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Last Updated: 10/10/18

University of Colorado Cancer Center Lung Cancer SPORE

Principal Investigator Contact Information

Robert C. Doebele, MD, PhD
Associate Professor
University of Colorado Anschutz Medical Campus
Medical Oncology/Department of Medicine
12801 E. 17th Ave.
MS 8117
Aurora, CO 80045
Tel: (303) 724-2980
Fax: (303) 724-3889
Email: robert.doebele@ucdenver.edu

Paul A. Bunn, Jr., MD
Director
University of Colorado Health Science Center
Department of Medicine
4200 East Ninth Avenue
Box B - 188
Denver, Colorado 80262
Tel: (303) 315-3007
Fax: (303) 315-3304
Email: paul.bunn@uchsc.edu

Project 1: Targeting FGFR1 Signaling in Lung Cancer

Project Co-Leaders:
Lynn E. Heasley, PhD (Basic)
Fred R. Hirsch, MD PhD (Applied)
D. Ross Camidge, MD PhD (Clinical)

This is a new SPORE project that evolved from a previously-funded SPORE Pilot project. The overall goal of this project is to develop the Fibroblast Growth Factor Receptor (FGFR) pathway as a therapeutic target in lung cancers of any histology. Tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK have impacted greatly the treatment of lung cancers driven by oncogenic forms of these receptor tyrosine kinases (RTKs). Still, the driving oncogenes in many lung cancers, especially of non-adenocarcinoma histologies, have not been identified. Such lung cancers remain an unmet clinical need. Our studies have unveiled a role for non-mutated FGFR1 as an oncogene driver in NSCLC cell lines of diverse histologies. Although rare somatic mutations and gene rearrangements in FGFR2 and FGFR3 have been reported in lung cancers, their potential as oncogene drivers has not been defined. In some cases, FGFR-dependency occurs through FGFR1 gene copy number gain (CNG), especially in squamous lung cancers. In fact, FGFR1 CNG is already being employed as a pre-selection marker in squamous NSCLC for early phase trials of the FGFR-specific TKIs, AZD4547 and BGJ398. While we will further explore FGFR1 CNG, our preclinical findings reveal that other predictive biomarkers (FGFR1 mRNA and protein expression) identify FGFR1-dependence more comprehensively than CNG, alone. Specifically, we have shown that FGFR activity depends on increased expression of FGFR1 through gene amplification or transcriptional induction as well as co-expression of FGF2 or FGF9, thereby establishing an autocrine mechanism to drive increased FGFR1 activity. In this project, we will test the hypothesis that an FGF-FGFR1 autocrine pathway serves as a frequent oncogenic driver across all lung cancer histologies and that FGFR1 mRNA and protein expression, better than FGFR1 CNG, will serve as a predictive biomarker of lung cancer patients likely to respond to FGFR-selective TKIs. To test this hypothesis, we will complete the following specific aims. Aim 1: Define signaling mechanisms and biomarkers that accurately identify lung cancer cell lines exhibiting FGFR dependency. Aim 2: Develop assays for biomarkers identified in Aim 1 suitable for use with formalin-fixed, paraffin-embedded lung tumor tissues. Aim 3: Conduct a biomarker selected, multiple cohort, Phase II clinical trial with ponatinib in lung cancer patients. Successful completion of this project may impact lung cancer treatment by unveiling a novel and substantial subset of lung tumors for personalized therapy.

Project 2: Improving Outcome from EGFR Specific TKIs Using Rational Combinations

Project Co-Leaders:
James DeGregori, PhD (Basic)
Paul A. Bunn, Jr, MD (Applied)

