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Lung Cancer SPORE Grant
Project and Cores Project 1: Intersection of Estrogen Receptor Signaling and Epidermal Growth Factor Receptor Signaling in Lung Cancer 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 inpreclinical 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: (1) Determine signaling molecules involved in ER-EGFR pathway interactions in NSCLC cell lines.
(2) 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.
(3) Determine if aromatase is present and functional in normal and malignant lung cells and if an aromatase inhibitor has anti-tumor activity.
(4) Analysis of ER and EGFR status in tissues obtained from NSCLC patients treated on clinical trials of combination therapy (anti-estrogen and EGFR TKI). Translational Value of Project One
Project 2: Cyclin B1 Immunotherapy Specific Aims When we began this project four years ago, the most recent statistics listed lung cancer as the leading cause of cancer deaths in the US, surpassing the combined total of deaths caused by breast, colon and prostate cancer [1]. Most patients, even those who present early and with localized disease, eventually succumb to metastatic disease. Standard therapy currently represented by cytotoxic agents has had very low response rates and high toxicity [2]. The clear need for new therapeutic options has led to increased efforts to treat lung cancer with more specific targeted therapies, such as targeting ER and EGFR in Project 1. A prototype of a targeted therapy is immunotherapy. The immune system has the greatest potential for tumor specific destruction with no toxicity to normal tissue, and for long-term memory that can prevent recurrence. Tumor specificity of the immune response resides in the recognition of tumor antigens. While a large number of tumor antigens have been identified for many malignancies, relatively few are known for lung tumors. More importantly, while the identification of tumor antigens led to many immunotherapy trials in other malignancies, such as melanoma, breast, colon and prostate cancer, very few such trials have been attempted in lung cancer. A recent review of 334 cancer biotherapy/immunotherapy trials carried out over a five-year period (1998-2002), shows only two in lung cancer [3]. Since then, there have been only three other vaccine trials reported. Thus, immunotherapy of lung cancer has been curiously neglected. In the past grant period, we focused on the validation of cyclin B1 (CB1) as a lung tumor antigen and a candidate for lung cancer vaccines. We had discovered that in several types of tumors CB1 was constitutively overexpressed and mislocalized in the cytoplasm rather than the nucleus, which led to an increased presentation of the protein and its processed peptides to the immune system [4]. As will be evident from our Progress Report, we have confirmed CB1 as a tumor antigen in all types of lung cancer, both by documenting its overexpression in tumors, as well as by finding anti-cyclin B1 immune responses in lung cancer patients [5]. We have defined the molecular mechanisms responsible for aberrant CB1 expression [6]. We have also performed experiments in mice to show that anti-CB1 immunity can result in rejection of CB1 overexpressing tumors. The first hypothesis that we propose 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. We have also discovered that CB1 overexpression might be an early event in malignant transformation [5], suggesting that the protein and/or the immune response against it may be used as an indication of preneoplastic changes in the lung or risk for future lung cancer development. We have taken the opportunity presented by the PLuSS lung cancer screening study in the previous Project 5, now continued within the Clinical Core, to begin to evaluate anti-CB1 immunity in older active smokers and former smokers at risk for developing lung cancer. Our preliminary data show that we can reproducibly measure the presence of antibody in the PluSS subjects. We have also seen in preliminary analysis that anti-CB1 immunity correlates with protection from recurrence in a pilot study of Stage IB and IIA lung cancer patients. The second hypothesis we propose to test is that the immune response (in this case 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. We are in an especially good situation to test this hypothesis because in addition to having access to a well-defined large population of individuals at risk from the PluSS cohort, we will be able to evaluate immune response as a biomarker in the context of all other biomarkers being identified and tested in the same patient population within Projects 3 and 4. We also have access to a large retrospective set of lung tumors (NSCLC Retrospective Patient Cohorts A and B, discussed in the Tissue and Blood Core), with stored plasma, that have been clinically annotated to include stage, treatment history, time to recurrence and overall survival. These cohorts can be used to determine the relationship of CB1 immunity to CB1 protein expression in lung tumors and to outcome. 