SPOREs : Organ-Specific SPORE Programs : Lung

DANA-FARBER/HARVARD CANCER CENTER SPORE IN LUNG CANCER

Bruce Johnson, M.D.
Director, Lung Program
Dana-Farber Cancer Institute/Harvard Cancer Center
44 Binney Street, Suite 1234
Boston, MA 02115
Tel: (617) 632-4790
Fax: (617) 632-5786

For more information on this specific SPORE's institution, please visit: http://www.dfhcc.harvard.edu/spores/

Overview

The Dana-Farber/Harvard Cancer Center (DF/HCC) Lung Cancer SPORE includes investigators from the Harvard-affiliated hospitals in Boston, Harvard Medical School, and the Harvard School of Public Health. The DF/HCC Lung Cancer SPORE will build on the strengths of established ongoing scientific investigation within the DF/HCC. Five major projects are proposed. Project 1 will use single nucleotide polymorphisms in germline DNA to examine their associations with patient outcome following treatment for non-small cell lung cancer. Project 2 will examine the transcription factors Foxa2 and the C/EBP family members in the pathogenesis and potential treatment of lung cancer. Project 3 plans to target erlotinib-resistant lung cancer with other tyrosine kinase inhibitors and irradiation to provide further information on effective combinations of targeted agents. Project 4 will characterize the effect of Hsp90 inhibitors in NSCLCs with different genomic changes to help identify patients who may benefit from this therapy. Project 5 will study the mechanisms of acquired resistance to epidermal growth factor receptor–targeted agents in cell lines and human trials for patients with lung cancer. The 4 cores established in 2003 integrate these Projects. These include 1) Tissue and Pathology Core, 2) Administration, Evaluation and Planning Core, 3) Biostatistics Core, 4) Genomics and Bioinformatics Core. The SPORE application describes a Development Research Program that includes our past performance and plan for selection of new projects. The Career Development Program describes our recipients and outlines the mechanism for the identification and support of talented young investigators in lung cancer. The Developmental Research and Career Development Programs will provide the focus for involvement of the community in planning and financial support of the DF/HCC Lung Cancer SPORE. The goal of the DF/HCC Lung Cancer SPORE is to continue the translation of biological and technological advances into clinically meaningful advances for patients with lung cancer and at risk for lung cancer.

PROJECT 1: GENETIC ANALYSIS OF NON-SMALL CELL LUNG CANCER SURVIVAL

Project Co-Leaders

David C. Christiani, MD, MPH (HSPH)
John C. Wain, MD (MGH)
Rebecca Suk Heist, MD, MPH (MGH)

Project 1 will focus on identifying prognostic and predictive markers of survival in lung cancer. The ultimate goal of identifying such markers is to find ways to select the best treatment course for each patient. Recent studies by our group have demonstrated the importance of germline polymorphic variants as prognostic and predictive factors, but these studies have investigated only a few candidate polymorphisms relative to survival outcomes. In this SPORE renewal, we have adopted a high-density pathway approach to investigate more extensively and efficiently the role of entire pathways in survival outcomes. We selected pathways with biologic evidence for a role in tumor aggressiveness or treatment response. Although the eventual goal will be to evaluate germline DNA, serology, tumor-based tissue, and clinical factors in one cohesive model, at present we will focus on germline DNA to identify critical pathway markers. To achieve this goal, we will utilize a large (n=1,000), mature NSCLC case series, early and late stages, with annotated DNA and clinical data to assess genetic variation in selected pathways as prognostic and predictive markers in NSCLC. In Aim 1 (gene discovery), we will use the Illumina Bead Station GoldenGate assay system for genotyping of single nucleotide polymorphisms (SNPs), which allows large-scale genotyping for up to 1,536 customized SNPs, to systematically assess the effects of genetic variation in these pathways on survival outcomes in 60% of our large sample size (discovery phase). For polymorphisms that cannot be assayed with this system and for candidate genes to be used in a validation phase (Aim 2) on the whole population, we will utilize other in-house techniques in the Genomics Core, including Sequenom and ABI 7900 Taqman. Though our primary endpoint will be overall survival (OS), we will also assess disease-free survival (DFS) and progression-free survival (PFS), where appropriate. Aims 3-4 will include assessing the role of gender and other factors in the genetic predictors of survival among lung cancer patients, using both stratified and interaction analyses; and assessing additional candidate genes (e.g. EGFR) and pathways identified from companion basic and translational science studies (Projects 2–5) in lung cancer outcomes. The detailed clinical annotation of our case series is a unique resource with which to investigate prognostic and predictive markers, as well as for gene-environment interactions, in lung cancer survival.

