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MEMORANDUM
All Faculty at the University of Colorado Denver (UCD); all Members of the University of Colorado Cancer Center; and Faculty at the Medical University of South Carolina Lung SPORE Career Development Committee: York Miller MD, Chair; Anna Barón PhD; Daniel Chan PhD; Robert Gemmill PhD; Mark Geraci MD; Marileila Varella-Garcia PhD; Robert Winn MD; Robert Sclafani PhD; and Laurie Gaspar MD Career Development Awards

Investigators at the University of Colorado Cancer Center and the Medical University of South Carolina
(MUSC) hold a SPORE (Specialized Program of Research Excellence) in Lung Cancer grant award from the
National Cancer Institute (P50 CA058187 / Bunn). The grant includes support for career development
research projects in lung cancer. Each year at least one Career Development award of up to $50,000 is
supported. The deadline for applications this year will be June 22, 2011.

The purpose of the SPORE in Lung Cancer grant is to promote translational research1 objectives in lung
cancer by moving basic research findings into studies for improving the detection, diagnosis, treatment, and
prevention of human lung cancer; and/or by investigating patient phenomenon at the bench – e.g. identifying a
gene altered by a chromosomal rearrangement that has occurred in a patient with the disease.
The goal of the Career Development Program is to prepare new investigators for careers in lung cancer
research. Funds from this program may be used to support advanced post-doctoral or clinical fellows (who
will be independent investigators within the next year), junior faculty, or established investigators who wish to
develop or refocus their careers on translational research. SPORE career development programs are not
intended for pre-doctoral candidates or junior level post-doctoral and clinical fellows.
Applications will be judged on 1) the potential of the applicant for a successful career in lung cancer research;
2) the quality of the research proposed; and 3) the mentor. Applications from Full and Associate Professors
are generally more appropriate for the SPORE Pilot Project Program. Awards will be for 12 months and may
be renewable for one additional year, given adequate progress of the candidate towards an independent
career in lung cancer research.
Applications should include:
1. Title Page identifying the applicant, the mentor(s), and the title of the project. 2. A 1 – 2 page description of the path the candidate will follow as he/she moves into an academic research career in lung cancer. The description should include information on how a career development award from the SPORE will support their path; and their career path should include plans to write an independent lung cancer research grant in the second year of their program. 3. Translational Research Statement: A short description (no more than ½ page) of the translational 1 Translational research uses knowledge of human biology to develop and test the feasibility of cancer-relevant interventions in humans AND/OR determines the biological basis for observations made in individuals with cancer or in populations at risk for cancer. The term “interventions” is used in its broadest sense to include molecular assays, imaging techniques, drugs, biological agents and/or other methodologies applicable to the prevention, early detection, diagnosis, prognosis or treatment of cancer. Translational research in SPOREs is always based upon knowledge of human biology stemming from research involving the use of any cellular, molecular, structural, biochemical, genetic, or other appropriate experimental approach. (NCI SPORE Guidelines, September 2008). 4. Project Narrative: A complete but concise description of the project including Specific Aims (no more than ½ page), Background & Significance (limited to 1 page), Preliminary Studies (limited to 1.5 pages),
Experimental Design and Methods (limited to 3 pages), and any other information required to fully
describe the proposed work. The Project Narrative should be no more than 6 pages, including
figures, tables and other relevant data.
 Margins must be at least ½ inch all around.  References cited are not included in the 6 page maximum. 6. Mentor’s curriculum vitae 7. A list of the mentor(s) pre- and post-doc candidates they have mentored in the past and the current Applicants who are funded will be expected to present a seminar on their research approximately 9 months into their 12 month project. Funding will be awarded on a one-year basis only. Additional years of funding (up to 2 total are possible) will require the submission of a competitive application and will be reviewed on the basis of the progress of the candidate on both the career path and on scientific progress on the funded project. Email an electronic copy of your application (PDF format) to Michaela Montour at
[email protected] by 5:00 p.m. June 22, 2011.
If you have any questions about the application process, please call Michaela Montour at 303-724-3151. SPORE IN LUNG CANCER
The projects and cores of the SPORE in Lung grant focus on translational research objectives that move basic
research findings into studies for improving the detection, diagnosis, treatment and prevention of human lung
cancers.