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 to compare immunity in lung cancer patients at different stages of disease and among subjects 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 (naïve, 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 immune response. This information will be analyzed in the context of clinical outcome, to define immune correlates of protection. This information will also be important for defining 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. Project 3: Serum Proteomic Biomarkers for Lung Cancer Detection and Prognosis Specific Aims Given the ongoing clinical and public health burden from lung cancer, it is critical to develop, validate, and implement new early detection and screening, diagnostic, and prognostic biomarkers and therapeutic modalities to improve survival for patients with lung cancer. With the widespread and expanding clinical utilization of thoracic CT screening, such biomarkers are urgently needed to improve the specificity of clinical CT screening in high risk populations wherein findings of indeterminant lung nodules are frequent, but only a fraction are malignant. Lastly, improved biomarkers to predict both which patients are at highest risk for recurrence and which can provide longer clinically useful lead times are also of important clinical benefit. Overall Hypothesis and Approach Serum proteomic patterns and biomarker profiles contain biological information reporting the molecular etiology and host response of lung cancer initiation and progression and therefore are a biological resource for discovery of disease specific diagnostic features and biomarkers applicable to early detection, molecular classification, and recurrence. Specific Aim 1: Evaluate and refine MALDI-TOF-MS and Luminex LabMAP® serum proteomic profiling for lung cancer early detection and diagnosis. The overall objective of this Aim is to develop and optimize a combined MALDI-TOF-MS and Luminex LabMAP® multimarker serum proteomic panel (MS/LabMAP® panel) and analytical statistical model diagnostic of lung cancer. Our Preliminary Studies demonstrate that both of these proteomic platforms provide robust discrimination of serum patterns of lung cancer patients and disease free controls including subjects with benign lung disease. In this project we propose to extend, refine, and verify these findings combining state-of-the-art high-resolution MALDI-TOF mass spectrometry on the Bruker ClintProt™ UltraflexII MALDI-TOF/TOF mass spectrometry system with the novel Luminex LabMAP® technology that allows for simultaneous evaluation of multiple (up to 100) biomarkers in one sample. Optimization of the ClintProt™ UltraflexII MALDI-TOF/TOF mass spectrometry system will include evaluation of multiple Bruker functionalized superparamagnetic microparticles for proteomic profiling of unfractionated serum and evaluation of immunodepletion and size fractionation methods to remove highly abundant high molecular proteins, followed by profiling of the lower abundance low molecular serum proteome. Optimization of the Luminex-based LabMAP® system will include evaluation of commercially available serum analyte assays together with a panel of assays we have developed, for multiplex analysis of most of the known lung cancer serological biomarkers including cytokines, chemokines, angiogenic and growth factors and their receptors, as well as circulating antibodies against previously-described lung cancer antigens. Refinement of these MS/LabMAP® proteomic biomarker assays will utilize serum samples from newly diagnosed UPCI lung cancer cases and matched controls including patients with benign lung disease to:
The anticipated results from Specific Aim 1 are the identification of an optimized MS/LabMAP® panel and analytical statistical model for detection of early stage lung cancer. The predictive power of this selected panel and analytical model will then be further evaluated in an independent lung cancer case series and prospectively in subjects at high risk for lung cancer in Specific Aim 2. Specific Aim 2: Test the optimized MS/LabMAP® panel and analytical statistical model discovered in Aim 1 to:
