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University of Pittsburgh Lung Cancer SPOREScientific questions regarding this program can be addressed to: Administrative questions regarding this program can be addressed to:
OverviewJill M. Siegfried, PhD, Principal Investigator The University of Pittsburgh Cancer Institute (UPCI) is conducting a Specialized Program of Research Excellence (SPORE) in Lung Cancer. The overall goals of the Lung Cancer SPORE are to improve detection and treatment of lung cancer and to understand the mechanisms of increased susceptibility of women to lung cancer. The SPORE program consists of four major translational research projects in lung cancer, three research cores, an administrative core, a developmental research program, and a career development program. The Lung Cancer SPORE uses interdisciplinary approaches to meet its objectives by carrying out projects with co-investigators in basic, applied, and clinical science. It is also organ-specific in its approach; all projects test hypotheses about lung cancer biology, susceptibility, detection, or treatment. The long-term goal of the UPCI SPORE is to conduct clinical trials, based on research results from its translational research projects, that will serve as the basis for improving the outcome of patients diagnosed with lung cancer. The main projects are:
The research cores will assist the main research projects, developmental research projects, and career development investigators in carrying out lung cancer translational research. The research cores are Tissue and Blood Bank Core, Clinical Core, and Biostatistics Core. The Administrative Core will provide scientific and fiscal oversight for the program. The Clinical Core interacts with the laboratory investigators and other cores to initiate and implement the clinical activities. UPCI SPORE investigators work together as a team to meet the goals of the program and will also interact with investigators from Lung Cancer SPOREs at other institutions to improve outcome for lung cancer patients.
ProjectsPROJECT 1: INTERSECTION OF ESTROGEN RECEPTOR SIGNALING AND EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING IN LUNG CANCERJill M. Siegfried, PhD Co-Project Leader Lung cancer incidence is increasing in women worldwide and it is apparent from epidemiological studies that sex differences exist in the presentation of lung cancer. The proportion of patients diagnosed with lung cancer under age 50 is significantly higher for women compared to men (1). Women also are diagnosed to a greater extent than men with adenocarcinoma and small cell carcinoma (2, 3), both of which are secretory-type tumors. Never smokers diagnosed with lung cancer are also predominantly female (4). These differences in presentation suggest there are sex differences in the development of lung cancer. We hypothesize that one component of these sex differences is related to estrogen and its receptors. Evidence from our laboratory obtained during the first SPORE grant period shows that both known estrogen receptors (ERs), ER alpha (ERα) and ER beta (ERβ), are commonly expressed in non-small cell lung cancers (NSCLCs) of different histologic types. ERα appears to be mainly present as a variant protein of smaller molecular weight than full-length ERα, while ERβ protein is present at the expected size. These receptors are localized in both the nucleus and the cytoplasm, as well as some membrane localization, in NSCLC tissues and in normal lung. Genomic signaling through ERβ has been clearly demonstrated by us in NSCLC, as well as non-genomic signaling involving activation of the epidermal growth factor receptor (EGFR). The non-genomic signaling may involve both ERα and ERβ. We have evidence that combined targeting of the ER and the EGFR produces enhanced anti-proliferative effects in preclinical models. We also discovered that tumors from males contain ERs and can respond to estrogens. Many male lung tumors also appear to contain aromatase. This suggests that although some of the hormonal effects due to estrogen may be more pronounced in women compared to men due to a greater lifetime production of ligand, the ER pathway might also be targeted in males with NSCLC, especially if local estrogen production in lung tissues is present via aromatase, or if ligand-independent signaling plays a role in ER action in the lung. The hypothesis under investigation in Project One of the UPCI Lung Cancer SPORE renewal is that ER expression and signaling have functional significance in NSCLC. Based on results obtained in the first SPORE grant period, we hypothesize that ER and EGFR both activate proliferative signaling pathways in NSCLC; these pathways overlap and interact. Co-inhibition of ER and EGFR may show greater anti-tumor activity in NSCLC than inhibition of either pathway alone. THE SPECIFIC AIMS ARE:Determine signaling molecules involved in ER-EGFR pathway interactions in NSCLC cell lines. We will ask the following questions in this aim: (a) Does EGFR cause ligand–independent activation of ERα and ERβ in NSCLC cells, resulting in genomic signaling in the absence of estrogen? (b) Does the ligand-dependent activation of ER that causes EGFR activation (non-genomic signaling) depend on Src, and can EGFR activation by ER be interrupted by Src inhibitors? We will examine cell lines that have both wild-type EGFR and EGFR with mutation in the tyrosine kinase domain. Examine effectiveness of joint inhibition of the ER-EGFR pathways on tumor growth in NSCLC compared to single therapy in NSCLC, using clinically relevant agents. We will ask the following question in this aim: Is the anti-tumor efficacy of combined ER/EGFR and/or Src targeting using clinically relevant agents superior to targeting individual pathways in preclinical models? Determine if aromatase is present and functional in