Project 1: SEMA3F and ZEB1 in Lung Cancer: Therapy and Target Gene Discovery
Co-Principal Investigators: Harry Drabkin MD and Robert Gemmill PhD
Abstract:
A major component in the development / progression of lung cancer is loss of the tumor suppressor genes, E-cadherin
and the secreted semaphorin, SEMA3F. We originally identified the SEMA3F gene and reported correlation of
downregulation with advanced-stage disease. SEMA3F binds high affinity Neuropilin receptors on tumor and endothelial
cells, which mediate its biologic actions together with plexin-A co-receptors. SEMA3F potently inhibits tumor cells in vitro
and in vivo, and has additional anti-angiogenic effects on endothelial cells, where the Neuropilins function as co-receptors
for VEGF. We reported that SEMA3F downregulates activated v3 integrin in tumor cells with loss of phospho-ERK, AKT
and STAT3, and inhibitory effects on HIF and VEGF. Our current data indicate that SEMA3F also inhibits certain non-
VEGF angiogenic factors known to be regulated by NF-kB. Thus, SEMA3F can block two major pathways of neo-
angiogenesis, emphasizing the therapeutic potential of this secreted tumor suppressor. However, it’s important to
determine if local production of SEMA3F is required for these effects, or whether exogenously administered SEMA3F also
affects tumor cells, endothelial cells, or both.
In lung cancer, we’ve shown that ZEB-1 is the major E-box transcriptional repressor regulating E-cadherin. E-box
repressors are responsible for the epithelial-mesenchymal transition (EMT), which underlies the invasive / metastatic
nature of epithelial cancers. We’ve also shown that ZEB-1 expression and E-cadherin loss confers resistance to EGFR
inhibitors, which has led to three ongoing cancer trials combining erlotinib with SAHA, MS-275 or celecoxib. We’ve now
discovered that ZEB-1 is responsible for suppressing SEMA3F and that the mechanism of EGFR inhibitor resistance
appears to involve MET activation, possibly via Neuropilin upregulation.
Two Specific Aims are proposed. In Aim 1, we will: 1) determine whether constitutive expression of VEGF can overcome
the anti-tumor activity of SEMA3F, 2) determine whether exogenously administered SEMA3F affects tumor cells,
endothelial cells or both, and 3) define a signature of SEMA3F responsiveness in lung tumors. In Aim 2, we will
determine: 1) if ZEB-1 induced resistance to EGFR therapy is dependent upon MET activation, 2) how ZEB-1 activates
MET and whether this is neuropilin-dependent, and 3) if selected MAGE genes, which appear to be regulated by ZEB-1,
can provide a complementary biomarker for the EMT process in tumors and pre-malignant lesions.

Project 2: Growth Factor Inhibitors for Lung Cancer Therapy and Prevention
Co-Principal Investigators: Paul Bunn MD; and Dan Chan PhD
Co-Investigators: Lynn Heasley PhD; Barbara Helfrich MSc; and Fred Hirsch MD PhD
Abstract
The long-term goal of this project is to develop novel therapeutic and chemoprevention strategies for lung cancer through
combinatorial inhibition of different autocrine / paracrine growth factor signal pathways. Previously, we developed a novel
bradykinin-derived “biased agonist”, CU201, defined its spectrum of activity and pharmacokinetic and toxicity profiles. In
the next grant cycle, we will precisely define the molecular mechanism of action of CU201 including the requirement for
the bradykinin B2 receptor (BK2R) and specific downstream signal pathways. We will also complete late preclinical and
early clinical development of CU201. During the past grant, EGFR-specific inhibitors emerged as therapeutic agents with
activity towards a subset of lung tumors. Our studies defined predictive biomarkers for selection of patients for EGFR
inhibitor therapy including a specific gene expression pattern indicative of more-differentiated epithelium as well as EGFR
gene amplification. Importantly, the limited action of EGFR inhibitors, when employed as single agents, indicates that
additional growth factor autocrine loops participate in lung tumorigenesis. Our preliminary studies, in fact, provide
compelling evidence for the frequent activity of FGF and FGFR-mediated autocrine signaling in NSCLC and SCLC cell
lines. Based on our published and preliminary studies, we hypothesize that multiple autocrine and paracrine growth factor
signaling pathways driven by EGFR, FGFRs and BK2R participate in the pathogenesis of lung cancer. Moreover, we
hypothesize that specific biomarkers and gene expression signatures can be identified that will predict the autocrine
growth loops, either singly or combined, that are active in a given lung tumor. To explore these hypotheses, we will
complete these specific aims. Aim 1: Determine the role of bradykinin receptor (BK2R) and specific signaling
pathways that dictate therapeutic responsiveness to the bradykinin receptor antagonist, CU201. 1A. Define the
mechanism of action of CU201 and the role of BK2R in CU201 efficacy. 1B. Explore additive / synergistic interactions of
CU201 with rationally selected agents. 1C. Determine the frequency and prognostic relevance of BK2R expression in our
lung cancer TMAs and preneoplastic tumors. 1D. Conduct a phase I clinical trial of CU201. Aim 2: Define specific
FGFs and FGFRs as components of a novel autocrine signaling pathway in NSCLC and SCLC that can be
targeted with existing FGFR inhibitors. 2A. Determine the correlation of FGF2, FGF9, FGFR1c and FGFR2c mRNA
and protein expression in NSCLC and SCLC cell lines with response to FGFR TKIs (pazopanib) and an inhibitory FGFR1c
mAb (IMC-A1) .2B. Test for additive/synergistic growth inhibition by rationally designed combinations. 2C. Determine the
frequency and prognostic relevance of FGF2, FGF9, FGFR1c and FGFR2c expression in our lung cancer TMAs and
preneoplastic tissues.