The anticipated results from Specific Aim 2 are the verification of the optimized MS/LabMAP® panel and analytical statistical model for detection of early stage lung cancer and the identification of features of this MS/LabMAP® panel that predict the emergence of clinical lung cancer in high risk subjects in the UPCI Lung Cancer SPORE PLuSS high-risk sub-cohort. Specific Aim 3: Identify and evaluate features of the baseline MS/LabMAP® serum panel to predict recurrence and survival, and investigate the temporal persistence of the baseline lung cancer specific MS/LabMAP® panel in serial blood samples:
The anticipated results from Specific Aim 3 are the identification of features of the baseline lung cancer specific MS/LabMAP® serum panel that predict recurrence and survival and that change over time in patients following curative surgical resection or RFA treatment. Our overall goal in this Aim is to evaluate the predictive power of the baseline lung cancer specific MS/LabMAP® serum panel for patient outcomes and to identify temporal features of the baseline pattern whose reemergence in follow up blood samples would predict clinical recurrence of lung cancer. Specific Aim 4: Perform biochemical identification and characterization of the diagnostic features (peaks) discovered in the MALDI-TOF-MS proteomic profiles in the studies undertaken in Specific Aims 1-3. Integrated with the MALDI-TOF mass spectrometry serum profiling studies in Specific Aims 1-3 will be biochemical analyses to identify and characterize peptide/protein species that contribute to the discrimination of lung cancer case and control patterns. These biochemical studies, utilizing a spectrum of standard fractionation, separation, and purification technologies followed by MS/MS analysis and identification will be undertaken at the point when robust and reproducible diagnostic features are identified in Specific Aims 1 and 2. The anticipated results from Specific Aim 4 are the identification of serum peptide/protein species associated with lung cancer. Biochemical identification of these analytes will permit the development of targeted detection and quantitation of these diagnostic species and, with availability of suitable antibodies, the eventual incorporation of these newly-discovered analytes into the LabMAP® serum panel.
Project 4: Nucleotide Excision Repair/Cell Cycle Control Haplotypes and Lung Cancer Risk and Prognosis Marjorie Romkes, Ph.D., Co-Project Leader Specific Aims 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 870A variant allele and XPD Gln allele (OR=7.1, 95%CI 4.0-12.5)(1,Appendix). We propose 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 tag SNPs identifying haplotypes for genes of the NER and cell cycle control pathways. In a set of 184 healthy control subjects (92 Caucasians and 92 African Americans), we will infer haplotypes for each locus for all subjects using a maximum of 10 SNPs/gene, establish Hardy-Weinberg equilibrium and assign gene haplotypes using Stram’s program for tag SNP selection which incorporates HAPLOVIEW and the HapMap ENCODE genotype data (2,3). Specific Aim 2. To develop a model relating NER and cell cycle control pathway gene haplotypes to lung cancer risk. We will evaluate the association of NER and cell cycle control pathway gene haplotypes with lung cancer risk among smokers. We will conduct analyses of multiple SNPs per gene and/or haplotypes using joint SNP-genotype-and SNP-haplotype based models. We will test our hypothesis that the NER and cell cycle control pathway haplotypes are associated with an elevated risk of lung cancer by extending our initial observations from two genes in a larger patient population case control study group. Cases (n=1100) and controls (n=1100) recruited by both the University of Pittsburgh Cancer Institute lung cancer SPORE Clinical Core and the Vanderbilt lung cancer SPORE will be studied. We will screen for these gene haplotypes in a series of frequency age (±10 years), gender, race and smoking history (pack-year ±10) matched lung cancer cases and controls. 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. We will evaluate the association of NER and cell cycle control pathway gene haplotypes with the development of lung cancer in the PLuSS (n=1100) and Moffitt Cancer Center (n=1151) 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. The data sets obtained from Specific Aims 2 and 3 each have unique value. Aim 2 will have a large number of cases, supporting exploration of more complex model spaces which utilize known biology of the genes studied. Aim 3 will have the advantage of being prospective, eliminating some sources of selection bias. The two databases together provide even greater scientific value. A global validation test will lead to a final predictive model with greater precision, and permit examination of biological