normal and malignant lung cells and if an aromatase inhibitor has anti-tumor activity. We will ask the following questions in this aim: (a) How common is the expression of aromatase, the enzyme that synthesizes estrogen, in normal and malignant cells from the human airway? (b) Does aromatase function sufficiently in cultured normal and malignant cells from human airway to result in measurable production of estrogen? (c) Do primary NSCLC tissues from males and females contain aromatase, which cell types within tumors express it, and is aromatase related to other parameters such as ER expression, sex, histology, or outcome? (d) Does an aromatase inhibitor have anti-tumor effects against NSCLC in preclinical models? Analysis of ER and EGFR status in tissues obtained from NSCLC patients treated on clinical trials of combination therapy (anti-estrogen and EGFR TKI). We will ask the following questions in this aim: (a) Does combination therapy produce anti-tumor effects against late-stage NSCLC? (b) Is combination therapy superior to targeting the EGFR pathway alone? (c) What is the relationship between response to therapy and ER and EGFR pathway signaling in NSCLC patients? (d) Are variations in the EGFR gene observed in association with therapeutic response to combination therapy, and what are the characteristics of patients who show clinical benefit? TRANSLATIONAL VALUE OF PROJECT ONETargeting the EGFR through small molecule tyrosine kinase inhibitors (TKIs) to date is of limited utility in the absence of an EGFR mutation, which occurs in a minority of lung cancer patients. Even with an EGFR mutation, duration of response to EGFR TKIs may be short and resistance also develops through selection of further EGFR mutation (T790M) (5). Understanding how ER and EGFR interact in NSCLC will provide a rational basis for therapies targeting these two pathways to increase the effectiveness of EGFR targeted therapy. Combination therapy may increase duration of response in the presence of mutant EGFR, as well as improve therapeutic response in patients with wild-type EGFR. Results to date of a Phase I clinical trial being carried out in the first SPORE grant period (described below) targeting both pathways together with a gefitinib/fulvestrant combination showed that combination therapy is safe and has anti-tumor activity in Stage IIIB/IV female post-menopausal NSCLC patients. Further testing of combination therapy (erlotinib/fulvestrant) compared to single therapy in animals and humans, proposed in this project, will determine whether combination therapy gives superior anti-tumor effects compared to EGFR TKI monotherapy. Since erlotinib increased survival in NSCLC patients in a Phase III trial vs. placebo/best supportive care, while gefitinib did not, erlotinib will be substituted for gefitinib in this project. Increased understanding of the role of estrogen, estrogen synthesis, and ER in lung cancer will provide a rationale for future targeting of this pathway for therapy earlier in the course of disease as well as for future testing of a role for anti-estrogens in lung cancer prevention. Role of Inter-SPORE Collaborations: Aims 3 and 4 of this project are collaborations with the UCLA Lung Cancer SPORE (Steven Dubinett, MD, PI). Regarding Aim 3, the UCLA SPORE is also examining aromatase in NSCLC and finds expression of this enzyme in both lung tumor cell lines and in tissues from lung cancer patients. The UCLA SPORE has also documented conversion of testosterone to estrogen in NSCLC cell lines and has shown anti-tumor effects of the aromatase inhibitor, anastrazole, in the NSCLC cell lines A549 and H23. We plan in our Aim 3 to utilize cell lines (including NSCLC cell lines, normal lung fibroblasts and human bronchial epithelial cells) and NSCLC tissues not being studied at UCLA, to demonstrate how widely aromatase protein and function is present in lung cancer. We will also examine a different set of NSCLC patients’ tumor and normal tissues for aromatase activity by immunohistochemistry. Since the role of aromatase in NSCLC is an entirely novel area of investigation, this joint endeavor will help to increase new knowledge and to confirm each SPORE’s findings. We plan to share our preclinical data and compare results with different aromatase antibodies in Aim 3 as well as to share the data from the other aims with the UCLA group, thus allowing the work to proceed at a faster pace. In Aim 4, the Phase II clinical trial involving erlotinib alone versus erlotinib plus the anti-estrogen fulvestrant will be conducted jointly at UCLA and Pittsburgh. We intend to enroll patients at each institution and to carry out the analysis of clinical response and signaling molecules in the patients’ paraffin-embedded tumors jointly. We will analyze the data from the clinical trial together and present and publish it together. Aims 1 and 2 are also collaborations with the University of Pittsburgh Head and Neck Cancer SPORE (Jennifer Grandis, M.D., PI). Drs. Siegfried, Stabile, and Grandis are undertaking a developmental research project in the Pittsburgh Head and Neck Cancer SPORE to determine the extent of ER expression in head and neck cancers, and the signaling pathways activated by estrogen. The preliminary data suggest that ERβ is expressed by all head and neck cancer cell lines examined, and estrogens increase cell proliferation and ERE transcriptional activity in head and neck cancer cell lines, while the anti-estrogen fulvestrant can inhibit these responses. Knowledge from each tumor type will be shared between our two SPOREs, and if the preclinical data from head and neck cancers provides a rationale for treatment with anti-estrogens (alone or in combination with an anti-EGFR agent), Drs. Grandis and Siegfried will propose a clinical trial for head and neck cancer patients in the Head and Neck SPORE.
