bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B19: Reasons for refusal to participate in an epidemiologic study of minority women
Authors: Sexton Krystal R. , Wiggins Shannon N. , Bondy Melissa L.
Published: June 2012

Purpose: It is widely believed that minorities are less willing than non-Hispanic whites to participate in biomedical research studies. However, to our knowledge, there are no data comparing refusal rates between African-Americans and Mexican-Americans. We assessed refusal rates and reasons for non-participation in an epidemiologic study of breast cancer in African-American and Mexican-American women.

Methods: The multi-center ELLA Bi-National Breast Cancer Study compares patterns of breast cancer tumor markers between women of Mexican descent in both the United States and Mexico. At the University of Texas MD Anderson Cancer Center (MDACC), both Mexican-American and African-American women are screened and recruited by trained study personnel, and an in-person interview is conducted. For women refusing to participate, demographic and clinical characteristics and reasons for refusal are collected at the time of refusal. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between race/ethnicity and refusal to participate. The current study uses data only from MDACC.

Results: Approximately 1,870 women were screened to determine eligibility. Of those, 914 were eligible, and 850 (93%) of the eligible women agreed to participate. The two most common reasons for refusal were lack of interest and being too overwhelmed with their breast cancer diagnoses, and 10% of the women stated that their families did not approve of their participation. Those refusing to participate were more likely to be African-American (p<0.001), late stage (p=0.01), and older age at diagnosis (p=0.02). Among African-American women, those refusing to participate were older (p=0.02), later stage at diagnosis (p=0.06), and less educated (p=0.06) compared to the participants. There were no significant differences between the Mexican-American participants and refusals. After adjusting for age and stage at diagnosis, African-American women were twice as likely to refuse participation as Mexican-Americans (OR=2.06, 95% CI: 1.11–3.83).

Conclusions: Overall, African-American and Mexican-American women were willing to participate in an epidemiologic breast cancer study, and our participation rates were higher than those previously reported for both African-Americans and Hispanics. Studies have shown that participation rates are higher among women and among cases, two factors potentially contributing to our low refusal rates. It is also possible that our study of only minority women led to low refusal rates among African-American and Mexican-American women. However, African-American women were more than twice as likely to refuse participation, and we must identify which factors influence the decision of minority women to participate in medical research studies.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B19.
Abstract B35: SLUG-induced plakoglobin gene repression in triplenegative breast cancer cells
Authors: Bailey Charvann K. , Mittal Mukul K. , Misra Smita , Chaudhuri Gautam
Published: June 2012

Breast cancer with the triple-negative phenotype (TNBC) are ER-negative, PR-negative and ERBB2 (HER2)-negative and represent one of the most aggressive and difficult to treat subtypes of human breast cancer. TNBC is highly over-represented in African American breast cancer patients and determining the genetic and molecular basis for this incidence and the biological basis for the aggressiveness of TNBCs are largely unknown and of high priority. The transcription factor SLUG, which controls epithelial to mesenchymal transition, stem cell phenotypes and therapeutic responsiveness, is highly expressed in the basal-type TNBC cells, making it a candidate master regulator of the TNBC phenotype. Plakoglobin, also known as γ-catenin or JUP, is a member of the armadillo motifcontaining proteins. This protein is a critical component of the desmosomal structure conferring structural integrity and resistance from mechanical stress to epithelial cells in tissues. We report here that SLUG inhibits the expression of several desmosomal proteins including the plakoglobin gene directly and thus, among other downstream effects, help disseminating the TNBC cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high TNBC cells elevated the levels of plakoglobin. Inhibition of SLUG activity with a molecular decoy in the TNBC cells abrogated the inhibitory effect of SLUG on plakoglobin gene expression. Although overexpression of SLUG in the SLUG-deficient cells elevated the invasiveness and motility of these cells, knockdown of plakoglobin only affected the growth and migration rates of these cells. This study thus implicates high levels of SLUG and low levels of plakoglobin as determinants in the progression of highly disseminating breast cancer of the TNBC type.