differences between screening CT-detected cases and clinically ascertained cases. Specific Aim 5. To evaluate whether the NER pathway haplotypes are associated with platinum drug resistance and survival. The correlation between NER haplotype and prognosis will be assessed by following the lung cancer cases for disease progression, survival and development of platinum drug resistance. The NER haplotype may not only predict lung cancer risk, but also drug resistance. It is well known that resistance to platinum-based drugs, a chemotherapeutic regimen often used in the treatment of lung cancer, is associated with the NER pathway. In order to further evaluate the NER haplotype/phenotype relationship, we propose to study the relationship of the NER/cell cycle control haplotype with response to platinum-based drug treatment among the lung cancer cases. Translational Relevance. The discovery of common low-penetrant genes that are associated with lung cancer risk, either directly or through interaction with environmental exposures, particularly smoking, would be of great importance, and would open new avenues of prevention. Studying the relationship between a gene and disease requires assessment of more than just a single variant within that gene. The haplotype-based approach will provide a great amount of information about genes and pathways and will help to evaluate how variation relates to lung cancer risk. We have chosen to focus on the NER and cell cycle control pathway genes for which there is strong rationale for genetic involvement in risk and risk modification by environmental exposures. In addition, the possibility of individualizing DNA repair profiles is becoming a central issue in not only predicting risk of lung cancer, but also in the search for improved chemotherapeutic efficacy. Many cancer chemotherapeutic agents, including cis-platinum, cause interstrand breaks and consequently cytotoxicity. Several recent studies have shown that reduced NER DNA repair capacity may be associated with enhanced response and survival with platinum-based chemotherapy. We have proposed to evaluate the relationship of the NER pathway haplotype with risk and response to platinum therapy in order to ultimately be able to identify patients who would benefit from platinum-based chemotherapy and/or dose modification. The proposed studies will provide important data to support the application of these endpoints as clinical markers of risk and prognosis. Biological markers that reflect events in target tissue are required to identify high-risk subgroups for future chemoprevention intervention strategies and to help in making strategic decisions regarding therapy. The ability to rapidly screen individuals for risk, using non-invasive procedures, has tremendous potential for future clinical application.
Administrative Core/Core A Jill M. Siegfried, Ph.D., Principal Investigator The Administrative Core will oversee the organizational, fiscal, and scientific activities of the UPCI Lung Cancer SPORE, including oversight of financial expenditures, scheduling regular meetings of the SPORE investigators, organizing our participation in annual SPORE meetings, facilitating collaborations with other SPOREs and co-operative groups, and developing and preparing annual reports. The Core will also coordinate retreats for program investigators and the Internal/External Advisory Board members, interact with our patient advocates, facilitate team science between investigators of different disciplines, and undertake periodic evaluations of progress and direction of the SPORE Projects. The Core will coordinate travel of SPORE investigators to the annual NCI-sponsored SPORE Investigators’ Workshop, and the annual Midyear Lung Cancer SPORE Investigators’ Meeting. The Core will also assist SPORE investigators in the preparation of manuscripts for publication. The Core will interact with the Developmental Research Program and Career Development Program to ensure smooth functioning of these SPORE components. The Core will coordinate SPORE Research Core activities with the UPCI to avoid redundancy and ensure that joint activities between the UPCI Lung and Thoracic Malignancies Program and the Lung Cancer SPORE are carried out efficiently, and that the two Programs act to complement and synergize with each other. The Administrative Core will interact with the NCI Program Office to ensure that SPORE guidelines are followed and that the SPORE mandate is carried out. The Core will also work to collaborate with the UPCI Head and Neck Cancer SPORE, with SPOREs at other institutions, and with the Early Detection Research Network, the Eastern Co, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO).