PROJECT 2: FOXA2 AND C/EBP TRANSCRIPTION FACTORS IN THE PATHOGENESIS AND TREATMENT OF LUNG CANCER (OK PER DAN C TO POST)

Project Co-Leaders

Daniel G. Tenen, MD (BIDMC)
Daniel B. Costa, MD (BIDMC)
Balazs Halmos, MD (Case Western Reserve University)

Investigator

Susumu Kobayashi, MD, PhD (BIDMC)

Despite recent progress in diagnosis and treatment of non-small cell lung cancer (NSCLC), survival continues to be poor. Better understanding of the molecular mechanisms that lead to lung cancer and other malignancies are urgently necessary. Most of the research over the last decade in lung cancer has focused on oncogenes, as highlighted in Projects 3, 4, and 5 of this SPORE submission. However research regarding tumor suppressor genes involved in lung cancer has lagged behind, and no specific therapies targeting these genes have emerged to help patients. Since the original Lung Cancer SPORE proposal in 2002, we have studied two specific genes necessary for normal lung development that may act as tumor suppressor genes in lung cancer. These are the transcription factors C/EBPalpha and Foxa2. Our groups’ work has demonstrated that both factors act in a pathway commonly downregulated in many lung cancers and further experiments will enhance understanding of their clinical consequences. The goal of this research is to eventually devise therapies that can re-establish their differentiation-inducing and tumor suppressive pathways, which may expand the therapeutic and chemopreventive options for this malignancy. Therefore, based on the novel findings obtained in 2003 to 2007, we propose to further expand our studies of these transcription factors and move the pathways and potential targets closer to effective clinical applications in malignancies of the airway epithelium with the following Specific Aims: 1) To establish the main mechanisms of inactivation of Foxa2 in lung cancer, its downstream targets (15-PGDH) and prognostic significance; 2) To establish the induction of C/EBPbeta as a novel strategy for lung cancer treatment; 3) To evaluate the synthetic triterpenoids (CDDO and derivatives) as compounds capable of inducing C/EBPbeta and as potent therapeutic options for lung cancer. The foreseeable clinical potential of these studies are the identification of novel prognostic markers in early stage non-small cell lung cancer (Foxa2) and the sound introduction of oral compounds – currently in human phase I clinical trials (as is the case of CDDO-Me) – that can re-activate the crucial C/EBP lung differentiation pathway and halt proliferation as well as induce apoptosis in NSCLC. These studies will likely be the springboard to future clinical trials in patients with this malignancy.

PROJECT 3: TARGETING ERLOTINIB-RESISTANT LUNG CANCER WITH RATIONAL COMBINATION TREATMENTS

Project Co-Leaders

Jeffrey Settleman, PhD (MGH)
Henning Willers, MD (MGH)

Consultants

Daniel Haber, MD, PhD (MGH)
Lecia Sequist, MD, MPH (MGH)