EGFR mutant NSCLCs account for 15% of the 220,000 new lung cancers annually (33,000/yr) in the U.S. and usually respond to EGFR TKIs. However, complete responses are rare, and progression free survival remains less than 12 months. Development of drug resistance and progressive disease is universal. EGFR mutant lung cancers possess inherent or acquired survival mechanisms that protect the cells from EGFR inhibition. Thus, the discovery of pathways that mediate these compensatory survival mechanisms should reveal novel therapeutic targets that in combination would render kinase inhibition a more effective therapy. In the last grant period, we used a genome-wide shRNA screen and gene expression profiling to identify genes that when inhibited sensitize EGFR mutant NSCLC cells to EGFR inhibition. These studies identified the FGFR and Wnt/Β-catenin pathways as mechanisms allowing the survival of EGFR mutant NSCLC cells in the presence of EGFR TKIs. We further showed that genetic and pharmacological inhibition of the FGFR pathway and multiple components of the canonical Wnt/Β-catenin pathway identified in this screen, including tankyrase and casein kinase 2 (CK2), potentiated EGFR inhibitor therapy in vitro and in vivo. Since then, third generation EGFR TKIs that inhibit EGFR activating mutations as well as the T790M gatekeeper mutations (e.g., AZD9291) have entered the clinic with the promise of preventing T790M resistance and thereby prolonging the time to progression without affecting innate survival pathways but increasing reliance other signal pathways. In this project, we propose to identify, validate and characterize signaling mechanisms underlying the inability of both first and third generation EGFR TKIs to elicit more complete therapeutic responses, in order to develop novel therapeutic combinations that can improve outcomes. Importantly, we have been successful in the past in translating discoveries into biomarker-driven clinical trials. We will achieve these goals through three aims: 1) Pre-clinically evaluate the roles for FGFR signaling in early innate and late acquired resistance to EGFR TKI therapy in EGFR mutant NSCLC and determine the ability of FGFR TKIs to overcome these resistance mechanisms, 2) Conduct a phase Ib/II trial combining EGFR and FGFR TKIs in EGFR mutant patients, and 3) Determine the pre-clinical efficacy of combining EGFR inhibitors with canonical Wnt pathway. For all aims we will determine the frequency of alterations of cell signaling pathways at the time of progression in the preclinical models and patient biopsies using FGF biomarkers, EMT markers, AXL, MER and MET markers as well as discovery efforts using RNA-seq approaches in pan-negative biopsies. By targeting multiple pathways, the ultimate goal of these studies is the development of therapeutic strategies for NSCLC patients that minimize the development of drug resistance and improve therapeutic outcomes.

Project 3: Prostacyclin and Peroxisome Proliferator-Activated Receptor-? in Lung Cancer

Project Co-Leaders:
Raphael Nemenoff, PhD (Basic)
Robert Keith, MD (Clinical)

Alterations in eicosanoid production play a complex role in cancers, including lung cancer. Preclinical studies from our group have demonstrated that increased levels of prostacyclin (PGI2) are chemopreventive in multiple models of lung cancer. Furthermore, the orally active PGI2 analog iloprost has both chemopreventive and chemotherapeutic activity in mouse models of lung cancer. These studies resulted in a double-blind, placebo controlled clinical chemoprevention trial in which patients at high risk for lung cancer were treated with iloprost. This trial demonstrated significant reversal of endobronchial dysplasia in ex-smokers, one of the few chemopreventive trials to show a positive effect. There are currently plans to move forward PGI2 analogs in a larger Phase II/Phase III trial examining the prevention of lung cancer. We demonstrated that the protective effects of PGI2 were independent of the cell surface receptor but were mediated through activation of the nuclear receptor PPAR?. These studies, along with retrospective studies showing reduced incidence of lung cancer in patients taking thiazolidinediones (TZDs), resulted in a second, ongoing clinical trial assessing the role of the TZD pioglitazone in patients at risk for lung cancer (PIOuS trial). The goal of the current proposal is to examine PGI2 analogs and define the cellular and molecular mechanisms mediating the effects of PGI2 analogs and pioglitazone. Three specific aims are proposed. Due to the discontinuance of oral iloprost, aim 1 will test the preventive and therapeutic effects of a novel PGI2 analog in three mouse models of lung cancer. Effects on eicosanoid production and on recruitment of inflammatory cells will be examined. Aim 2 will define the cellular and molecular targets of PGI2 and PPAR?. Targeted deletions of PPAR? in myeloid cells and epithelial cells will be used to define the critical target cell mediating the chemopreventive response of PGI2 and PPAR?. Our studies have demonstrated that expression of the Wnt receptor Frizzled 9 (Fzd9) is necessary for growth inhibition and activation of PPAR? in human NSCLC. The role of Fzd9 in mediating the chemopreventive effects of PGI2 will be determined using Fzd9 knockout mice. Finally, aim 3 will develop both predictive biomarkers for response to Iloprost and PPAR? modifying therapies and prognostic biomarkers that characterize dysplasia risk. In samples from the iloprost and PIOuS trials, changes in inflammatory cells and in expression of Fzd9 will be examined as predictive biomarkers for response to therapy. Expression profiling and genomic instability as assessed by copy number with SNP arrays will be used to identify gene signatures associated with prognostic biomarkers of persistent and regressive dysplasia. risk and predictive biomarkers for response to Iloprost and PPAR? modifying therapies.

Project 4: Predictors of Lung Nodule Malignancy

Project Co-Leaders:
York E. Miller, MD (Applied)
Anna Barón, PhD (Biostatistics/Prediction Modeling)
Stephen Malkoski, MD (Applied)
Fred Hirsch, MD PhD (Basic)

Our overarching goal is to develop biomarkers that are useful in informing clinical management of CT detected lung nodules of indeterminate etiology. Biomarkers assayed in non-invasively obtained biospecimens need to be developed to enhance the performance of currently evolving lung cancer risk models which are based solely on demographics, clinical and imaging characteristics. We hypothesize:

  1. Biomarkers measurable in non-invasively obtained specimens can improve discrimination between benign and malignant lung nodules above that achieved by imaging and demographic parameters alone.
  2. These biomarkers can be incorporated into a prediction model to aid clinical decision making and lay the foundation to improve outcomes by shortening time to diagnosis, decreasing biopsy and/or surgery for benign disease, reducing patient anxiety, and decreasing costs.

