bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B41: Molecular linkages between metabolic imbalance, genome stability, and triple-negative breast cancer
Authors: Byun Jung S. , Taylor Tara J. , Wakano Clay , Di Li-jun , Khramtsova Galina , Olopade Olufunmilayo I. , Gardner Kevin 
Published: June 2012

Abstract
Breast cancer remains a worldwide threat to public health with over one million new cases, and nearly half a million deaths each year. Defining the mechanisms underlying the causes and risks of breast cancer remains a major challenge to global health. Though numerous population-based studies have demonstrated a indisputable link between obesity and breast cancer, the underlying molecular mechanisms and their association with elevated circulating hormones and inflammatory cytokines remain poorly defined. Similarly, the reasons why young women of African descent show a nearly two fold higher frequency of the more aggressive forms of breast cancer including the Triple Negative and basal-like phenotypes, are not understood. Recently we have defined a role for the transcriptional repressor protein CtBP in the control of proteins important for DNA repair including the early onset breast cancer gene BRCA1. In response to elevated levels of the high energy metabolic intermediate, NADH (nicotinamide adenine dinucleotide), nuclear levels of CtBP are stabilized and target a transcriptional program that impairs DNA repair in breast cancer cells. Loss of CtBP or growth under calorie restricted conditions increases the ability of breast cancer cells to repair DNA damage. Genome-wide location analysis by chromatin immuno-precipitation combined with deep sequencing (ChIP-Seq) reveals that CtBP targets gene classes that play a significant role in epithelial-to-mesenchymal transition, genome stability and stem cell transcriptional programs. Moreover, by Kaplan-Meier survival analysis of several published gene expression studies, CtBP targeted gene lists distinguish breast cancer patients with worst outcome/survival. Finally, profiling of CtBP protein expression in tissue micro-array studies of breast cancer in African American and Nigerian populations demonstrates elevated levels of CtBP expression in patients with more aggressive disease phenotypes. We explore the role of CtBP and its gene regulatory network (the “CtBP Web”) in the population-based association of breast cancer with obesity and racial/ethnic groups at higher risk for triple negative breast cancer.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B41.
Abstract B67: Phenotype-specific role for protein kinase CK2 in luminal and basal-like breast cancer cells
Authors: Williams Christopher Charles , Patton Michelyn C. , Campbell Melody M. 
Published: June 2012

Abstract
Protein Kinase CK2 is a hetero-tetrameric serine/threonine kinase which has been shown to have increased expression in most types of cancer. Previous studies have identified roles for CK2 in transcriptional regulation, proliferation and survival, as well as in epithelial mesenchymal transition. Our previous studies have shown that CK2 is responsible for the phosphorylation of the estrogen receptor (ERα) at two previously unidentified sites. Here we sought to delineate the specific functions of CK2 in ERα (+) luminal and ERα (−) basal-like breast cancer. Breast tissue microarrays studies show that CK2 is expressed in both ERα (+) and ERα (−) breast tumors. In ER dependent cell lines, inhibition of CK2 causes a substantial inhibition of transcriptional activity in luciferase reporter assays. Furthermore, CK2 was found to interact with the promoters of estrogen responsive genes in an ER-dependent fashion. Despite the selective effects on ER dependent gene expression, inhibition of CK2 attenuated proliferation/ cell viability both ERα (+) and ERα (−) cell lines, suggesting that CK2 may have distinct roles in the function of specific breast cancer cell phenotypes. Indeed, Inhibition of CK2 caused cell-type specific changes in the expression of vimentin and E-cadherin, as determined by flow cytometry, as well as cell morphology. Taken together, these studies suggest that CK2 utilizes multiple molecular mechanisms to promote tumorigenesis. Inhibition of CK2 may be a viable therapeutic targeting strategy for treatment of patients with ERα (+) and ERα (−) breast tumor phenotypes.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B67.
Abstract B69: SHP2 as a novel therapeutic target for triple-negative breast cancer
Authors: Matalka Fatimah , Agazie Yehenew 
Published: June 2012