Project 3: Prostacyclin and Peroxisome Proliferator-Activated Receptor  in Lung Cancer
Co-Principal Investigators: Raphael Nemenoff PhD; and Mark Geraci MD
Co-Investigators: Robert Keith MD; Robert Winn MD; Daniel Merrick MD; and Xue-Qing Wang PhD
Abstract
Increased prostaglandin (PG) production has been associated with many types of cancer including lung cancer. Inhibition
of cyclooxygenase (COX, PGH2 synthase) decreases PG production and prevents lung cancer in animal models.
Prostacyclin (PGI2) is a PGH2 metabolite with anti-proliferative and anti-metastatic properties. Our laboratory has shown that targeted overexpression of PGI2 synthase or chemoprevention with the PGI2 analog iloprost reduced lung tumor multiplicity and incidence in mice, suggesting that manipulation of the arachidonic acid pathway downstream from COX is a target for prevention of lung cancer. These studies led to a chemoprevention trial in which patients at risk for lung cancer are treated with iloprost. Studies performed during the previous funding period have shown that the anti-tumorigenic effects of PGI2 are not mediated through its cell-surface receptor (IP), but instead via activation of the peroxisome proliferator-activated receptor- (PPAR). Retrospective studies indicate that thiazolidinediones such as rosiglitazone or pioglitazone, which are specific PPARactivators, reduce the risk of lung cancer. We have shown that mice with targeted overexpression of PPAR are also protected against lung tumorigenesis. In human NSCLC cell lines, PPAR activation inhibits transformed growth and invasiveness, and promotes differentiation. These effects are associated with inhibition of COX-2 and decreased production of angiogenic cytokines. PGI2 and its analogs activate in non-transformed epithelial cells but not in many NSCLC lines. We have demonstrated that the ability of PGI2 to engage PPAR in NSCLC is correlated with the expression of the Wnt family receptor Frizzled 9 (Fzd9). The goal of the current proposal is to examine the role of PGI2 and PPAR in the development and progression of lung tumors. Studies will use human NSCLC cell lines and mouse models to define molecular effectors and markers of response. These
findings will be applied to analyze human samples from the iloprost trial and a new proposed pioglitazone
chemoprevention trial, as well as samples from human lung tumors. Three specific aims are proposed. Aim 1 will use in
vitro approaches to define biomarkers of iloprost and pioglitazone sensitivity in a panel of NSCLC, and to examine
interactions between these agents and EGFR-TKIs. Aim 2 will use a chemical carcinogenesis mouse model to examine
the effects of agent combinations, including iloprost plus pioglitazone and iloprost or pioglitazone with erlotinib. Xenografts
of human NSCLC will examine the interactions between iloprost and Fzd9 and establish the basis for therapeutic trials
using iloprost in combination with other agents. Aim 3 will use expression profiling of samples from chemoprevention trials
to define expression signatures of dysplasia and response to iloprost or pioglitazone. Expression of molecules studied in
Aims 1 and 2 will be examined in human tumors and correlated with clinical data. These studies will establish the role of
this pathway in lung cancer initiation and progression, and help define new therapeutic targets.