Supported by the DOD-CDMRP BCRP Grants W81XWH-06-1-0466, W81XWH-08-1-0446, BC086542, and the Susan G. Komen Breast Cancer Foundation grant# BCTR0707627 to GC.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B35.
Abstract B36: Development of calcitrol-resistance in triple-negative breast cancer cells through SLUG-mediated coordinate repression of CYP2R1, CYP27B1, and VDR gene promoters
Authors: Johnson Shari M. , Mittal Mukul K. , Bailey Charvann K. , Misra Smita , Chaudhuri Gautam
Published: June 2012

Metastatic breast and other cancers are often found to be refractory to vitamin D therapy. Vitamin D is synthesized from 7-dehydrocholesterol, an intermediate metaboltie in cholesterol synthesis. Ultraviolet irradiation in sunlight-exposed skin induces a photochemical reaction of 7–25-position by vitamin D 25-hydroxylase (CYP2R1), to yield 25-hydroxyvitamin D3 (cholecalciferol). Vitamin D3 is hydroxylated at the 25-position by vitamin D 25-hydroxylase (CYP2R1), to yield 25-hydroxyvitamin D3 (25(OH)D3; 25-hydroxycholecalciferol), the major form of vitamin D in the circulation. 25(OH)D3 is further hydroxylated at the 1 -position by the 25-hydroxyvitamin D 1 -hydroxylase (CYP27B1) to produce calcitrol (VD3). VD3 exhibits physiological and pharmacological effects by binding to the vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. Although photoactivated cholecalciferol is mainly hydroxylated in the liver and kidney, many other cells including breast cells have significant expressions of CYP2R1, CYP27B1 and VDR. Breast cells thus should be able to activate and utilize cholecalciferol if these proteins are not suppressed. We report here that the metastasis modulator protein SLUG, which is often overexpressed in metastatic triple negative breast cancer cells, coordinately repressse the levels of CYP2R1, CYP27B1 and VDR proteins in the breast cancer cells to induce vitamin D-resistance in these cells. SLUG inhibited CYP2R1, CYP27B1 and VDR gene promoter activities in these cells. ChIP assays revealed that SLUG is recruited at the CYP2R1, CYP27B1 and VDR gene promoters. Knockdown of SLUG in highly invasive MDA-MB-231 and BT549 cells increased their CYP2R1, CYP27B1 and VDR gene expression and decreased their resistance their resistance to VD3 in vitro. Our data established that SLUG regulates vitamin D metabolism and contributes to the induction of VD3-resistance in human breast cancer cells through the inhibition of CYP2R1, CYP27B1 and VDR gene promoters epigenetically through chromatin remodeling.

Supported in parts by the DOD-CDMRP grants BC050641 and BC103645.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B36.
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

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

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

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

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

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

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

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

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

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

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 <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

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.
Abstract A225: The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG
Authors: Keen Heather , Ricketts Sally-Ann , Bales Juliana , Shannon Aoife , Logie Armelle , Odedra Rajesh , Wedge Steve , Guichard Sylvie
Published: June 2012

Introduction: mTOR is a a sensor of mitogen, energy and nutrient levels and a central controller of cell growth. mTOR is present in two multi-protein complexes: mTORC1, rapamycin sensitive and containing raptor, and mTORC2, rapamycin-insensitive. AZD8055 is a small molecule ATP competitive inhibitor of mTOR kinase, thus inhibiting both mTORC1 and mTORC2. This results in a greater reduction of mTORC1 substrates pS6 on Ser235/236 and p4EBP1 on T37/46 compared to rapamycin. AZD8055 also reduces the mTORC2 substrate pAKT on Ser473. The PI3K-AKT-mTOR pathway is involved in glucose uptake/metabolism. 18F-Flurodeoxyglucose (18F-FDG) is a biomarker for glucose metabolism detectable by positron emission tomography (PET). It is used in clinical oncology for tumor diagnosis and is currently under evaluation for therapy monitoring. The aim of this study was to assess the impact of a single and 4 daily dosing of AZD8055 on 18F-FDG uptake in U87-MG human glioma xenografts implanted subcutaneously in nude mice.

Methods: AZD8055 was administered orally at a dose of 20 mg/kg qd for 1 or 4 days. Animals received either vehicle or AZD8055 1 hour prior to imaging. Mice were anaesthetised and then injected with approximately 15 MBq 18F-FDG i.v. via the tail vein. Forty-five minutes later, mice underwent PET scanning (20 minute scan, 3D histogramming and OSEM2D reconstruction) followed by biodistribution analysis. Image analysis was carried out using Inveon Research Workplace (IRW) software. Biodistribution data were derived from gamma counting.