In the current SPORE grant period, we have developed several promising biomarkers and carried out initial validation steps. We now are in the position to assess these prospectively and simultaneously in a population in which they would have immediate clinical applicability, through the following Specific Aims:

  1. Develop and test novel measurement tools for the following biomarkers in non-invasively obtained specimens: a. Epithelial chromosomal imbalances. b. Circulating protein levels. c. Exhaled breath volatile organic compounds. d. miRNA expression patterns.
  2. Compare the performance of the individual biomarkers singly and in combinations in discriminating benign from malignant nodules in a cohort of subjects with indeterminate lung nodules referred to specialty clinics for evaluation.
  3. Develop a model based on biomarker outcomes, smoking history, clinical and imaging features for the prediction of malignancy in CT detected lung nodules.

We envision that at the end of this project, the above predictive model can be subjected to further prospective validation in independent cohorts of patients with indeterminate CT detected lung nodules, in which changes in specific outcomes (time to diagnosis, invasive procedures for benign disease, costs) can be simulated.

Tissue Bank / Biomarkers Core

Core Co-Directors:
Daniel T Merrick, MD FCAP
Adrie van Bokhoven, PhD

The Tissue Bank and Biomarkers Core (TBBC) is the central repository of specimens necessary for the execution of the studies of the Colorado SPORE in Lung Cancer program. Furthermore, as an extensive resource for lung cancer related specimens, the TBBC also provides specimens to extramural investigators when there are adequate materials to accommodate these requests beyond the needs of the internal projects. The three primary goals of the TBBC are to procure, characterize and process, and distribute specimens. The provision of these services takes advantage of a close working relationship with the existing facilities, infrastructure, and personnel for biobanking and histology operations of the University of Colorado Cancer Center Tissue Biobanking and Processing Shared Resource. Two general banks are maintained: a tumor bank and a premalignant bank. Specimens for these banks are collected as archival tissue or in collaboration with the Clinical Trials Core. SPORE trial-associated specimens are obtained under IRB approved protocols. In addition to tissue, ancillary specimens, including blood, sputa, urine, exhaled breath and special bronchoscopic specimens are collected. The TBBC, in collaboration with the Biostatistics and Bioinformatics core of the SPORE, also collects correlative clinical and biologic information that can be included in specimen distributions. The TBBC provides histologic and cytologic interpretation, prepares RNA, DNA and protein samples, creates TMAs and provides molecular analysis on selected specimens required by the SPORE projects. This includes histologic review and classification by up-to-date published WHO classification systems for malignant and pre-malignant lesions of the lung by the pathologist members of the core. The core designs its activities to meet the needs of each of the SPORE projects as outlined in the proposal. In order to meet the tissue needs and achieve the goals of the projects, the TBBC collects and processes tissues in a specific manner as determined via collaboration with project investigators. The TBBC also collaborates in the performance of project related studies in which expertise of TBBC personnel can benefit study design, data generation, and data analysis.

Clinical Trials Core

Core Co-Directors:
Robert Keith, MD
D. Ross Camidge, MD PhD

The goal of the Clinical Trials Core (CTC) is to provide support for clinical trials designed and implemented for SPORE projects. The support includes assistance with trial preparation, regulatory issues, data safety and monitoring, auditing, conduct, and reporting. Our increasing understanding of the molecular basis of lung cancer has reinforced the need to continue conducting studies which involve the collection of both clinical data and specimens for molecular analyses. This translational approach allows for the investigation of biological pathways of lung carcinogenesis in human tissue, and acts as a powerful tool in the evaluation of novel strategies for the prevention, screening, early detection, and treatment of lung cancer. The CTC has been essential in translating the science generated from each of the individual projects.

