consistently lower than those to low affinity G209 and G280 peptides. Notably, we observe a correlation between DC IL-12p70 production, immune responses to gp100, and clinical efficacy of vaccination. Patients (n=3) with highest DC IL-12p70 production levels exhibit high gp100 antigen-specific frequencies and are in remission (n=1) or have stable disease (n=2). A qualitative analysis of T cell responses generated among patients is currently underway. These results underscore the important role of DC activation status in vaccination and provide an immunological rationale for vaccine design whereby IL-12p70 contributes to effective immune-based therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5519. doi:10.1158/1538-7445.AM2011-5519
Abstract 5538: Sarcomas in TP53 germline mutation carriers
Authors: Ognjanovic Simona , Olivier Magali , Bergemann Tracy L. , Hainaut Pierre 
Published: June 2012

Abstract
Sarcoma plays a central role in Li-Fraumeni syndrome (LFS) definition. Germline mutations in TP53 gene underlie this rare familial syndrome and are detected in over 80% of LFS patients.
The International Agency for Research on Cancer (IARC) maintains a database of germline TP53 mutations that collects published data on LFS and related syndromes and provides baseline information about TP53 mutation prevalence and phenotype in these patients.
We analyzed the characteristics of germline TP53 germline mutations in LFS and related syndrome patients with sarcoma using the IARC TP53 Database. The prevalence of individual sarcoma types and their age/gender distribution in TP53 mutation carriers were compared to sporadic sarcomas in Caucasians obtained by SEER registry analysis using the SEERStat program.
Sarcoma represented 25% of all tumors diagnosed in TP53 carriers in this study. We confirmed young age of sarcoma onset among carriers, with 95.6% of cases diagnosed before the age of fifty years, as opposed to 38.3% of sporadic cancer. Carriers had increased risk for osteosarcoma in both children/adolescents and adults (OR=1.41, 95% CI=1.02-1.94, and OR=4.61, 95% CI=2.72-7.83), while increased risk for rhabdomyosarcoma was confined to carriers younger than 5 years (OR=11.6, 95%CI=6.1-21.9, p&lt;0.00001). Analysis of the association of mutations with specific sarcoma types revealed that mutations in the oligomerization domain (codon 344 and 337) increased the risk of leiomyosarcoma (OR=10.1, 95% CI=3.4-29.9). Analysis of codons most frequently mutated in sarcoma showed that four codons (220, 275, 282, 344) were associated with 3-fold increased risk of sarcoma, compared to other cancers in TP53 carriers.
In conclusion, this study provided further evidence for genotype-phenotype correlations in germline TP53 mutations carriers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5538. doi:10.1158/1538-7445.AM2011-5538
Abstract 5540: CCN5/WISP-2 prevents leptin-induced breast cancer cell growth and migration
Authors: Haque Inamul , Banerjee Snigdha , Dhar Kakali , Chattopadhyay Indranil , Ray Amitabha , Banerjee Sushanta K 
Published: June 2012

Abstract
In menopausal women, one of the important risk factors for breast cancer is obesity/adiposity. Despite multiple studies, the biological mechanism by which obesity influences the breast carcinogenic process is still unclear. It is evident from various studies that leptin, a 16 kDa protein hormone over produced in obese people, plays a critical role in neovascularization and tumorigenesis in breast and other organs. Present studies demonstrate that leptin is able to induce proliferation and migration of estrogen receptor positive MCF-7 and ZR-75-1 breast tumor cell lines in a dose-dependent fashion but these effects are minimal in ER-negative MDA-MB-231 cells. Additionally, these studies found that leptin suppresses the transcriptional activation of anti-invasive gene CCN5/WISP-2. Although the suppression of CCN5 has no impact on the constitutive proliferation of these cells, it is critical for leptin-induced proliferation and necessary for the induction of in vitro migration of these cells because the addition of CCN5 recombinant protein into the media markedly inhibits the leptin-induced proliferation and migration. Collectively, these in vitro studies suggest that CCN5 may serve as a gatekeeper for leptin dependent breast carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5540. doi:10.1158/1538-7445.AM2011-5540
Abstract 556: Extracellular sulfatase 2; enzymatic inhibition by OKN-007 a disulfonylphenyl nitrone with anticancer activity and other sulfamate and sulfone compounds
Authors: Floyd Robert A. , Chandru Hema K. , Towner Rheal A. 
Published: June 2012