Results: Plasma drug concentrations were not modified significantly by anesthesia and the imaging procedure. In the vehicle and AZD8055-treated groups, tumor volumes were comparable after single dose, but differed significantly following 4 days of treatment due to drug effect. Image analysis of 18F-FDG uptake after single and multiple doses showed that there was a significant difference (p<0.05) in meanSUV, maxSUV and the percentage of injected dose per gram of tissue (%ID/g) between vehicle and drug treated tumors. Biodistribution analysis showed that the average 18F-FDG %ID/g in vehicle-treated tumors was significantly higher than in AZD8055-treated tumors (p<0.05).

The changes in glucose uptake after 1 and 4 administrations were consistent with the pharmacodynamic effects of AZD8055 on pS6 and pAKT biomarkers in U87-MG tumors collected at the same time-points.

Conclusions: AZD8055 reduces significantly 18F-FDG uptake in U87-MG human glioma xenografts, as early as 1 hour after a single dose. This data suggests that 18F-FDG uptake could be used as an early sign of metabolic response to AZD8055.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A225.
Abstract A241: Searching for extracellular signal-regulated kinase (ERK)-independent molecular targets of sorafenib in hepatocellular carcinoma (HCC)
Authors: Fan Hsiang-Hsuan , Yu Sung-Liang , Ou Da-Liang , Shen Ying-Chun , Huang Yi-Ting , Hsu Chiun , Cheng Ann-Lii
Published: June 2012

We have recently identified Bim, a pro-apoptotic factor regulated by ERK signaling pathway, is an important mediator of sorafenib-induced apoptosis in HCC cells.. In this study we further explored other possible mediators of sorafenib activity in HCC cells that is independent of mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK)/ERK signaling. Huh7 cells were treated with sorafenib or the MEK inhibitor CI-1040, alone or in combination, for 24 hours. The gene expression profiles were analyzed by Affymetrix oligonucleotide microarray analysis using HG_U133A chip, and the candidate genes were selected if (1) they had > 1.2 fold or < 0.8 fold change than control after treatment with sorafenib 10 M and (2) they had been reported to be involved in important carcinogenesis-related cellular signaling pathways, such as apoptosis regulation, cell proliferation/survival, cell cycle control, and angiogenesis. The gene expression was considered MEK/ERK-dependent if the direction of changes was similar after treatment with sorafenib 10 M or CI-1040 1 M; otherwise it was considered MEK/ERK-independent. Thirty candidate genes of interest were identified and the expression patterns were validated by real-time PCR (see table). The 14 genes whose expressions were considered ERK-independent involved apoptosis regulation (GADD45b, BAX, JUN), cell proliferation (PCNA, RPS6KA3, SMAD7, BMP2, DUSP1, DUSP8, IL1RAP, RHEB), cell cycle control (CCNE1, CDC25A), and angiogenesis (VEGF). Validation of the biological significance of these markers is ongoing. The preliminary data revealed that induction of GADD45b and JUN gene expression after sorafenib treatment was correlated with intrinsic or acquired resistance of HCC cells to sorafenib. Our data indicated that MEK/ERK-independent signaling pathways may also contribute to sorafenib-induced apoptosis and growth regulation in HCC cells. The signaling molecules identified in this study can serve as novel therapeutic targets for HCC. (Supported by grants NSC97-3112-B-002-012, NSC98-3112-B-002-007, NSC98-3112-B-002-037)

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A241.
Abstract B121: Phase I study of MK-0646, a humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine + erlotinib (E) for advanced previously untreated pancreatic cancer
Authors: Javle Milind , Varadhachary Gauri , Bhosale Priya , Shroff Rachna , Ukegbu Lerma , Overman Michael , Wolff Robert , Abbruzzese James
Published: June 2012

Background: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/Akt signaling. Collectively, these pathways are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. IGF-1R + EGFR antagonists result in synergistic anti-tumor activity in preclinical pancreatic cancer models.