Abstract
The basal-type/triple-negative breast cancer (BTBC) has the worst clinical outcome primarily because of its invasive nature and lack of targeted therapy. In addition, BTBC is more prevalent in younger African-American women. Therefore, there is an urgent need for discovering and characterizing potential drug targets for BTBC. In this study, we have focused on the Src homology phosphotyrosyl phosphatase 2 (SHP) which seems to play critical roles in promoting BTBC. The major reason for focusing on SHP2 is its positive role in mitogenic and cell survival signaling induced by receptor tyrosine kinases such as EGFR (HER1), PDGFR, IGF-1R, and the cytoplasmic tyrosine kinase Src, which are known to be elevated in BTBC. Here, we have shown that the SHP2 protein is elevated in approximately seventy percent of BTBC tumors, and is highly correlated with overexpression of the EGFR (HER1), suggesting their potential synergistic role to promote BTBC. Functional studies demonstrated that SHP2 is essential for EGF-induced mitogenic and cell survival signaling and for maintenance of the transformed phenotype in BTBC cells. More dramatic was that the invasive phenotype of BTBC cells in 3D matrigel was completely blocked by inhibition of SHP2, suggesting that the invasive property of these cells is dependent on SHP2. Even more dramatic was that the tumorigenic and metastatic potential of BTBC cells was abolished by SHP2 inhibition. These results show that SHP2 has untapped potential to serve as a drug target in BTBC.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B69.
Abstract B78: Final results of a prospective observational study comparing African American and Caucasian patients receiving second-line treatment with pemetrexed for advanced non-small cell lung cancer (NSCLC)
Authors: Pennella Eduardo , Schwartzberg Lee S. , Adjei Alex , Pohl Gerhardt , Peltz Gerson , Girvan Allicia , Winfree Katherine , Martinez Betzaida , Obasaju Coleman , Walker Mark , Stepanski Edward J. 
Published: June 2012

Abstract
Background: Few prospective studies have evaluated the impact of race and ethnicity on clinical outcomes, during lung cancer treatment. This prospective observational study evaluated the impact of ethnicity on disease control rate (DCR) in patients with NSCLC treated with second-line pemetrexed (P).
Methods: Eligibility criteria included stage IIIB or IV NSCLC pts receiving single-agent P for second-line therapy in routine clinical practice. Sites were selected to ensure high minority representation. Due to persistent challenges in achieving desired enrollment of minority, the focus of the study was narrowed to a comparison of patients self-reporting as either Caucasian (C) or African American (AA). This report describes findings regarding the primary endpoint of the study, DCR. Non-inferiority was evaluated using logistic regression analysis for DCR controlling for predefined covariates: age, gender, income, marital status, insurance type, smoking status, ECOG performance score, disease stage, histology, comorbidities, time from end of first-line to initiation with P, prior exposure to first-line platinum, exposure to first-line paclitaxel, and number of first-line cycles. The DCR of AAs was considered non-inferior to Cs if the upper 95% confidence bound on the adjusted odds ratio (OR) for Cs vs AAs was less than 1.78, corresponding to a difference in proportion of 14% assuming Cs to have a DCR of approximately 50%. The pre-specified bound was chosen to be one-half of the anticipated difference between treatment and no second-line treatment. Secondary endpoints reported here include progression-free survival (PFS) and overall survival (OS).
Results: The unadjusted DCR was 43.4% (116/267) for C and 45.8% (27/59) for AA (unadjusted OR=0.91). The adjusted OR for the comparison of C to AA in the final logistic regression model was 0.79 (95% CI, 0.41, 1.51). This upper 95% confidence bound was within the pre-specified acceptable bound of 1.78. Median PFS times were 2.7 months (95% CI: 2.4, 3.4) for Cs and 3.0 months (95% CI: 2.3, 4.7) for AAs (P=0.91). Median OS times were 6.7 months (95% CI, 5.7, 7.9) for Caucasians and 6.9 months (95% CI: 4.5, 8.9) for AAs (P=0.92).
Conclusions: Based on pre-specified analyses, DCR of AAs was non-inferior to Cs. The adjusted and unadjusted OR (0.79 and 0.91) were in favor of AA. Hence, ethnicity is not considered a significant predictor of disease control following second-line treatment with P.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B78.
Abstract ED01-03: Collecting blood biospecimens from Asian American communities through trust and informed consent
Authors: Dang Julie H.T. , Fang Dao M. , Chen Moon S. 
Published: June 2012