Lung cancer is the leading cause of cancer deaths, and is largely refractory to standard chemotherapy. Selective EGFR inhibitors (e.g., erlotinib) elicit clinical responses in 10-20% of non-small cell lung cancers (NSCLC), which correlates with activating EGFR mutations. However, there remains a large fraction of patients for which erlotinib, as monotherapy, is ineffective. EGFR is expressed in most NSCLCs, suggesting that it may still be an important therapeutic target, in conjunction with additional treatment. We propose to expand the clinical utility of erlotinib by identifying a rational combination with a second treatment to benefit an additional subset of NSCLC patients. Aim 1: To establish the efficacy of erlotinib in combination with a second treatment. By utilizing 108 NSCLC erlotinib-refractory cell lines, we will test the ability of erlotinib plus an additional treatment to produce cytostatic or cytotoxic activity. We will focus on inhibitors of the MET and IGF-1 kinases, as well as HSP90. We will also test the ability of ionizing radiation to synergize with erlotinib. Together, these studies are expected to reveal subsets of NSCLCs that are sensitive to the proposed combination therapies. Aim 2: To establish mechanisms by which combination treatment with erlotinib and a second agent inhibits cell survival. In NSCLC cell lines with synergistic response to combination treatment, we will test the hypothesis that inhibition of survival pathways that may be redundant to EGFR-derived signals produces synthetic lethality. We will also characterize radiation-induced EGFR activation in NSCLCs that are sensitive to erlotinib and radiation, and we will confirm that such EGFR activation is also seen in NSCLC patient explants. We hypothesize that cell death observed in highly sensitive cell lines resembles the previously described apoptotic response to erlotinib in cells with EGFR mutations. Aim 3: To identify biomarkers that predict sensitivity to treatment combinations. In cell lines sensitive to combination treatment, we will correlate sensitivity with: (i) recurrent gene mutations in NSCLC, (ii) comparative genome hybridization array data, and (iii) gene expression profiles. Our findings are expected to inform clinical trials for NSCLC patients with acquired erlotinib/gefitinib resistance (in development in Projects 4 and 5 of this SPORE) and ultimately lead to genotype-driven trials of novel drug combinations or molecularly targeted radiation therapy in patients whose tumors exhibit primary erlotinib resistance.

PROJECT 4: TRANSLATIONAL STUDIES OF HSP90 INHIBITORS IN NSCLC

Project Co-Leaders (ok per G. Shapiro)

Geoffrey I. Shapiro, MD, PhD (DFCI, BWH)
Kwok-Kin Wong, MD, PhD (DFCI, BWH)

Investigator

Lecia Vandam Sequist, MD, MPH (MGH)

The Hsp90 chaperone is required for the stability of multiple Oncogenic kinases that drive signaling, proliferation and survival of non-small cell lung cancers (NSCLCs), including mutant EGFR, Her2, B-Raf, c-Met and cdk4. Inhibitors of Hsp90 will be studied including geldanamycins such as 17-AAG, the water-soluble derivatives IPI-504 and 17-DMAG, and STA-9090, a novel non-geldanamycin, to compare their relative potencies, to define pharmacodynamic endpoints and to conduct clinical trials in molecularly defined patient subgroups. In the first specific aim, these compounds will be studied in EGFR mutant NSCLC cells, including those expressing mutant EGFR harboring the T790M secondary mutation conferring erlotinib resistance. The ability of Hsp90 inhibitors to deplete mutant EGFR and to suppress downstream signaling of the PI3K-Akt-mTOR-p70S6K pathway will be assessed. The relative potencies of 17-DMAG and STA-9090 will be compared to 17-AAG in isogenic cell line models in vitro, and in EGFR mutant/T790M NCI-H1975 xenografts in vivo. The activity of these compounds will also be evaluated in mutant EGFR-driven models of lung adenocarcinoma. In the second specific aim, the activity of Hsp90 inhibitors will be assessed in EGFR wild-type cells driven by other Hsp90 clients. Additionally, Hsp90 inhibitor-mediated depletion of IGF-1R will be evaluated in cells expressing EGFR: IGF-1R heterodimers to determine if there is cytotoxic synergy with erlotinib. In the third specific aim, synergism of 17-AAG with other agents that disrupt chaperone function or Hsp70 induction will be explored, including inhibitors of HDAC6, the proteasome or cyclin-dependent kinase 9. In the fourth specific aim, a Phase I/II Trial of IPI-504 will be conducted; after establishment of the maximum tolerated dose (MTD), preliminary antitumor activity will be defined in NSCLC patients harboring either EGFR mutant or wild-type tumors. A Phase I trial of STA-9090 will also be performed to establish the MTD and safety profile. Hsp90 client depletion will be evaluated in tumor biopsy specimens and peripheral blood mononuclear cells.