Methods: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0–1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Arm A: G 1000 mg/m2 over 100 min, weekly × 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly × 4; Arm B: same schedule of G and MK-0646 as Arm A + E 100 mg daily. Cycles were repeated every 4 weeks. Radiologic responses measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival (PFS), response rate, toxicity and overall survival.

Results: 22 pts enrolled, 15 males, 2 priorWhipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1–8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Two dose limiting toxicities observed in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Best radiologic responses: 6 PR (including 1 hepatic CR), 7 PD, 3 SD, 4 too early, 1 not evaluated, 1 not treated. PFS range in weeks for evaluable patients (n=12) was (4, 36+).

Conclusion: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B121.
Abstract B163: Pharmacokinetic analysis and preclinical evaluation of the SMAC mimetic TL32711 in an orthotopic human breast tumor xenograft model
Authors: Moore Mitchell M. , Estrada Vanessa A. , Nieves Francis E. , Burns Jennifer M. , Mitsuuchi Yasuhiro , Chunduru Srinivas K. , Graham Martin A. , McKinlay Mark A. , Tolcher Anthony W. , Wick Michael J.
Published: June 2012

Inhibitor of Apoptosis Proteins (IAPs) are cellular proteins that prevent cell death by apoptosis and are frequently overexpressed in cancer cells resulting in elevated levels leading to cancer survival and progression. Currently we are developing a class of compounds called SMAC mimetics that reverse the effects of IAPs including XIAP, cIAP-1 and cIAP-2 and ML-IAP causing cancer cells to undergo apoptosis in a broad range of tumor types. TL32711 is a SMAC mimetic which has demonstrated potent and selective activity in several human tumor cell lines as well as in vitro inhibition of IAP target proteins. To determine translational effects in vivo, we evaluated PK/PD and single agent antitumor activity of TL32711 in an orthotopic human breast tumor xenograft model. Single agent toxicity as well as tumor growth inhibition, delay and regression were monitored in the study. The designated endpoint for the efficacy experiment was a mean control tumor volume of approximately 1 cm3.

TL32711 administered by intravenous injection on a q3dx5 schedule was well tolerated up to 10 mg/kg alone, the highest dose tested. The minimal effective dose was determined to be 1.25 mg/kg. When tumors were allowed to grow to 260 mm3 prior to initiation of treatment, the treatment effect was not diminished. PK/PD analysis of TL32711 found a longer half-life of TL32711 in tumor compared to normal tissue and a time and dose dependent inhibition of the target protein cIAP-1. The effects on the cIAP-1 target were in good agreement with the tissues levels measured using a LC/MS method. TL32711 was not found to cross the blood brain barrier in this analysis.

Results from these studies confirm translational effects of TL32711 in a preclinical model of human breast cancer. In addition, PK/PD analysis demonstrated dose and time dependent target inhibition in vivo and decreased half life in tumor tissue.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B163.
Abstract B166: Effects of PTX-008, a non-peptidic topomimetic targeting galectin-1 in human epithelial cancer cells
Authors: Astorgues-Xerri Lucile , Serova Maria , Bieche Ivan , Vivier Sabrina , Cvitkovic Esteban , Noel Kay , Raymond Eric , Faivre Sandrine
Published: June 2012