The CTC has played a crucial role in the Colorado SPORE due the nature of our trials. Our trials have largely focused on chemoprevention, early detection, and tissue acquisition, and have robust enrollments and specimens. Trial subjects are predominantly enrolled from pulmonary clinics at affiliated Hospitals where Cancer Center personnel are not located. These are high risk subjects who do not yet have lung cancer. In addition, specialized training is required for the collection and handling of large numbers of specimens from each procedure at each visit. Special processing to allow separation of diagnostic tissue from remnant tissue and for cell culture is required. The Clinical Trials Core utilizes two databases. The SPORE Bioinformatics core provides a biorepository database that manages the storage and retrieval of biospecimens related to SPORE trials. This database also tracks all SPORE study subjects, enrollments, and personnel providing key statistics for grant reporting. The NCIs Center for Bioinformatics provided our remote data capture management system in Oracle Clinical, and this provides a full suite of capabilities to facilitate study design, data entry, replication, and discrepancy management. We have a team of clinical research associates expertly trained to accrue subjects and collect data/tissue samples for all SPORE-supported trials. All data is entered into a web database designed to link the clinical information to the biological correlative studies for future analyses. During the previous five year funding period there have been 9 trials supported by the Clinical Trials Core and these trials have enrolled 931 subjects. Additional trials are being actively planned based on basic science and clinical discoveries. The CTC support has led to 47 publications involving all of the projects and to multiple vertical collaborations and subsequent trials.

Biostatistics / Bioinformatics Core

Core Co-Directors:
Anna E. Barón, PhD
Aik-Choon Tan, PhD

The Lung Cancer SPORE Biostatistics, Informatics and Bioinformatics Core (BIBC) provides support in the areas of biostatistics, clinical informatics, and bioinformatics to SPORE investigators. The Core comprises long-standing and new SPORE collaborators who provide expertise in study design, data management, data analysis, clinical informatics system creation, and bioinformatics data management and interpretation. The Biostatistics group assists primarily with study and protocol design, data analysis and interpretation, and review of requests presented to the Tissue Use Committee. The Informatics group assists with data quality control, data sharing, designing and maintaining the SPORE database that captures clinical, pathologic, and laboratory data into a relational database. The Bioinformatics group assists with computational evaluations of large databases, especially those created with genomic and proteomic analysis using gene expression and SNP arrays and proteomic profiles. All Core members participate in preparation of reports, presentations, and manuscripts. BIBC members will work with SPORE investigators in the following areas:

  1. Experimental design: Design of both pre-clinical and clinical experiments that can provide useful answers to scientific questions of importance in lung cancer.
  2. Data collection/storage/retrieval/sharing: Creation and maintenance of a sound and user-friendly infrastructure for data collection, storage, quality assurance, retrieval, and sharing in support of SPORE trials and tissue banking.
  3. Data analysis and manuscript preparation: Structuring of data analyses to provide clear answers to questions, and to communicate those findings in reports and papers.
  4. Translational research methodology: Development and implementation of coherent methods that improve the efficiency and effectiveness of research across the wide spectrum from pre-clinical research to clinical studies, including work in the development of better understanding of the causes of lung cancer, early detection of lung cancer, biomarkers of lung cancer risk, and lung cancer therapeutics.

In addition to these activities, Core members will continue their efforts to develop new approaches to improve the efficiency and outcomes of the process of translational research.

Administration Core

Core Co-Directors:
Paul A. Bunn, Jr., MD
Robert Doebele, MD PhD
York E. Miller, MD

Administrator:
Kristin Herbst

The Administrative Core provides the overall scientific leadership for the University of Colorado SPORE in Lung Cancer as well as providing outstanding administrative and fiscal support for the Program. The Administrative Core oversees all administrative and scientific activities of the SPORE Program; reviews and regulates financial expenditures; and prepares all reports. The Core consists of the SPORE Principal Investigator, Dr. Bunn, and the Co-PI, Dr. Miller; the SPORE Administrator, Michaela Montour; a finance specialist; and effort from the Cancer Center’s grants manager, human resource manager, and operations manager for SPORE-related activities. These individuals provide a network of administrative and fiscal support to facilitate the scientific goals set by the leadership. In addition, the Administrative Core insures adherence to SPORE Guidelines, NIH policies, and other applicable federal, state and institutional policies. The Core works closely with institutional and Cancer Center leadership to insure the SPORE Program remains a priority at the institutional level; and it works closely with community advocates and fundraising groups to promote awareness of and support for the research conducted by the Program. The Core facilitates interactions with outside institutions including academic centers and industry. These interactions support visiting scientists and industry MTAs and contracts. The Core facilitates all planning and evaluation activities including the planning and support of the external and internal scientific advisory committees. The Core facilitates interactions with affiliated hospitals and medical centers including the VA Medical Center, the National Jewish Center, the University of Colorado Hospital, and institutions affiliated with the University of Colorado Comprehensive Cancer Center. Administratively, the Core performs fiscal management and oversight of the Program resources; facilitates planning and evaluation activities; schedules and staffs committees and other meetings related to the Program; exercises oversight of the other shared resource cores; disseminates information about national SPORE meetings and coordinates attendance; tracks publications by SPORE investigators; and facilitates the production of an annual progress report. The goal of these activities is the promotion of translational science that will facilitate interactions between basic and applied scientists to bring innovation to the clinic to reduce the burden of lung cancer.