In summary, survival for advanced NSCLC remains poor. Many proteins that drive lung cancer growth depend on a chaperone called Hsp90 for their stability and function. This work will explore compounds that inhibit Hsp90 in preclinical models and clinical trials as potential treatments for lung cancer.

PROJECT 5: MECHANISMS OF ACQUIRED RESISTANCE TO EPIDERMAL GROWTH FACTOR RECEPTOR–TARGETED AGENTS (OK WITH PASI & JEFF TO POST DESCRIPTION)

Project Co-Leaders

Pasi A. Jänne, MD, PhD (DFCI)
Jeffrey A. Engelman, MD, PhD (MGH)

Investigator

Lewis C Cantley, PhD (BIDMC)

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective therapeutic agents for patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in EGFR. Most, if not all, patients who initially develop a partial or complete response to gefitinib or erlotinib will eventually develop progression of their cancer while taking these therapies. The only known mechanism of resistance, a secondary mutation in EGFR itself (a substitution of methionine for threonine at position 790, EGFR T790M) has been detected in approximately 50% of patients developing resistance to gefitinib or erlotinib. This finding has spurred the clinical development of irreversible EGFR inhibitors that can inhibit an EGFR T790M to treat cancers that have become resistant to gefitinib/erlotinib. To identify of mechanisms of acquired resistance to gefitinib or erlotinib, we have generated gefitinib-resistant clones of EGFR mutant NSCLC cell lines by exposing them to increasing concentrations of gefitinib. In previous work, we identified an EGFR T790M in vitro model of resistance, thereby demonstrating that in vitro models can be used to discover resistance mechanisms observed in patients. These paired (parental and resistant clone) cell lines provide valuable preclinical models in which to systematically determine mechanisms of gefitinib resistance and their in vitro sensitivity to novel therapeutic agents. Once identified, tumor specimens from EGFR mutant patients that have developed acquired resistance to gefitinib/erlotinib will be assessed to determine if these resistance mechanisms can also be detected in patients. Furthermore, based on the findings above, novel therapeutic combinations will be evaluated in the gefitinib-resistant cell line models with differing mechanisms of resistance. These studies will serves as the basis for rationally designed clinical trials for patients with gefitinib/erlotinib resistance. These studies will be accomplished through the following specific aims: Aim 1: To discover mechanisms of acquired resistance to EGFR-targeted agents. Aim 2: To determine whether targeting resistance mechanisms in vitro using pharmacologic inhibitors or by RNA interference (RNAi) will lead to growth inhibition of resistant NSCLC cell lines Aim 3: To design and conduct clinical studies in NSCLC patients with different mechanisms of acquired resistance to gefitinib/erlotinib. Since EGFR TKIs are highly effective initial treatments for patients with EGFR mutant cancers, it will be critical to identify the how these cancers eventually become resistant. The studies in this grant proposal will help develop the future treatments for patients with different mechanisms of acquired resistance to EGFR TKIs.

CORE A: TISSUE AND PATHOLOGY

Core Director

Massimo Loda, MD (BWH)

Core Co-Director

Lucian Chirieac, MD (BWH)

Investigators

Neal Lindeman, MD (BWH)
William Richards, PhD (BWH)