Clinical Core/Core B Joel Weissfeld, M.D., M.P.H., Co-Director Clinical Core Goals and Objectives The Clinical Core for the University of UPCI Lung Cancer SPORE creates and supports the infrastructure needed to satisfy the clinical and translational research needs of the individual SPORE projects. Fulfillment of SPORE translational research aims requires access to human subjects and associated clinical outcome information and biological materials (blood and tissue). In addition, successful completion of SPORE clinical trials and other interventions requires human research conducted according to exacting standards designed to protect research subjects from unnecessary research risks. The Clinical Core provides the expertise and resources needed for four major specific aims: 1) Design and implement clinical trials and clinical studies; 2) Identify, solicit, and enroll subjects into SPORE clinical trials, patient registries, and high risk cohorts; 3) Collect, manage, and store high quality risk factor and clinical outcome information; and 4) Deliver protocol-directed interventions and collect blood and tissue samples. Specific Aim 1: Design and implement clinical trials and clinical studies The Clinical Core forms a central hub for all clinical trial activities proposed for the UPCI Lung Cancer SPORE. Clinical Core members are experienced and active lung cancer clinical investigators with direct access to lung cancer patient populations. The series of steps needed to design and to gain approval for human clinical trials and clinical studies utilizing human biomaterials can overwhelm inexperienced investigators and significantly delay the translation of promising clinical interventions. Collaborating with investigators from the individual projects and the Biostatistics/Bioinformatics Core, Clinical Core investigators design feasible clinical trials and clinical studies and prepare the written documents needed for institutional approval. The Clinical Core also benefits directly from an important UPCI-supported core facility, Clinical Research Services (CRS). The CRS centrally manages a group of specially trained and supervised oncology protocol nurses, who help clinical investigators implement all phases of a clinical trial, aspects that include not only the protocol approval process, but also subject recruitment, baseline data collection, delivery of protocol-directed interventions, subject retention, and follow-up for study endpoints. Using these resources, the Clinical Core prepares written applications, including protocol summaries and informed consent materials, needed to gain approvals from the UPCI Protocol Review Committee (an approval based on scientific merit), from the University of Pittsburgh Institutional Review Boards (IRB) (an approval based on safety and on protecting human subjects in medical research), and from the Food and Drug Administration (FDA) (an approval addressing the use of investigational new drugs (IND) in human subjects). Specific Aim 2: Identify, solicit, and enroll subjects into SPORE clinical trials, patient registries, and high risk cohorts The Clinical Core is a component of the Lung Cancer Center at UPCI and UPMC Cancer Centers. The Lung Cancer Center brings together a multidisciplinary team comprised of medical oncologists, thoracic surgeons, pulmonologists, radiation oncologists, pathologists, radiologists, and protocol nurses. The Lung Cancer Center is a cohesive unit that has provided multidisciplinary lung cancer care and contributed to clinical and translational research for many years. Convening the Thoracic Cancer Tumor Conference, Lung Cancer Center members meet weekly to discuss ongoing projects, new projects, and difficult patient management problems. The Lung Cancer Center also operates three outpatient lung cancer clinics, the Thoracic Medical Oncology Clinic, Thoracic Oncology Surgery Clinic, and Multidisciplinary Lung Cancer Clinic. The Multidisciplinary Lung Cancer Clinic, in particular, an activity held Tuesday, Wednesday, and Thursday mornings in the Cooper Pavilion of the Hillman Cancer Center, provides a venue for new lung cancer patients, who frequently require input from multiple clinical specialists. Most patients accrued to investigator-initiated lung cancer studies at UPCI have been recruited from the Lung Cancer Center and from the clinical practices of Lung Cancer Center leaders and Clinical Core members. Human subjects enrolled, by the Clinical Core, to tissue and blood collection protocols, in addition to specific clinical intervention studies, support the translational work of each of the major projects proposed for the SPORE renewal. The Clinical Core supports specific tissue and blood specimen needs for SPORE renewal Projects 1, 2, 3 and 4. The Clinical Core recruits, treats, and follows subjects needed for specific clinical trials proposed as part of SPORE renewal Projects 1 and 2. Specific Aim 3: Collect, manage, and store high quality