Abstract
Sulfatase 2 (Sulf2) is an extracellular enzyme which catalyzes the removal of 6-O-sulfate groups on glucosamine from subregions of the glycosaminoglycan heparin sulfate. Sulf2 action alters the binding of protein ligand growth factors such as VEGF, FGF-2, TGF and SDF-1 to heparin and cellular receptors. Sulf2 is enriched in several tumors including breast cancer, pancreatic cancer, lung cancer and liver cancer and studies in experimental models have shown its action is important in cancer development. We have shown that PBN (α-phenyl-tert-butylnitrone) nitrones have anti-cancer activity in experimental cancer models including the rat choline deficiency liver cancer model, the mouse APCmin model of colon cancer and the rat C6 glioma model. Studies of the PBN derivative 2,4-disulfonylphenyl-tert-butylnitrone in the C6 glioma model showed that it has more potent anti-cancer activity in this model than PBN. We considered that the sulfonyl groups on OKN-007 acting to inhibit the activity of Sulf2 could account for its anti-cancer activity and therefore set up experiments to test this concept. We have shown that OKN-007 does inhibit Sulf2 at biological meaningful concentrations. In addition we have partially completed an MCF-7 xenograph study that indicates OKN-007 administered orally does suppress cancer growth in this model. We have also shown that another compound suramin that has 6 sulfonyl groups and has been shown to have anti-cancer activity also suppressed the enzymatic activity of Sulf2. In addition we have also tested some compounds that have sulfamate and sulfone functional groups and have found that they also show some activity in suppressing the enzymatic action of Sulf2. Studies are continuing to elucidate the significance of the action of OKN-007 on Sulf2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 556. doi:10.1158/1538-7445.AM2011-556
Abstract 5589: An aqueous extract of Allspice (berries of Pimenta dioica) inhibits breast cancer growth through autophagy by targeting the estrogen receptor
Authors: Zhang Lei , Shamaladevi Nagarajarao , Lokeshwar Bal L. 
Published: June 2012

Abstract
Background: Breast cancer (BrCa) ranks second as cause of cancer deaths in women. However, &gt;90% of BrCa patients survive &gt;5 years after diagnosis, thus providing an chance to prevent clinical progression and metastasis. Several chemopreventive agents are currently under investigation, however, no single agent is highly effective. Dietary agents offer an advantage for long-term, well tolerated and personalized treatment for chemoprevention. With this goal, we investigated anticancer effects of an aqueous extract of a common spice, the unripe berries of Pimenta dioica (Allspice).
Methods: An aqueous exact of Allspice was prepared, lyophilized and a solution of suitable strength was tested on several BrCa cell lines (MCF-7, MDA-MB231, SKBr3) for potential inhibition of clonogenic growth, autophagy and estrogen-receptor inactivation using commonly used analytical techniques. Potential effect on estrogen receptor (ERα) levels and transcriptional activities were determined using quantitative-real time PCR and western blotting.
Results: AAE reduced the viability and clonogenic growth of BrCa cells (IC50≈ 100μg/ml). Importantly, AAE was selectively effective against proliferating cells but not quiescent cells. In addition to cytotoxicity, AAE reduced ERα in an estrogen-dependent BrCa cell line, MCF-7. ERα protein levels were significantly decreased in AAE treated MCF7 cells (IC50≈ 100μg/ml). The decrease in ERα protein level by AAE was not rescued by MG132, a proteasome inhibitor, treatment indicating, it is likely due to AAE effect on ERα synthesis and not turnover. We did not detect AAE induced apoptosis in MCF-7 cells as confirmed by several assays. However AAE induced the expressions of autophagy-related proteins, microtubule-associated protein 1 light chain 3 (LC3).
Conclusion: We demonstrate anti-proliferative and anti-ERα activity of the aqueous extract of Allspice, a highly aromatic and delectable culinary additive world over. The cytotoxicity of this anticancer agent encompassed multiple pathways, including autophagy and ERα down modulation. These results, if found corroborative using studies in vivo models, should provide a strong rationale to test as an anti-cancer agent in breast cancer. [Grant Support: 1R01AT003544 (BLL)]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5589. doi:10.1158/1538-7445.AM2011-5589
Abstract 567: Tumor suppressor merlin and WWOX involve in regulating tumor cell growth via epithelial mesenchymal transition (EMT)
Authors: Shen Wan-Jou , Huang Yu-Feng , Lin Han-Yu , Sze Chun-I , Chang Nan-Shan 
Published: June 2012