Galectin-1, a lectin implicated in several biological processes, selectively binds neuropilin-1, enhances VEGFR2 signalling, and contributes to membrane anchorage of H-RAS in cancer cells. PTX-008 is a calyx[4]arene analogue designed as a galectin-1 mimetic, showing antiangiogenic properties in vitro and in vivo in tumor models. In this study, we investigated the potential antiproliferative effects of PTX-008 in a panel of colon (HT29, HCT116, COLO205, HCC2998), breast (MCF7, MDA-MB-435, SKBR3, ZR-75-1), ovarian (OVCAR3, IGROV1, SKOV3), lung (HOP62, HOP92), prostate (PC3, DU145), head and neck (SCC61, SQ20B, HEP2), hepatocellular carcinoma (SK-HEP1) and renal (CAKI1) human cancer cell lines. Antiproliferative effects were detected in several cancer cell lines (SQ20B, HT29, and COLO205 cell lines, range 3–9µM). In contrast, HEP2 and DU145 cell lines appear to be resistant to PTX-008 (>27µM). The antiproliferative effects of PTX-008 were mainly associated with G2/M accumulation with marginal apoptosis induction. No correlation was found between the antiproliferative effects of PTX-008 and the mRNA expression of several growth factors and tyrosine kinase receptors such as VEGF/VEGFR, EGF/EGFR, and PDGF/PDGFR as determined by qRT-PCR analysis. In our panel, epithelial cancer cells - expressing high mRNA levels of E-cadherin and low levels of N-cadherin and vimentin - were more sensitive to PTX-008 than mesenchymal cells. Interestingly, antiproliferative effects of PTX-008 in cancer cells were more pronounced in cancer cells with low galectin-1 mRNA and protein expression. Exogenous semaphorin-3A exposure potently inhibits cell proliferation, mimicking the effects of PTX-008, while concomitant exposure to PTX-008 with exogenous semaphorin-3A has strong antiproliferative effects in SQ20B cells. Furthermore, modulation of galectin-1 with PTX-008 followed by VEGFR/PDGFR inhibition with sunitinib resulted in enhanced antiproliferative effects in SQ20B. In SQ20B cells, PTX-008 as well as exogenous semaphorin-3A activate rapidly p-AKT473 and p-ERK1/2Thr202/Tyr204 but have no effect of p-S6KSer235/236, further suggesting that some of the antiproliferative effects of PTX-008 may be related to the modulation of neuropilin-1. These findings suggest that PTX-008 may have direct antiproliferative activity in cancer cells, with a novel mechanism that differs from the currently available kinase inhibitors.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B166.
Abstract B242: A phase I/II study of oncolytic reovirus plus chemotherapy (carboplatin/paclitaxel) in patients with advanced solid tumors (with emphasis on patients with squamous cell carcinoma of the head and neck (SCCHN)
Authors: Harrington Kevin J. , Karapanagiotou Eleni M. , Hardev Pandha , Nutting Christopher M. , Gore Martin , Karl Mettinger , Geoff Hall , Melcher Alan , Mercel Ball , Coffey Matt , Thompson Brad , Chester John
Published: June 2012

Background: Reovirus is a double-stranded RNA virus which replicates in cells with activated Ras signaling pathway, while sparing normal cells. Following our recent study of intravenous (i.v.) reovirus in patients with advanced malignancies1, we have conducted a Phase I/II dose escalation study of i.v. reovirus in combination with chemotherapy.

Methods: REOLYSIN® was administered to cohorts of 3 patients in escalating doses (3 × 109, 1 × 1010, 3 × 1010 TCID50) on days 1–5 while carboplatin AUC 5 and paclitaxel 175 mg/m2 were administered on day 1 of a 3-weekly schedule. Eligible patients had good performance status (ECOG PS: 0–2) with advanced cancers which were not amenable to curative treatment or were refractory to standard therapy for which paclitaxel/carboplatin was appropriate palliative chemotherapy.

Results: Twenty-three patients (15 males, median age 56.9 years) with head and neck cancer (n=17), melanoma (n=4) or peritoneal/endometrial cancer (n=2) received 106 cycles (median 6, range 1–8) of combination treatment. In the dose-escalation phase of the study, there were no dose-limiting toxicities. Grade 3/4 toxicities included anaemia, leucopenia, neutropenia, lymphopenia, thrombocytopenia, infection and hypotension. Viral shedding (as assayed by reverse transcription PCR) has been documented in 2 patients. Neutralising anti-reovirus antibody responses have been measured using a previously reported technique2 and will be presented.

In the Phase 1 study partial responses (PR) were noted in one of four patients with melanoma and in two of five patients with head and neck cancer. An expanded cohort of head and neck cancer patients was therefore treated at the maximum dose level (3 × 1010 TCID50) in order to further assess tumor response in this setting.

To date, 14 patients with head and neck cancer have received at least two cycles and are evaluable for response. Most of them were refractory to previous platinum-based chemotherapy for recurrent/metastatic disease. PR was seen in 6 patients (43%), SD in 5 (36%) and PD in 3 (21%). The study is ongoing.

Conclusion: Intravenous administration of reovirus in combination with carboplatin/paclitaxel is a safe and well-tolerated combination with promising anticancer activity in SCCHN. Further evaluation of this combination in a randomized Phase III trial in SCCHN is planned.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B242.