Project 4: The Biology of Pulmonary Premalignancy: Application to Risk Assessment and
Chemoprevention
Co-Principal Investigators: York Miller MD; Tim Byers MD MPH; Fred Hirsch MD PhD; Marileila Varella-Garcia
PhD
Co-Investigators: Mark Duncan PhD; Robert Keith MD; Timothy Kennedy MD
Abstract
The overarching goal of this project is to reduce the lung cancer burden through the discovery and translation of
knowledge regarding the biology of broncho-pulmonary premalignancy. Specifically, we aim to discover and validate
clinically useful biomarkers of risk in sputum and to identify early events in pulmonary tissues that lead to lung cancer.
Biomarkers of lung cancer risk in both sputum and bronchial tissues could have many clinical uses, including population
screening for early detection, either alone or in combination with CT imaging, and to assist in clinical decisions regarding
the management of patients found to have a pulmonary nodule of undetermined significance. We have established
unique prospective cohorts of subjects in whom both prevalent and incident lung cancer is tracked, and we harvested and
stored biological samples from them. We will build on our considerable preliminary evidence to further optimize and then
validate a panel of biomarkers in sputum, including cytology, chromosomal aneusomy, and gene promoter methylation.
We will also continue to develop tissue biomarkers of lung cancer, various types of biomarkers in bronchial alveolar
lavage (BAL), and proteomic biomarkers in the blood.
Specific Aim 1. Identify and validate candidate biomarkers in sputum that may be useful for population
screening and clinical decision making. We will test additional probes in chromosomal regions known to be amplified
in lung cancer, and will assess additional methylated genes. We will then optimize panels of multiple biomarkers from both
types of measures, as well as sputum cytology, for the prediction of lung cancer risk. We will subsequently assess the
most promising set of biomarkers in a validation set of subjects sampled from the National Lung Screening Trial, an
ongoing trial of CT screening. Analyses will determine the performance of this panel of sputum biomarkers for lung
cancer screening, as well as for aiding clinical decisions regarding the management of pulmonary nodules of
undetermined significance.
Specific Aim 2. Assess tissue biomarkers of lung cancer risk and evaluate tissue biomarkers as intermediate
biomarker endpoints in chemoprevention trials. We will continue to identify and characterize biomarkers on the
causal pathway to lung cancer from lung tissues, including bronchial biopsies and both cells and proteins found in BAL
fluids. BAL is an understudied sample source that could well be very useful in the diagnosis of lung adenocarcinomas
arising from for peripheral nodules. We will continue work tying molecular changes to bronchial histology, bronchial
histology to lung cancer risk, and assessing biomarker modulation in past, current, and future chemoprevention trials.

SPORE Cores
Core 1:
Tissue Bank / Biomarkers
Co-Directors: Wilbur Franklin MD; and Fred Hirsch MD PhD Co-Investigators: Marileila Varella-Garcia PhD; and Daniel Merrick MD Clinical Trials
Biostatistics and Informatics
Co-Directors: Anna Barón PhD and Jessica Bondy MHA Award Administration

1.
Career Development awards are contingent upon the annual receipt of the SPORE in Lung Cancer grant (P50 CA058187) from the National Cancer Institute. Awards will be issued for a twelve-month period in accordance with the SPORE in Lung Cancer grant’s budget period. Requests for additional time to complete a project must be submitted via email to Michaela Montour on or before the end of the career development award. A brief progress report will be required approximately nine months into the award period. These reports will be included in the annual non-competing grant application for the SPORE in Lung Cancer award. A request for the progress report will be sent to each recipient at least one month prior to the date the report is needed by the Cancer Center. Awardees are expected to present on a yearly basis to the SPORE Research in Progress Seminar. Presentations typically occur at the beginning of the research period, so as to identify collaborations and resources within the SPORE, and on a yearly basis thereafter. A final report is to be submitted electronically to the Cancer Center two months after the final date of the career development award period. In addition to the progress and final reports, award recipients will be asked on an annual basis to identify any publications or grant submissions that have transpired as a result of the career development award. This information will be included in each annual non-competing grant application for the SPORE for the duration of the SPORE’s project period (2008 - 2013). Please note – this information is used to document the success of the Cancer Center’s career development program, which is considered by NCI to be a critical component of a SPORE grant award. Career Development recipients interested in seeking a second year of funding may do so by submitting a competitive application responsive to the RFA on or before the due date specified on the annual request for application for the Career Development program. We recognize that a Career Development Program that is successful in engaging investigators in careers in lung cancer research will often include support for two years. However, funding for a second year of support is not guaranteed and depends on adequate progress in the first year and a compelling application. Support for a third year would occur under exceptional circumstances only.

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