PROJECT 2: CYCLIN B1 IMMUNOTHERAPYCo-Project Leaders: Olivera J. Finn, PhD This project is a continuation of a project carried out in the first 5-year grant period that validated Cyclin B1 (CB1) as a lung tumor antigen. The first hypothesis that we proposed to test in the continuation of this project is that vaccines will elicit or boost CB1-specific immunity in lung cancer patients and this will result in an anti-tumor effect. The second hypothesis we proposed to test is that the immune response against CB1 could be a biomarker of risk for development of future lung cancer in subjects with a positive smoking history, or for recurrence among early-stage patients newly diagnosed with lung cancer. To test these hypotheses we proposed three specific aims. SPECIFIC AIM 1. Test in phase I/II clinical trials toxicity and immunogenicity of cancer vaccines composed of CB1 peptides and proteins processed and presented by dendritic cells (DC), in combination with novel delivery of adjuvants, and evaluate immune effector mechanisms generated. Patients in these trials will be those with resectable stage I and II lung cancer. The first trial will be carried out in HLA-A2+ patients and will test a vaccine composed of DC loaded with two CB1 peptides known to elicit HLA-A2 restricted CTL, and transdermal adjuvant. The second trial will test DC loaded with recombinant CB1 protein plus transdermal adjuvant, and thus it will be open to patients of all HLA types. Vaccinated patients will be observed for signs of toxicity or adverse reactions to the vaccine, and examined pre and post vaccination for the following immune responses: CB1 specific antibodies (IgM, IgG, IgA) by ELISA; CB1 specific CD4 and CD8 T cells (IFN- or IL-4), by ELISPOT and intracellular cytokine staining; for general immune responsiveness that may reveal existence of T regulatory cells. Future trials will be designed based on the analysis of data from these two trials and availability of new adjuvants and methods to increase vaccine efficacy. SPECIFIC AIM 2. Perform detailed quantitative and qualitative analysis of spontaneously occurring CB1 specific antibodies and T cells in lung cancer patients at different stages of disease and in the PLuSS High Risk Sub-Cohort (described in Clinical Core). We will analyze antibody isotype, titer, and affinity. T cells will be studied for their phenotype (nave, effector memory, regulatory T cells) and cytokine production (Type I versus Type II). Fine antigen specificity will also be analyzed using a CB1 peptide library composed of overlapping 15-mer peptides, to look for evidence of immunodominant versus sub-dominant epitopes, which may influence effectiveness of the immune response. This information will be analyzed in the context of clinical outcome, in an attempt to define immune correlates of protection. This information will also be important for defining certain immune responses as surrogate end-points for monitoring efficacy of CB1 vaccines. SPECIFIC AIM 3. Assay for the presence or absence of CB1 specific antibodies in individuals at high risk for developing lung cancer (3,600 PluSS subjects) and in two retrospective sets of lung cancer cases, in order to evaluate the potential of the immune response to be a biomarker of risk for future lung cancer and/or a useful prognostic indicator. We will perform semi-automated high-throughput ELISA assays for detection of anti-CB1 antibodies that we have developed. ELISA will be designed to be isotype specific. Isotype switching is a T cell mediated event and different isotypes are promoted by the action of Th1 versus Th2 cells. The antibody data will be added to the information about other biomarkers defined elsewhere in the SPORE. Lung nodules that are resected as part of the diagnostic procedures for PLuSS participants with CT screening results of high suspicion will be stained for CB1 and immunohistology data correlated with ELISA data. A long-term follow up of antibody positive and antibody negative groups will test if the presence of antibody correlates with a higher or lower rate of lung cancer development in the entire PluSS cohort, and whether presence of antibody correlates with extent of CB1 expression in the resulting lung tumor. We will also determine whether CB1 immunity is associated with protection from recurrence by monitoring outcome of PLuSS participants as well as patients from Retrospective NSCLC Cohorts A and B. Data from this aim will be contributed to the data set on biomarkers being generated by Projects 3 and 4 using the PLuSS High-Risk Sub-Cohort, and the data on estrogen receptors and aromatase expression as it relates to clinical outcome in Project 1. The value of the immune response as a biomarker will be evaluated relative to the other markers. Our aims have not changed and in this first year of our project we have focused on Aims 1 and 2.
PROJECT 3: SERUM PROTEOMIC BIOMARKERS FOR LUNG CANCER DETECTION AND PROGNOSISCo-Project Leaders: William L. Bigbee, PhD OverviewOur ongoing effort in the second year of the new Project 3 has been focused in six areas: 1) the final analysis of the preliminary Luminex and SELDI-TOF-MS data and manuscript preparation; 2) database development and clinical annotation of the SPORE Lung Cancer Registry case/control patient cohort and standardized blood sample collection resources; 3) optimization and refinement of the initial Luminex multianalyte serum panels (xMAP) to include new candidate lung cancer markers and independent verification of preliminary results on the Searchlight multiplexed immunoassay platform; 4) development and finalization of new workflows for the depletion and fractionation of plasma/serum specimens for MALDI-T0F-MS comparative proteomic profiling and, most recently, LC-MS based label-free peptide quantitation and protein identification profiling for biomarker discovery; 5) final study design and case/control sample pooling strategy for analysis using the parallel MS discovery workflows; and 6) development and funding of complementary collaborative biomarker studies.