Abstract
Personalized medicine cannot be achieved without the public's willingness to contribute biospecimens for cancer research and their support for the research being conducted. In many cases, the historical and cultural mistrust by racial/ethnic minorities in biomedical research stem from the adverse legacy of uninformed consent in communities of color; from Tuskegee to the Havasupai Indians, these events have amplified the disconnect between researchers and these minority communities. Engaging these communities in biospecimen contribution for cancer research requires: time, trust and talent. For sustained and respectful relationships, collecting blood biospecimens must be viewed as mutually beneficial and not as a one-sided effort. These collaborations should build community capacity to not only understand the value of biospecimens for cancer research but also advocate for their need. Researchers should commit to investing the time necessary to developing community relationships and earning community trust. Simultaneously, educational outreach efforts need to be ethnically specific, linguistically diverse, culturally appropriate and cognitively empowering. Building upon the past decade of the NCI funded Asian American Network for Cancer Awareness, Research and Training (AANCART)’s foundation of trust and service with the Asian American community, researchers were able to leverage relationships to not only introduce the idea of biospecimen contribution to the community, but to also exceed our expectations in collecting blood biospecimens from Asian Americans.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):ED01-03.
Abstract ED03-03: Tools for analysis of genome-wide methylation data: An application to prostate cancer
Authors: Devaney Joseph M. , Suer Funda , Kwabi-Addo Bernard 
Published: June 2012

Abstract
One of the major obstacles to effect treatment of cancer is tumor heterogeneity. Identification of markers that dictate avenues of treatment would be powerful tools in the fight against cancer. One potential marker that could be used is epigenetics. New analysis methods for epigenetic include genome-wide chips covering over 450,000 methylation sites located throughout the genome. This talk will focus on different methods of analysis for genome-wide methylation data from prostate cancer, and samples from healthy prostate samples. In addition, integration of methylation data with genetic data and additional molecular data (RNA profiling) will be discussed.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):ED03-03.
Abstract ED04-02: Are we moving beyond race in clinical care? Lessons from the RACE Project
Authors: Bonham Vence L. 
Published: June 2012

Abstract
Physicians hold attitudes about the causes of racial differences in health conditions, and they use race as a heuristic in their clinical practice. The presentation will explore the interaction of patient and provider characteristics on health care providers’ use of genetics and genomics knowledge in their clinical practice. Advancing this field of study requires research to assess how clinicians use and think about race and human genetic variation. Understanding physicians’ perceptions of race and genetics and its use in the clinical encounter as a context to shed light on contributors to racial and ethnic health disparities and the role genetic screening programs and genomic medicine may or may not have in reducing those racial and ethnic health disparities.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):ED04-02.
Abstract PL05-03: Tobacco-related disparities and the Family Smoking Prevention and Tobacco Control Act
Authors: Backinger Cathy L. 
Published: June 2012