Abstract
Cancer radiotherapy may complicated by chemo/radiation-induced resistance. Gene expression profiling studies have revealed that the tumor carries mesenchymal signature is a poor prognostic predictor. Our laboratory had generated post-irradiated 1306-MG glioblastoma (GBM) cell line which expresses epithelial mesenchymal transition (EMT) markers such as vimentin, fibronectin, desmin, and carbonic anhydrase III. Nuclear translocation of vimentin also occurs in these cells. These findings all indicate EMT. EMT requires cells transition and detachment which is mainly driven by a hyperactive Raf/MAPK pathway via transforming growth factor β (TGF-β) signaling. TGF-β signaling interacts with cell surface Hyal-2 and recruits WWOX. We treated 1306-MG with hyaluronan (HA) and co-transfected with wild type, active form, and inactive form merlin plus WWOX. By fluorescence resonance energy transfer (FRET) and co-immuoprecipitation (CO-IP) assays, our data showed that WWOX interacted with merlin in GBM cell line after treated with hyaluronan (HA). This finding suggest that WWOX participates in the regulation of CD44/merlin signaling. The growth of 1306-MG in merln or WWOX transfected cells showed more cells in S/G2M phases than co-tranfected cells. The co-tranfected WWOX with wild type or active form merlin induced growth arrest in cell cycle were greater than single-tranfected merlin or WWOX. However, inactive form merlin and WWOX co-tranfection caused a growth permissive state was identified by flow cytometry analysis. Using soft agarose colony survival assay, we determined that colony number in co-transfected cells with WWOX plus wild type and active form merlin were more doubled than cells transfected with inactive form merlin plus WWOX. On the contrary, co-transfected cells with wild type and active form merlin plus WWOX, colony size was smaller than co-transfected with inactive form merlin plus WWOX. Given the presence of EMT marker proteins in post-irradiated GBM cell lines, we hypothesize that merlin interacts with WWOX may interfere TGF-β signal pathway and EMT. Analysis data from 1306-MG cells after 12 Gy irradiation and transfected WWOX plus individual types of merlin, we found EMT makers such as vimentin and fibronectin were also significantly increased, especially in cells co-transfected with WWOX and inactive form merlin. Data obtained from cells treated with TβRI/II inhibitor suggested that these changes were TGF-β-dependant. According to these results, we conclude that TGF-β signaling recruits merlin/WWOX and via its interaction to promote cell growth and EMT in post-irradiated GBM cell line in vitro.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 567. doi:10.1158/1538-7445.AM2011-567
Abstract 585: PTEN is a critical determinant in sensitizing cells to γ-secretase inhibitors
Authors: Nair Jayasree S. , Sheikh Tahir N. , Li Yueming , Schwartz Gary K. 
Published: June 2012

Abstract
Phase I studies of gamma secretase inhibitors (GSIs) that block Notch signaling have indicated clinical activity, especially in patients with sarcomas and melanoma. None of these patients had activating mutations, yet they showed intrinsic sensitivity to the drug. Therefore, an understanding of the mechanisms for de novo sensitivity and resistance to this class of drugs would be critical for drug development. Towards this end, we treated a panel of human melanoma and sarcoma cells lines with JC-34, a potent inhibitor of gamma secretase. Even though all the cell lines showed inhibition of cleaved Notch 1 and suppression of Hes1 luciferase, only some of the cell lines showed inhibition of growth or induction of apoptosis. The sensitive cell lines also underwent G1 cell cycle arrest. In addition, all the sensitive cell lines were characterized by induction of PTEN and suppression of p-AKT (473) after the administration of JC-34. Melanoma cell lines with wild type PTEN were sensitive (SKMEL 32 and SKMEL 267) while PTEN mutant/ null cells were insensitive (SKMEL 39 and 133). In order to further assess the impact of PTEN status upon drug susceptibility, we compared the impact of JC-34 upon isogenic breast cancer cell lines that differ only in PTEN status. In the breast cancer cell line MDAMB468, proliferation inhibition was approximately 50% in the presence of PTEN expression compared to 10% in MDAB468 cells without PTEN expression. In this system, induction of apoptosis was a significant contributor to inhibition of proliferation. Taken together, these data suggest that the status of PTEN before and/or after drug treatment may play a critical role in determining tumor susceptibility to Notch pathway inhibition. As PTEN is negatively regulated by Notch, modulation of PTEN status by GSIs may provide a rationale means to explain sensitivity of this class of drugs to particular subsets of tumor. This hypothesis will be validated in planned clinical trials with GSIs in patients with these diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2011-585