risk factor and clinical outcome information In a SPORE context, collection, management, and storage of high quality risk factor and clinical outcome information requires standardized data collection forms, well trained and supervised research personnel, and professionally managed electronic databases. The Clinical Core aims to fulfill these requirements with support provided by the Biostatistics/Bioinformatics Core and by CRS oncology protocol nurses. Depending on work load demands, the Clinical Core proposes to dedicate a portion of effort from specified oncology protocol nurses to each SPORE clinical trial. Partial support of two Clinical Coordinators in Oncology is requested in the budget justifications, and this will be supplemented by institutional commitment with effort of other nurses provided periodically as required for the different protocols. Clinical Core leaders (primarily Dr. Luketich, Weissfeld, Landreneau, and Belani) will co-supervise the activities of the oncology protocol nurses, in close collaboration with CRS managers and with principal investigators from the relevant SPORE scientific projects. Using written protocols, data forms, and data systems developed by Clinical Core and Biostatistics/Bioinformatics Core members, oncology protocol nurses collect risk factor and clinical outcome information that is 1) accurate, 2) accessible by investigator in de-identified and HIPAA compliant formats, and 3) linked to pathology information stored in hospital databases and to laboratory results stored in basic science laboratory databases. Specific Aim 4: Deliver protocol-directed interventions and collect blood and tissue samples To enable translational aims of the SPORE scientific projects, the Clinical Core will deliver drug-based and vaccine-based interventions to participants and collect, with the assistance of the Tissue and Blood Bank Core, blood and tissue samples from participants in SPORE clinical trials, research registries, and high-risk cohorts. The Clinical Core aims to fulfill these requirements, particularly requirements related to timing of interventions, timing of blood and sample collections, and technical specifications related to blood and tissue collection, with technical support provided by the SPORE Tissue and Blood Bank Core and, again, with coordination provided by the specific CRS oncology protocol nurses dedicated to each SPORE clinical activity. Tissue and Blood Bank Core/Core C
The Tissue and Blood Bank Core for the Lung Cancer SPORE will serve as a shared resource for the main Research Projects and for the Career Development and Developmental Research Programs. The Core will collect, process, store and distribute tissue and body fluid specimens from patients diagnosed with lung cancer or with suspected lung cancer, and from subjects who are members of the PLuSS cohort and the PLuSS High-Risk Sub-Cohort. Triage and distribution of all specimens will be prioritized according to a plan established with all SPORE investigators, and approved by the Tissue and Blood Bank Core Pathologists. The Core will procure and triage fresh human lung tissue, including tumor, adjacent uninvolved, and normal tissues distal from the tumor, and bronchial biopsies of the airway, from lung cancer patients undergoing resections or bronchoscopies, as well as individuals undergoing these procedures for reasons other than lung cancer. After triage under sterile conditions, tissues designated by the Core Pathologist as normal or abnormal will be either immediately distributed to investigators for tissue culture, protein analysis, RNA analysis, or DNA analysis, or will be stored for future use. Lymphocytes, serum, and plasma will be separated from other blood components and used immediately or stored for future analysis. Fragments of tissue will also be formalin‑fixed for paraffin embedding. Fixed tumor blocks from patients enrolled in clinical trials will also be obtained and stored by the Core. Some paraffin embedded specimens will be sectioned, examined by a Core Pathologist and normal and abnormal area separated by microdissection; others will be used for the preparation of tissue microarrays (TMAs). The Core will also carry out EGFR mutation analyses on microdissected tumor specimens and will utilize tumor tissue sections for EGFR amplification analyses by fluorescence in situ hybridization (FISH). The Core will also carry out routine and special pathology such as immunohistochemistry, morphometry, digital imaging and photography. Tissue/fluid procurement will be linked to ongoing SPORE projects and modifications will be made as necessary to meet any changes in SPORE research goals. All tissues will be collected through IRB-approved protocols on which Tissue and Blood Bank Core pathologists will be co-investigators. The Tissue and Blood Bank Core will take advantage of the UPCI infrastructure already existing for procurement of tissue and will not duplicate it. Biostatistics/Bioinformatics Core/Core D