Abstract
With the passage of the June 2009 Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act), the Food and Drug Administration (FDA) has regulatory authority over tobacco products, their manufacture, and their distribution and marketing. Since enactment, FDA has already taken significant regulatory actions including banning cigarettes with fruit of candy characterizing flavors; prohibiting the labeling of products with misleading terms such as ‘light,” “low tar,” and “mild;” issuing a broad set of restrictions regarding access to and marketing of cigarettes and smokeless tobacco products to those under 18; and issuing a final regulation requiring graphic health warnings for cigarettes. In addition, The FDA's Tobacco Product Scientific Advisory Committee (TPSAC) has addressed the public health effects of menthol in cigarettes, harmful and potentially harmful constituents, and “dissolvables.” Unlike other parts of FDA addressing the safety and efficacy of the products it regulates, the Center for Tobacco Products (CTP) bases its actions on a public health standard, i.e., CTP considers the risks and benefits to the population as a whole, including users and nonusers of tobacco products and addressing tobacco-related disparities is integral. For example, the TPSAC menthol report needed to address the impact on use of menthol in cigarettes on the public health, including such use among children, African-Americans, Hispanics, and other racial and ethnic minorities. As the new cigarette graphic health warnings are implemented in September 2012, it will be important to assess impact among several subpopulations such as youth and those with low income. This presentation will provide an overall summary of the Tobacco Control Act, the science needed to implement FDA regulatory actions, and how FDA can address tobacco-related health disparities.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL05-03.
Abstract A100: A phase 1, first in human, study of SCH 900105, an antihepatocyte growth factor (HGF) monoclonal antibody, in subjects with advanced solid tumors
Authors: Ramanathan Ramesh K. , Payumo Francis C. , Papadopoulos Kyriakos P. , Weiss Glen J. , Chambers Glenda , Iyengar Tara , Cotreau Monette M. , Jac Jaroslaw , Beeram Muralidhar , Costanza Cathy , Tolcher Anthony W. , Isaacs Randi E. , Bhargava Pankaj , Patnaik Amita 
Published: June 2012

Abstract
Background: SCH 900105 (formally AV-299) is a humanized anti-HGF IgG1 monoclonal antibody with potent anti-tumor effects in vitro and in xenograft mouse models. The HGF/c-Met pathway was found to mediate several cellular functions involved in tumorigenesis and metastasis such as cell proliferation, angiogenesis, survival, migration and invasion. Clinical studies are ongoing to evaluate SCH 900105 in oncology patients.
Methods: A Phase 1 dose escalation study (3+3 design) was conducted in subjects with advanced solid tumors to evaluate the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and pharmacodynamics of SCH 900105. Administration of SCH 900105 was IV over 30–60 min, at a dose of 2, 5, 10 or 20 mg/kg once every 2 weeks (1 cycle).
Results: Twenty four patients are enrolled; 10M/14F, median age 63 (range 19–87), ECOG PS 0 (3), 1 (20), 2(1). No. of subjects per dose: 2 mg/kg (n=3), 5 mg/kg (n=3), 10 mg/kg (n=3), 20 mg/kg (n=15). Tumor types: mesothelioma, ovarian, sarcoma (n=3 each); GBM (n=2); colon, rectal, laryngeal, thyroid, hepatocellular, head & neck, urothelial, adenoid, vaginal, carcinoid, esophageal, pancreatic, breast. Preliminary data indicate that the most frequently reported GR1/2 AEs were fatigue (37.5%), peripheral edema (29.2%), nausea (25%), headache (20.8%), chills (16.7%) and dizziness (16.7%). GR 3 AEs were fatigue and vomiting (4.2% each). There were no GR 4 AEs reported and no DLTs occurred during the study. No HAHA to SCH 900105 have been detected in patient serum samples. The current median duration of treatment is 4 cycles (mean 5.3; range 1–17 cycles). Stable disease has been seen in 10/22 patients who were evaluable for response. Longest duration of SD (currently ongoing at 34 weeks) is in patient with papillary thyroid cancer. Preliminary data show dose proportional PK. Steady state serum levels of ∼19 g/mL were achieved after dosing at 2 mg/kg. Updated results, including serum HGF levels, will be presented at the meeting.
Conclusions: The study has completed accrual and SCH 900105 was safe and well tolerated at all dose levels evaluated. There were no DLTs noted and the highest dose evaluated (20 mg/kg) with 15 patients, is well tolerated. A Phase 1b combination study of SCH 900105 and erlotinib is underway and Phase 2 studies are being planned.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A100.
Abstract A109: BMS-754807, an oral, dual IGF-1R / insulin receptor (IR) inhibitor: Early pharmacodynamic (PD) and positron emission tomography (PET) imaging results from a daily-dose study in cancer subjects
Authors: Desai Jayesh , Solomon Benjamin , Davis Ian D. , Lipton Lara , Scott Andrew M. , Hicks Rodney J. , Hayes Wendy , Finckenstein Friedrich Graf 
Published: June 2012