PROJECT 4: NUCLEOTIDE EXCISION REPAIR/CELL CYCLE CONTROL HAPLOTYPES AND LUNG CANCER RISK AND PROGNOSISCo-Project Leaders: Marjorie Romkes, PhD, Joel Weissfeld, MD, M.P.H., Emanuela Taioli, MD, PhD Specific AimsProject 4 of the UPCI Lung Cancer SPORE is investigating the hypothesis that nucleotide excision repair and cell cycle control gene haplotypes may not only predict lung cancer risk, but also drug resistance and survival. The ability to identify individuals with the highest risk of developing tobacco-related cancers, most importantly lung cancer, has important public health and clinical implications for screening, early detection, prevention and treatment. In addition to variability in activation and detoxification pathways of mutagenic agents, there is a very strong biologic rationale to also study the variability in the capacity to repair smoking induced DNA damage as another major family of susceptibility biomarkers. The nucleotide excision repair (NER) pathway is important in the repair of chemical carcinogen induced genotoxic damage. The XPD protein is a key member of this pathway and mutations in the XPD gene, including the common A35931C (Lys751Gln) variant allele, result in reduced repair capacity. Furthermore, regulation of the cell cycle control mechanism can influence the potential for increased cell proliferation and the promotion of genetic instability. Cyclin D1 (CCND1) is an essential cell cycle regulatory protein and is involved in the regulation of proliferation and differentiation. The CCND1 G870A single nucleotide polymorphism (SNP) has been reported to enhance alternate splicing and increase cyclin D1 protein half-life. Our initial case/control studies, partially supported by the previous SPORE Genomics Core, of which Dr. Romkes was the Director, have demonstrated a significant association between elevated risk of upper aerodigestive tract cancer among individuals who carried both the CCND1 G870A variant allele and XPD Gln allele (OR=7.1, 95%CI 4.0-12.5). We proposed to further investigate these preliminary results and to conduct a genetic epidemiological haplotype association study by evaluating polymorphisms of genes in the NER and cell cycle control pathways in a series of NSCLC cases and controls. The following Specific Aims are designed to validate these initial observations in a larger patient population and to also extend the model to a prospective study to evaluate the prognostic significance of the “at risk” haplotypes. Specific Aim 1. To select tagSNPs identifying haplotypes for genes of the NER and cell cycle control pathways. Specific Aim 2. To develop a model relating NER and cell cycle control pathway gene haplotypes to lung cancer risk. Specific Aim 3. To test the prognostic significance of the NER and cell cycle control pathway gene haplotypes by genotyping the PLuSS and Moffitt Cancer Center High-Risk sub-cohorts. Specific Aim 4. To develop a final predictive model by combining the datasets from Specific Aims 2 and 3 for purposes of external validation. Specific Aim 5. To evaluate whether the NER pathway haplotypes are associated with platinum drug resistance and survival.
BIOINFORMATICS/BIOSTATISTICS CORECore members have participated in the regular meetings of the Pittsburgh Lung Cancer SPORE. Dr. Land serves on the SPORE Tissue Utilization and Prioritization Committee evaluating requests for sample use. Another major contribution of the Core in Year 2 is the development of an Access database for data from the Carinal Registry Study. This database includes patient characteristics and clinical follow-up for patients whose tissues have been banked. Those samples are a rich repository for the experimental studies related to Projects 1 and 2 of the SPORE. The use of the Core by SPORE projects was as follows: PROJECT 1 — INTERSECTION OF ESTROGEN RECEPTOR SIGNALING AND EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING IN LUNG CANCER.Several studies have been conducted that provide additional pilot information for Project 1. In one study, tumor tissue from Carinal Registry patients was analyzed for ER-alpha, ER-beta, PR, aromatase, and EGFR markers. Statisticians Land and Shuai analyzed the associations between these markers and patient and tumor characteristics. In addition, overall survival and progression free survival were modeled based on marker expression, age at tissue collection, smoking, gender, histology, and disease stage. Analytic techniques included tree-based methods, Cox regression and Fisher’s exact tests. A manuscript is in preparation. Dr. Land also provided sample size calculations for a xenograft experiment for Project 1. Dr. Land is providing support for the dissertation project of Ji Young Song, student of Dr. Weissfeld. That study will be a comparison of ER expression in Carinal Registry Study lung tissue with tissue from non-cancer controls, and an examination of the relevance of ER expression in normal lung tissue to lung cancer outcomes in Carinal patients. Dr. Land also provided a statistical analysis plan and sample size calculations for proposed work by Dr. H. Srinivas. In that project, we will test newly standardized ER-alpha and ER-beta antibodies on paraffin-embedded lung tumor sections of patients, which we have obtained from Lung SPORE tissue bank. We will perform statistical analysis of the associations between ER immunostaining and clinical and histopathological variables. PROJECT 2 — CYCLIN B1 IN IMMUNOTHERAPY, DIAGNOSIS AND PROGNOSIS OF LUNG CANCERStatisticians Land and Shuai examined laboratory assays of cyclin B1 antibody levels. We estimated the effect of each plate (assay) using linear regression in order to develop a normalization procedure, which is performed by subtracting the relevant plate effect from the value for each test sample. We also compared healthy controls with cancer patients (Carinal Registry), and tested the effect of age on antibody levels. The cyclin-B1 antibody levels were significantly lower among cancer patients (estimated difference in medians 0.053; p=0.0017). There was no significant difference by age (p=0.81). In a third analysis, we analyzed the association of survival time and progression free survival time with cyclin B1 antibody levels in tissue from non-small cell lung cancer patients from the Carinal Registry study. These analyses were performed with Cox proportional hazards regression. PROJECT 3 — SERUM-BASED PROTEOMICS FOR LUNG CANCER DETECTION AND PROGNOSISBioinformaticians Gopalakrishnan and Hauskrecht have been integral to the work of Project 3. Our goals for this year were to perform extensive analyses of the preliminary data generated in Project 3 by proteomic profiling of lung cancer in order to be able to (a) validate previous analyses of the same data; and (b) suggest protein identities for putative disease-specific biomarkers. To achieve these goals, we performed multiple analyses on the UPCI and Vanderbilt data that include and extend the machine learning analysis and validation conducted previously. We measured sensitivity, specificity and the achieved classification error across multiple techniques. The putative biomarker discovery phase utilized a rule learning algorithm, RL and two of the datasets used in the analyses.