Tissue resources are essential for studies of outcome markers, predictive markers, molecular epidemiology, and discovery of novel molecular therapeutic targets. Their importance is even more apparent in this evolving era of molecular imaging as well as high throughput technologies. The immense value of clinical biological sample collection is therefore readily apparent. Methods of harvesting, storage, and appropriate quality control are also vitally important to assure the high tissue quality required for advanced technology platforms. Finally, significant investments of skill, time and money have gone in to build these resources, and consideration and planning is given towards access and distribution of samples, so that these holdings have value-added as local, regional, national, and international resources. The Path Core will provide expertise and leadership for SPORE investigators in all areas of tissue acquisition and analysis. Human tumors are highly complex because of inter- and intra-tumoral heterogeneity. The development and implementation of highly innovative technologies for the simultaneous assessment of multiple antigens/genes at the tissue level will also be an integral part of this Core, underscoring its constant drive to improve upon molecular pathologic analysis. Specifically, the technologies we have developed and are continuing to refine as well as sophisticated imaging technologies, will allow the identification of multiple antigens/genes. The Pathology Core is a critical component of the lung SPORE effort and is uniquely positioned to characterize the morphologic phenotype of lung neoplasms, relate these findings to their molecular characterization, and rapidly advance our understanding of human tumors of the lung. The understanding produced by these investigations should ultimately lead towards the development of novel therapeutic strategies for this heterogeneous group of diseases within the funding period of this SPORE.

CORE B: ADMINISTRATION, EVALUATION AND PLANNING

Core Director

Bruce E. Johnson, MD (DFCI)

Core Co-Director

David C. Christiani, MD, MPH (HSPH)

The purpose of the Administration, Evaluation and Planning Core is to ensure the coordination of the Dana-Farber/Harvard Cancer Center (DF/HCC) Lung Cancer SPORE components and to provide oversight and leadership of the scientific, administrative, and fiscal aspects of the SPORE. The Administration, Evaluation and Planning Core allows for the provision of stimulating intellectual activities, organization of venues for planning future research through seminars and retreats, and the oversight of research and spending. This Core also provides the tools to work with institutions inside and outside of Harvard University to leverage the considerable power of the SPORE in order to raise more research funding for lung cancer. The responsibilities of the Administration, Evaluation and Planning Core are to: 1) Select research projects and evaluate research progress; 2) Foster collaborative research within the SPORE and between SPOREs; 3) Integrate the Lung SPORE into the DF/HCC structure; 4) Provide necessary resources and fiscal oversight and 5) Promote rapid dissemination of significant research findings and facilitate resource exchange.

CORE C: BIOSTATISTICS

Core Director

Beow Yong Yeap, ScD (MGH)

Core Co-Director

Dianne Finkelstein, PhD (MGH)

Investigators

Yi Li, PhD (DFCI)
Xihong Lin, PhD (HSPH)

The Biostatistics Core facility will provide statistical support, including related data and computing aspects, for lung cancer research proposed by the SPORE investigators at Dana-Farber/Harvard Cancer Center (DF/HCC). The Core activities will involve collaboration and consultation in genetic epidemiology studies, cell line experiments, animal models, clinical trials and translational analyses with molecular and cellular correlates. In particular, the specific aims are to provide ready and dedicated access to the following:

1. Statistical expertise for design, planning and conduct of research studies.
2. Statistical expertise for data analysis and interpretation, including interim monitoring and scientific reporting.
3. Consultation on developing and implementing plans for data collection and database specifications, including forms design and data entry.
4. Consultation on developing and implementing plans for data management, quality control and administrative reporting.
5. Computing facilities and resources for statistical and related requirements, including data transfer, merging, sharing and security.

CORE D: GENOMICS AND BIOINFORMATICS

Co-Directors

Matthew Meyerson, M.D, PhD (DFCI)
David Kwiatkowski, MD, PhD (BWH)

Investigator

Cheng Li, PhD (DFCI)