Abstract
Background: Inhibiting both IGF-1R and IR signaling may be required to disrupt the malignant phenotype regulated by the receptor family. BMS-754807 is a potent and selective reversible inhibitor of IGF-1R/IR family kinases (IGF-1R, IR; Ki &lt;2nM). In non-clinical studies BMS-754807 is an effective inhibitor in a broad range of human tumor types in vitro and in vivo and demonstrates synergies when combined with cytotoxic and targeted agents.
Methods: CA191002 is an ascending multiple-dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS-754807 in subjects with solid tumors. Dosing occurs daily 2 hours after a light breakfast and is followed by a 4 hour fast. PD effects on IR are studied by assessments of plasma glucose, insulin and C-peptide. 2-deoxy-2-[18F] fluoro-D-glucose (FDG)- and 3′-deoxy-3′-[18F] fluorothymidine (FLT)-PET imaging is performed both as imaging markers for PD and to assess anti-tumor activity.
Results: Sixteen subjects have been treated at daily doses of 4, 10, 20, 30 or 50 mg. No dose limiting toxicities have been observed and dose escalation is ongoing. Duration of dosing was between 8 and 197 days. Preliminary analysis shows dose related increases of plasma glucose, insulin and C-peptide at 2 hours post-dose (Table 1). The range [median] of plasma glucose at all time points was 68 –187 [95], 50 – 168 [103] and 54 –333 [124] mg/dL in subjects treated at the 4, 10 and 20, and 30 and 50 mg dose levels, respectively. 65 PET scans have been collected from 14 subjects. Preliminary analysis shows that 1 subject with osteosarcoma and 1 subject with adenoid cystic carcinoma achieved 57 and 28 % reduction of tracer uptake, respectively, on FLT-PET by D12. Both had stable metabolic disease on FDG-PET by D12 and D56.
Conclusion: PD effects of IR inhibition differentiate BMS-754807 from IGF-1R specific agents. PET results suggest anti-tumor activity. Future analysis of PD effects, PET imaging data, safety information and response assessments will provide the basis for a rational selection of subjects and a dose or dose range to be further explored.
Dose level (number of subjects) Plasma glucose [mg/dL] D1 and 8 2 h post-dose range [median] Insulin [µU/mL] D1 and 8 2 h post-dose range [median] C-peptide [ng/mL] D1 and 8 2 h post-dose range [median] 4 mg (3) 77 – 101 [94] 2 – 82 [12.5] 0.8 – 7 [1.8] 10 and 20 mg (7) 90 – 144 [97] 27 – 251 [58] 3 – 18 [4.6] 30 and 50 mg (6) 110 – 200 [137] 120 – 361 [210] 5 – 17 [12.1]
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A109.
Abstract A157: Double-targeted therapy against melanoma: p53 activation sensitizes melanoma cells to MEK inhibition
Authors: Ji Zhenyu , Njauw Ching-Ni , Tsao Hensin 
Published: June 2012

Abstract
BRAF is mutated in approximately 70% of human melanomas. Although depletion of oncogenic BRAF resulted in tumor regression in mouse melanoma model, clinical development of anti-BRAF signaling therapy has not been successful up to date. One of the possibilities is that human melanoma cells may use redundant signaling events to adapt to harsh environment induced by BRAF shutdown. p53 is a major tumor suppressor and is not mutated in most human melanomas, which makes p53 a valuble target for melanoma therapy development. Here, we show that p53 is inducible in most human melanoma cell lines in response to DNA damage. Nutlin-3a, an MDM2 inhibitor, increases p53 protein expression as well as its activities in melanoma cells. Addition of nutlin-3a significantly increases sensitivity of melanoma cells to MEK inhibitor U0126 induced cell death or cell cycle arrest. In addition, knockdown p53 by specific shRNAs effectively rescues apoptosis induced by MEK inhibitor and/or p53 activation. This data suggests that p53 activity is required for cell death induced by MEK inhibiors and/or p53 activators. In conclusion, p53 is a therapeutic target in human melanomas and its reactivation potentiates cell death induced by BRAF/MEK signaling inhibitory agents in p53 wild type melanomas.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A157.