CLINICAL COREA number of other clinical trials are currently ongoing at UPCI and most are expected to be completed in 2008. These studies include the following: Phase II Trial of RAD001 (Everolimus) in Previously Treated Small Cell Lung Cancer (Investigator-initiated. PI: Argiris. UPCI #06-049) A Phase II Study of Cetuximab in Combination with External Beam Radiation Followed by Consolidation Chemotherapy for Patients with Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (Investigator-initiated. PI: Argiris. UPCI #05-106) Phase II Study of Bortezomib (PS-341) for Patients with Advanced Bronchiolo-Alveolar Carcinoma (BAC) or Adenocarcinoma with BAC Features (NCI 7003, CCC-P PhII-57) (UPCI PI: Argiris. UPCI #04-163) Phase II Study of C225 (Cetuximab) for the Treatment of Patients with Advanced Bronchioalveolar Carcinoma (BAC) or Adenocarcinoma with BAC Features (ECOG PI: Ramalingam. ECOG 1504) (UPCI PI Argiris. UPCI #05-093)
TISSUE AND BLOOD BANK COREThe Tissue Resource has been involved in three major areas of support. The principal areas of activity for the tissue resource are: Collection of tissue and biological materials. Histology and immunohistochemical support. Paraffin Tissue Array construction and use.
AWARD PROGRAMSThe Lung Cancer SPORE announces the following award recipients for year seven of the grant: Developmental Research Program AwardsAwardee: Richard Steinman, MD, PhD Awardee: Steven D. Shapiro MD Career Development Award ProgramAwardee: Robert Binder, PhD Awardee: A. McGarry Houghton, MD Awardee: Ann Marie Egloff, PhD, MPH
PublicationsPROJECT 1Zhang, Q., Thomas, S.M., Lui, V.W.Y., Xi, S., Siegfried, J.M., Fan, H., Smithgall, T., Mills, G., Grandis, J.R. Phosphorylation of TNF- converting enzyme by Gastrin-releasing peptide induces amphiregulin release and EGFR receptor activation. Proc. National Acad. Science. 103: 6901-6906, 2006. Carlisle, D., Xuwan, L., Hopkins, T.M., Swick, MC., Dhir, R., Siegfried, J.M. Nicotine Activates Cell Signaling Pathways through Muscle-type and Neuronal nicotinic Acetylcholine Receptors in Non-small Cell Lung Cancer Cells. Pulmonary Pharmacology and Therapeutics doi:10.1016/j.pupt.2006.07.001. Kelloff GJ, Lippman SM, Dannenberg AJ, Sigman CC, Pearce HL, Reid BJ, Szabo E, Jordan VC, Spitz MR, Mills GB, Papadimitrakopoulou VA, Lotan R, Aggarwal BB, Bresalier RS, Kim J, Arun B, Lu KH, Thomas ME, Rhodes HE, Brewer MA, Follen M, Shin DM, Parnes HL, Siegfried JM, Evans AA, Blot WJ, Chow WH, Blount PL, Maley CC, Want KK, Lam S, Lee JJ, Dubinett SM, Engstrom PF, Meyskens FL Jr., O’Shaughnessy J, Hawk ET, Levin B, Nelson WG, Hong WK. AACR Task Force on Cancer Prevention. Progress in Chemoprevention Drug Development: the Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancera Plan to Move Forward. Clinical Cancer Research 12: 3661-97, 2006. Zhang, W, Stabile, LP, Keohavong, P, Romkes, M, Grandis, JR, Traynor, AM, Siegfried, JM. Mutation and Polymorphism in the EGFR-TK Domain Associated with Lung Cancer. Journal of Thoracic Oncology 7:635-647, 2006. Zhang, W, Z, Weissfeld, JL, Romkes, J, Land, SR, Grandis, JR, Siegfried, JM.. Association of the EGFR Intron 1 CA Repeat Length with Lung Cancer Risk. In Press, Molecular Carcinogenesis. Myerberg, M.M., Latoche, J.D., McKenna, E.E., Stabile, L.P., Siegfried, J.M., Feghali-Bostwick, C.A., Pilewski, J.M. HGF and other fibroblast secretions modulate the phenotype of human bronchial epithelial cells. In press, Am. J. Physiol. Lung, 2007. Liu, X, Carlisle, DL, Swick, MC, Gaither Davis, A, Grandis, JR, Siegfried, JM. Gastrin-releasing peptide activates Akt through the epidermal growth factor receptor pathway and abrogates the effects of gefitinib. In press, Experimental Cell Research, 2007. PROJECT 2Saito H, Dubsky P, Dantin C, Finn OJ, Banchereau J, Palucka AK. Cross-priming of cyclin B1, MUC-1 and survivin specific CD8+T cells by dendritic cells loaded with killed allogeneic breast cancer cells. Breast Cancer Res. 2006 Nov 27;8(6):R65 Vella, L.A., Finn, O.J., "Innate and Adaptive Immunity in Lung Cancer: The Balance between Cancer Progression and Prevention." In Novartis Found Symp. 2006;279:206-12 (book chapter) Vella, LA. and Finn OJ. "Humoral and Cellular Response to the Self(tumor)-antigen Cyclin B1 in Lung Cancer Patients and Healthy Donors" AACR Special Conference in Tumor Immunology, Nov 29-Dec 4, 2006, Miami, FL. Vella, LA, Yu, M, Siegfried, JM, Finn, OJ. Cyclin B1 and Lung Cancer: Significance of the Immune Response. 