Genetic and genomic analysis of lung cancer has yielded many important observations in recent years, including the identification of activating mutations in the epidermal growth factor receptor (EGFR) by this SPORE’s investigators. Recent studies have made it clear that there are numerous targets for both inactivating and activating mutations during lung cancer development, and there is steady progress in unraveling the nature and collective effect of these mutations on the pathogenesis of lung cancer. Genomic technologies have continued to develop at an impressive pace for the past 5-10 years, and it is expected that rapid technological progress will continue for at least the foreseeable future. These new technologies, approaches, and concepts require a high level of understanding and expertise for them to be applied for the most rapid progress by Lung SPORE investigators in their respective projects. This core will facilitate that use in several ways. First, it will provide access to state-of-the-art genomic technologies, with access to new technologies and approaches as they are developed, some of which cannot be foreseen at this time. Second, it will provide a high level of technical expertise in the application of these technologies, from laboratories with extensive experience with new and emerging technologies. Third, it will provide intellectual strength from seasoned genomics investigators to help SPORE investigators navigate choices among different technologies. Fourth, it will provide state-of-the-art bioinformatics and statistical support for SPORE projects. Fifth, through centralization of genomic data sets and provision of bioinformatics tools for SPORE projects, there will be synergies in data storage and sharing, enabling better integration of ideas and information across the various projects within the SPORE.

More specifically, the Genomics and Bioinformatics Core will deploy these resources to assist research progress by Lung SPORE investigators via three specific aims.

Aim 1: To assist SPORE projects with access to and guidance in the use of genomic and related technologies for utilization in SPORE research projects.

Aim 2: To support Lung SPORE investigators with bioinformatics and related expertise for design, data handling, and analysis of genomic studies.

Aim 3: To support data sharing within the DF/HCC Lung SPORE and the greater lung cancer research community.

Developmental Research Program

Co-Directors: Bruce E. Johnson, MD (DFCI) and David Kwiatkowski, MD, PhD (BWH

The objectives of the Developmental Research Program (DRP) are to continue to renew our innovative scientific endeavors within the DF/HCC Lung Cancer SPORE and to fund efforts that will complement and enhance the overall quality of the DF/HCC Lung Cancer SPORE. The Developmental Research Program will fund both established and junior investigators.

SPORE funds have been set aside for the Developmental Research Program Awards. The DF/HCC SPORE has an extensive track record of using institutional funds to support our Developmental Research Program and supplemental funds will be provided each year, as in the past. Three to 5 individuals will be awarded each year for as much as two years of funding. The second year of funding will be dependent on making sufficient progress on review by the Developmental Research Program. The award will facilitate the research and development of independence of basic biological science, translational science, and applied science investigators within the DF/HCC Lung Cancer SPORE program. Thus, candidates will be fellows, postdoctoral fellows, and faculty within the different training programs across the Harvard campus. Success in this Developmental Research Program will be defined as the development of innovative translational science that will generate cancer-relevant interventions in patients with lung cancer or populations at risk for lung cancer.

This program will use the infrastructure created by the Administration, Evaluation and Planning Core to:

1. Solicit applications and/or identify novel research projects in the area of lung cancer
2. Evaluate these projects for financial and core support
3. Fund innovative developmental research projects
4. Monitor progress on projects for potential transition into full project status
5. Evaluate the program’s success in achieving its goals as well as overall SPORE objectives

CAREER DEVELOPMENT PROGRAM

Co-Directors: David C. Christiani, MD, MPH (HSPH & MGH), Daniel G. Tenen, MD (BIDMC)

The investigators assembled in the DF/HCC Lung Cancer SPORE have a substantial record in mentorship and development of junior faculty members in lung cancer translational research. The goal of the Career Development Program (CDP) is to continue to build on this record and expand on the formal process for the identification, selection, funding, and mentoring individuals pursuing a career in the basic biologic sciences and applied sciences related to lung cancer.

$50,000 per year will be set aside for the Career Development Awards (CDA) from SPORE funds. The DF/HCC SPORE has an extensive track record of using institutional funds to support our Career Development Program. The SPORE funds will be supplemented with funds from institutional support as we have in the past. Two to 3 individuals will be awarded each year for as much as two years of funding. The second year of funding will be dependent on making sufficient progress on review by the CDP. The award will facilitate the research and development of independence of basic biological science, translational science, and applied science within the DF/HCC Lung Cancer SPORE program. Thus, candidates will be fellows, postdoctoral fellows, and junior faculty within the different training programs across the Harvard campus. It is our goal to continue to attract, mentor, and assure the success of the CDA recipients. Success in this CDA will be defined as the development of physician scientists in training to their independence as investigators.

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