SPECIFIC AIMS The Specific Aims of the Biostatistics and Bioinformatics Core are:
Developmental Research Program William L. Bigbee, Ph.D., Co-Program Director The Developmental Research Program of the University of Pittsburgh Cancer Institute Lung Cancer SPORE will be carried out for the purpose of identifying and facilitating innovative new pilot projects in lung cancer research. The overall goal of the Developmental Research Program is to provide seed funding to investigators for novel research in lung cancer to further the basic, clinical and translational research priorities of the Lung Cancer SPORE. The specific goals of this Program are : 1) to provide seed funding opportunities for initial investigation of promising novel research in lung cancer: 2) to stimulate basic, clinical, and translational lung cancer research in areas of high priority to the Lung Cancer SPORE; 3) to facilitate development of pilot projects into full project status in the Lung Cancer SPORE or to be competitive for independent investigator-initiated proposals to other funding agencies; and 4) to increase the visibility of Lung Cancer SPORE activities and increase participation among the institution’s clinicians and researchers. Our design for the Developmental Research Program in the renewal is similar to the process used during the first grant period. Drs. William L. Bigbee and Joel S. Greenberger will provide Program leadership for basic and clinical research, respectively. The Developmental Research Program will utilize institutional web-based resources and printed announcements to notify the research community at the UPCI, the University of Pittsburgh Medical Center (UPMC), and the affiliated Carnegie Mellon University of the availability of research funds to support pilot projects in lung cancer. In response to the new SPORE guideline encouraging inter-institutional collaboration, we will also make the program available to our sister Cancer Centers in Philadelphia, who are part of the statewide Pennsylvania Cancer Control Consortium (PAC-3) initiative. A standing Developmental Research Program Committee, together with ad hoc reviewers with specific expertise as needed drawn from the UPCI, UPMC, the Lung Cancer SPORE External Advisory Board, or other SPOREs will provide rigorous and consistent peer review of the solicited project proposals. The proposed Developmental Research Program budget will include $70,000 per year in funds from the NCI through this proposal, together with an additional $50,000 per year in matching funds from the UPCI. Proposals will be solicited and reviewed on an annual basis and grants of $30,000-$50,000 per year for 1-2 years will be awarded to the most meritorious proposals. These activities of the Developmental Research Program will stimulate innovative research toward meeting the translations goals of the Lung Cancer SPORE: reduction in the incidence, morbidity, and mortality from lung cancer. Career Development Program Joel Greenberger, M.D., Co-Program Director The mission of the Lung Cancer SPORE Career Development Program is to stimulate basic, translational and clinical research in lung cancer by recruiting new and established investigators in the area of lung cancer. The Career Development Program within the SPORE provides financial support for this mission, while the SPORE itself provides a nurturing and stimulating environment for those who are being initiated into lung cancer research. The Career Development Program has the following objectives: 1) To recruit physicians, scientist, and physician-scientist to direct their research efforts to the field of lung cancer; 2) To train and guide these investigators through the process of developing into outstanding investigators in the translational areas of lung cancer research, including laboratory, clinical, and population science. The faculty within the SPORE has a long-standing record in mentoring postdoctoral fellows, new independent investigators, and physician-scientists for careers in translational research. In the first grant period, we designed the Career Development Program with two components: support of new Faculty Members and support of both beginning and advanced Post-Doctoral Fellows. This plan was given a highly meritorious rating of outstanding by the SPORE peer review panel in 2000. During the ensuing five years, SPORE guidelines have changed and Career Development Awards to Post-Doctoral Fellows are restricted to those who are very close to a faculty appointment. We have designed a new Career Development plan in the renewal to accommodate this change in the guidelines, focusing only on Faculty Members and Fellows or Research Associates who are near to a faculty appointment. The SPORE Career Development Program will consider candidates identified through a well-defined recruitment process, and will especially seek to support women and minority candidates.
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