14th Annual SPORE Investigators’ Workshop, July 2006. PROJECT 3AbstractsIntersession Reproducibility and Independent Clinical Cohort Evaluation of Lung Cancer Serum Proteomic Profiling and Classification Using SELDI-TOF-MS. William L. Bigbee, David E. Malehorn, Talal El-Hefnawy, Milos Hauskrecht, James Lyons-Weiler, Richard C. Pelikan, Mai Sun, Rodney J. Landreneau, James D. Luketich, Joel L. Weissfeld, Jill M. Siegfried, and Pierre P. Massion. Presented at the Lung SPOREs Midyear Meeting, Los Angeles, CA, January 25-26, 2006. Proteomic Signature of Lung Cancer from Analysis of Unfractionated Serum. Yildiz PB, Shyr Y, Rahman SMJ, Wardwell NR, Zimmerman LJ, Shakhtour B, Gray WH, Shuo Chen, Moore JH, Liebler DC, Bigbee WL, Siegfried JM, Weissfeld JL, Gonzalez AL, Ninan M, Johnson DH, Carbone DP, Caprioli RM, and Massion PP. Presented at the Lung SPOREs Midyear Meeting, Los Angeles, CA, January 25-26, 2006. Metabolomic Biomarkers of Non-small Cell Lung Cancer. Thomas J. Colatsky, Judong Shen, Alan J. Higgins, Imran Shah, Talal El-Hefnawy, Jill M. Siegfried, and William L. Bigbee. Presented at the 14th SPORE Investigators’ Workshop, Baltimore, MD, July 15-19, 2006. Multiplexing Approach for Early Diagnosis of Lung Cancer. A. Lokshin, A. Lisovich, B. Nolen, A. Marrangoni, L. Velikokhatnaya, M. Winans, B. Bigbee, J. Siegfried, J. Weissfeld, T. El-Hefnawy, and A. Lokshin. Presented at the 14th SPORE Investigators’ Workshop, Baltimore, MD, July 15-19, 2006. PublicationsChen G, Wang X, Yu J, Varambally S, Yu J, Thomas DG, Lin M-Y, Vishnu P, Wang Z, Wang R, Fielhauer J, Ghosh D, Giordano TJ, Giacherio D, Chang AC, Orringer MB, El-Hefnawy T, Bigbee WL, Beer DG, Chinnaiyan AM (2007) Autoantibody profiles reveal ubiquilin 1 as a humoral immune response target in lung adenocarcinoma. Cancer Res (in press). Xi L. Coello MC. Litle VR. Raja S. Gooding WE. Yousem SA. El-Hefnawy T. Landreneau RJ. Luketich JD. Godfrey TE. A combination of molecular markers accurately detects lymph node metastasis in non-small cell lung cancer patients. Clinical Cancer Research. 12(8):2484-91, 2006 Liu Y. Lan Q. Siegfried JM. Luketich JD. Keohavong P. Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients. Neoplasia 8(1):46-51, 2006 Xi L, Nicastri DG, El-Hefnawy T, Hughes SJ, Luketich JD, Godfrey TE. Optimal markers for real-time quantitative reverse transcription-PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal,head and neck, and lung cancers. Clin Chem, In Press Accepted for PresentationPennathur A, Burton SA, Luketich JD, Abbas G, Chen M, Heron DE, Gooding WE, Ozhasoglu C, Landreneau RJ, Christie NA. Stereotactic Radiosurgery for the Treatment of Stage I Non-small Cell Lung Cancer in High-Risk Patients. American Association of Thoracic Surgery Washington, DC. May 5-7, 2007. Litle VR, Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M, Swanson SJ, Godfrey TE. MicroRNA Expression Profiles in Esophageal Cancer. American Association of Thoracic Surgery Washington, DC. May 5-7, 2007. d’Amato TA, Fernando HC, Chan BY, Ricketts WA, Luketich JD, Landreneau RJ. Differential gene expression associated with early tumor recurrence and long disease free survival in early stage lung cancer. Society of Surgical Oncology Washington, D.C. March 15-18, 2007 Schuchert MJ, d’Amato T, Landreneau RJ. Radiation exposure to treatment team from intraoperative 125I Brachytherapy Implants as Adjuvant Therapy to Sublobar Resection in Stage I Lung Cancer. Society of Surgical Oncology Washington, D.C. March 15-18, 2007 Shamji FM, d’Amato TA, Ashrafi AS, Maziak DE, Sundaresan SR, Al-Shehlb D, El-Sherif A, Ferson PF, Luketich JD, Landreneau RJ. Should pneumonectomy be avoided in patients with locally advanced non-small cell lung cancer following induction chemotherapy? Society of Surgical Oncology Washington, D.C. March 15-18, 2007 PROJECT 4PublicationsGao WM, Romkes M, Siegfried JM, Luketich JD, Keohavong P. Polymorphisms in DNA repair genes XPD and XRCC1 and p53 mutations in lung carcinomas of never-smokers. Mol Carcinogenesis. 2006;45: 828-32. Zhang W, Stabile LP, Keohavong P, Romkes M, Grandis JR, SchillerJH, Traynor AM, Siegfried JM. Mutation and Polymorphism in the EGFR-TK Domain Associated with Lung Cancer. J Thor Oncol. 2006;1:635-47. (see Project 1) Raimondi S, Paracchini V, Autrup H, Benhamou S, Boffetta P, Cote ML, Dialyna IA, Dolzan V, Dragani T, Garte S, Hirvonen A, Husgafvel-Pursiainen K, Imyanitov EN, Kalina I, Kang D, Kiyohara C, Kremers P, Lan Q, Neri M, Povey AC, Rannug A, Reszka E, Risch A, Romkes M, Ruano-Ravina A, Schneider J, Seow A, Shields PG, Sobti RC, Srensen M, Spitz MR, Strange RC, Stcker I, Sugimura H, To-Figueras J, Tokudome S, Yang P, Yokota J, Warholm M, Taioli E. Pooled and meta analysis of GSTT1 polymorphism and lung cancer: a HuGE-GSEC review. Am J Epidemiol. 2006;164:1027-42. Zhang W, Weissfeld JL, Romkes M, Land S, Siegfried JM. Association of the EGFR Intron 1 CA Repeat Length with Lung Cancer Risk. Mol Carcinogenesis. 2006, accepted (see Project 1) AbstractsRomkes M, Buch S, Taron M, Rosel R. Evaluation of Nucleotide Excision Repair (NER) gene pathway haplotypes with platinum drug resistance and survival in NSCLC. SPECS annual meeting, 2006;2:12. Styn MA, Perkins KA, Land SR, Romkes M, Weissfeld JL. Does an abnormal CT finding predict smoking cessation one year later? Society of Behavioral Medicine Annual Meeting, March 2007, accepted. ADMINISTRATIVE COREAnnouncement of Lung Cancer Awareness Month event on November 29, 2006 Reprint of Letter to the Editor from Dr. Jack Hill to the Woodland Progress (NJ) Reprint of Letter to the Editor from Dr. Jack Hill to the Pittsburgh Post-Gazette Text of testimony given by Dr. Jack Hill to the Pennsylvania State Senate Select Committee on Tobacco Settlement dated September 26, 2006 Reprint of article Women Lift Smokescreen on Lung Cancer published in Bay Area Business Woman (CA) in November of 2005 Reprint of article The Thinkers: Celebrity Deaths Shine Light on Lung Cancer published in the Pittsburgh Post-Gazette on March 27, 2006 UPMC Cancer Centers and University of Pittsburgh Cancer Institute capital campaign brochure feature Dr. Jill M. Siegfried, Lung SPORE PI, Dr. William L. Bigbee, Lung SPORE Basic science Associate Director, and Dr. James D. Luketich, Lung SPORE Clinical Associate Director TISSUE AND BLOOD BANK CORECarlisle, D., Xuwan, L., Hopkins, T.M., Swick, MC., Dhir, R., Siegfried, J.M. Nicotine Activates Cell Signaling Pathways through Muscle-type and Neuronal nicotinic Acetylcholine Receptors in Non-small Cell Lung Cancer Cells. Pulmonary Pharmacology and Therapeutics doi:10.1016/j.pupt.2006.07.001. (see Project 1) Stabile, L.P., Lyker, J.S., Land, S.R., Dacic, Sanja, Zamboni, BA, Siegfried, J.M. Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer. Carcinogenesis 27: 1547-55, 2006. BIOSTATISTICS/BIOINFORMATICS CORES. Land, A.M. Egloff, J. Weissfeld, and O. Finn, “Statistical Estimation of Normal Ranges for Serum Anti-Cyclin B1 Antibodies in a Population at High Risk for Lung Cancer”, Winter Lung SPORE meeting, Los Angeles, CA, January 2006. M.A. Styn, K.A. Perkins, S.R. Land, M. Romkes, J.L. Weissfeld "Does an abnormal CT finding predict smoking cessation one year later?" Society of Behavioral Medicine's 28th Annual Meeting and Scientific Sessions, March 21-24, 2007, Washington, DC (see Project 4) Egloff AM, Weissfeld J, Land SR, Finn OJ. Evaluation of anticyclin b1 serum antibody as a diagnostic and prognostic biomarker for lung cancer. Ann N Y Acad Sci. 2005 Dec;1062:29-40. PMID: 16461786 Stabile LP, Lyker JS, Land SR, Dacic S, Zamboni BA, Siegfried JM. Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer. Carcinogenesis 27(8):1547-55, 2006, PMID: 16513678. Stabile LP, Rothstein ME, Kim KJ, Land SR, Luong TM, Siegfried JM. Anti-HGF monoclonal antibody therapy decreases incidence of lung tumors in transgenic mice overexpressing HGF. AACR, 2007. (see Tissue and Blood Bank Core) Day, R. Joint Statistical Meetings, July 29-August 2, Salt Lake City, Utah, 2007. DEVELOPMENTAL RESEARCH PROGRAMXi L, Lyons-Weiler J, Coello MC, Huang X, Gooding WE, Luketich JD, Godfrey TE. Prediction of Lynph Node Metastasis by Analysis of Gene Expression Profiles in Primary Lung Adenocarcinomas. Clin Cancer Res 2005;11(11) 2005 Xi, L, Coello MC, Litle, VR, Raja S, Gooding WE, Yousem SA, El-Hefnawy T, Landreneau R, Luketich JD, Godfrey TE. A Comination of Molecular Markers Accurately Detects Lymph Node Metastasis in Non-SmallCell Lung Cancer Patients. Clin Cancer Res 2006;12(8), 2006. (see Project 3) Achiwa H, Lazo JS. “The Role of Cdc25B in Lung Carcinogenesis” Cancer Res 2007; 67(2), 2007. Styn MA, Perkins KA, Land SR, Romkes M, Weissfeld JL. Does an abnormal CT finding predict smoking cessation one year later? Society of Behavioral Medicine Annual Meeting, March 2007, accepted. (see Project 4) CAREER DEVELOPMENT PROGRAMPamela Hershberger, PhD:PublicationsParise PA, Egorin MJ, Kanterewicz b, Taimi M, Petkovich M, Lew AM, Chuang SS, Nichols M, El-Hefmawy T, Hershberger PA. CYP24, the enzyme that catabolizes the antiproliferative agent vitamin D, is increased in lung cancer. Int J Cancer 119, 1819-1828, 2006. AbstractsKanterewicz B, Nichols m, Hershberger PA. Elucidation of the mechanisms that control expression of the vitamin D metabolizing enzyme, CYP2, in lung cancer cells. Presented at the 14th SPORE Investigators’ Workshop, Baltimore, MD, July 15-19, 2006. Laura Stable, PhD:PublicationsStabile, L.P., Lyker, J.S., Land, S.R., Dacic, Sanja, Zamboni, BA, Siegfried, J.M. Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer. Carcinogenesis 27: 1547-55, 2006 (see Biostatistics/Bioinformatics Core) Stabile, L.P., Lyker, J.S., Gubish, C.T., Zhang, W., Grandis, J.R., Siegfried, J.M. Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer Shows Enhanced Anti-Proliferative Effects. Cancer Research 65 : 1459-1470, 2005. AbstractsStabile LP, Rothstein ME, Kim KJ, Land SR, Luong TM, Siegfried JM. Anti-HGF monoclonal antibody therapy decreases incidence of lung tumors in transgenic mice overexpressing HGF. AACR, 2007. (see Biostatics/Bioinformatics Core) Stabile LP, Paprzycki C, Grandis JR, Siegfried JM. Cross-talk between the estrogen receptor and the epidermal growth factor receptor in head and neck squamous cell carcinoma. Proceedings of the American Association for Cancer Research. Volume 47, April 2006. Washington, DC. Stabile LP, Lyker JS, Barrow ME, Gubish CT, Siegfried JM. Non-nuclear estrogen signaling mechanisms in NSCLC. Flight Attendant Medical Research Institute 5th Scientific Symposium. May 2006. Cambridge, MA. Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM. Combined targeting of the estrogen receptor and the epidermal growth factor receptor for lung cancer therapy. 17th Annual UPCI Scientific Retreat. June 2005. Pittsburgh, PA. Siegfried JM, Stabile LP, Liu X, Thomas SM, Grandis JR. Novel pathways for lung cancer therapy. AACR special conference. Molecular Pathogenesis of Lung Cancer: Opportunities for Translation to the Clinic. Feb 2005. San Diego, CA. Siegfried JM, Stabile LP, Hershberger PA, Lyker JS, Gubish CT, Vasquez C, Nichols MD. Targeting the estrogen receptor and the epidermal growth factor receptor for lung cancer therapy. Annual National Cancer Institute SPORE Investigators' Meeting. July 2004. Baltimore, MD. Stabile LP, Lyker JS, Gubish CT, Siegfried JM. Targeting the estrogen receptor and the epidermal growth factor receptor for lung cancer therapy. Proceedings of the American Association for Cancer Research. Volume 45, March 2004. Orlando, FL. Stabile LP, Lyker JS, Gubish CT, Siegfried JM. Targeting the estrogen receptor and epidermal growth factor receptor pathways for lung cancer therapy. Annual Flight Attendant Medical Research Institute Symposium. May 2004. Miami, FL. El-Hefnawy T, Stabile LA, Siegfried JM, Donovan MA, Davis DL, Luketich JD. Endocrine Disrupting Compounds Can Regulate Lung and Breast Cancer Proliferation, Migration and Response to Chemotherapy. 17th Annual UPCI Scientific Retreat. June 2005. Pittsburgh, PA. Lin Zhang, PhD:PublicationsYu, J., Yue, W., Wu, B. and Zhang, L. (2006) PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation. Clinical Cancer Research 12: 2928-2936. Ding, W.X., Ni, H.M., Chen, X.Y., Yu, J., Zhang, L., and Yin, X.M. (2007) A coordinated action of Bax, PUMA and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Molecular Cancer Therapeutics (In Press). Wang, P., Yu, J. and Zhang, L. (2007) The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage. Proc. Natl. Acad. Sci. USA. (In Press). Yu, J., Wang, P., Ming, L.H., Wood, M. and Zhang, L. (2007) SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. Oncogene [Epub ahead of print] Jan 22. Wu, B., Qiu, W., Wang, P., Yue, W., Yu, H., Cheng, T., Zambetti G.P., and Zhang, L.* and Yu, J.* (2006) p53-independent induction of PUMA mediates intestinal apoptosis induced by ischemia reperfusion. Gut [Epub ahead of print] Nov 24 (* corresponding authors). Ming, L.H, Wang, P., Bank, A., Yu, J., and Zhang, L. (2006) PUMA dissociates Bax from Bcl-XL to induce apoptosis in colon cancer cells. Journal of Biological Chemistry 281:16034-16042. Wang, H.J., Qian, H.L., Yu, J., Zhang, XY, Zhang, L., Fu, M, Liang, X, Zhan, Q.M. and Chen, L. (2006) Administration of PUMA adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs. Cancer Biology & Therapy. 5:380-385. Jiang, M., Wei, Q., Du, Q., Yu, J., Zhang, L. and Dong, Z. (2006) Regulation of PUMA by p53 in cisplatin-induced renal cell apoptosis. Oncogene 25:4056-4066. Yu, J. and Zhang, L. (2005) The transcriptional targets of p53 in Apoptosis Control. Biochem. Biophys. Res. Comm. 331:851-858. AbstractsYue, W., Guo, M.Z., Zhang, W.P., Jill Siegfried, J.M., Yu, J., Zhang, L. Identification of novel methylation markers of lung cancer. Proc Amer Assoc Cancer Res 2006; 47: [Abstract #48]. Yu, J., Yue, W., Wu, B., and Zhang, L., PUMA Sensitizes Lung Cancer Cells to Chemotherapeutic Agents and Irradiation. Proc Amer Assoc Cancer Res 2006; 47: [Abstract #2209]. |
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