Funded Projects

We fund translational research to move knowledge as quickly as possible from basic discovery to treatment of patients.

Since 2002, LUNGevity has invested in 200 research projects at 69 institutions in 24 states and the District of Columbia, for a total of $55,743,471.02.

2011

Targeted Therapeutics Research Award

Alexander Steven Whitehead, DPhil

University of Pennsylvania, Philadelphia, PA

Folate-related biomarkers as predictors of response to pemetrexed therapy

Pemetrexed is a chemotherapy drug commonly used for the treatment of non-small cell lung cancer. The drug blocks two proteins called DHFR and TS that cancer cells need to grow. Not all patients respond to pemetrexed. Dr. Alexander Whitehead is studying how changes in the DHFR and TS genes predict response of non-small cell lung cancer patients to pemetrexed.

Research Summary

Folate is a B vitamin that is very important for maintaining health and for protecting against a range of major diseases. It is obtained as ‘natural’ folate from food, in particular leafy green vegetables, or as the synthetic form folic acid from supplements and products made with fortified flour. There are genetic differences in the enzymes that control the way that folate is used inside cells; folate is actually present as multiple forms that support different biochemical processes, and these differences confer different levels of susceptibility to diseases that are associated with low folate and altered folate metabolism. Some of the genetic differences have been linked to lung cancer, and some have recently been linked to good responses to pemetrexed, an anti-folate drug that is used to treat lung cancer. The goal of this project is to define the main folate-related genetic variants AND the relative amounts of the different forms of folate inside cells in patients with lung cancer, and to establish whether any of these factors are over-represented in (i) lung cancer patients compared to healthy individuals, and, even more importantly, in (ii) lung cancer patients who show superior responses to pemetrexed. The project has the potential to identify genetic markers and/or biomarkers that could be used to guide lung cancer chemotherapy.

Technical Abstract

Folate/homocysteine (Hcy) metabolism facilitates the methylation of DNA, proteins and carcinogens; nucleic acid synthesis; and glutathione generation. Dysregulation of folate/Hcy metabolism, due to suboptimal vitamin status and/or functional polymorphisms of key enzymes, is an etiologic feature of some cancers, including lung cancer. Several drugs that target enzymes of folate/Hcy metabolism have become mainstays of cancer chemotherapy, most recently pemetrexed (PMX), which targets dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and is used to treat patients with non-small cell lung cancer (NSCLC). Our primary and secondary hypotheses are that folate/Hcy phenotype, perhaps underpinned by genotype, is a major contributor to (i) clinical response to PMX, and (ii) risk of NSCLC itself. We will use archived and newly acquired samples from PMX-treated NSCLC patients to define pre-treatment and in-treatment folate/Hcy phenotypes using LC-MRM/MS technology that can precisely determine the concentrations and relative proportions of key folates (tetrahydrofolate; 5-methyltetrahydrofolate; 5,10-methenyltetrahydrofolate) and Hcy. Genotypes will be determined for approximately twenty folate-related genes. Biostatistical analyses will be used to establish

whether aspects of folate/Hcy phenotype and/or genotype are prospectively or concurrently associated with time to tumor progression, survival time, toxicity, etc. Case-control analysis of genetic and phenotypic data will also be undertaken to determine whether any genetic and/or biomarker variables predict case status. This project has the potential to identify biomarkers and/or genetic factors that can be used to predict or monitor responses of NSCLC patients to PMX, and may provide the basis for the future deployment of personalized medicine strategies in lung cancer treatment.

2010

Early Detection Research Award

Protect Your Lungs/ LUNGevity Foundation Research Grant; funded in part by A Breath of Hope Foundation

Steven M. Dubinett, MD

David Geffen School of Medicine at UCLA, Los Angeles, CA

Krysan Kostyantyn, PhD

David Geffen School of Medicine at UCLA, Los Angeles, CA

Combined Protein and miRNA Profiles for the Early Detection of Lung Cancer

Lung cancer cells produce different types of proteins and RNA molecules that circulate in the blood. Dr. Steven Dubinett and his team have discovered 17 unique miRNAs in the blood of lung cancer patients and other high-risk individuals, such as smokers. Blood of healthy and low-risk people do not have these miRNAs. They are developing an miRNA-based blood test to predict which high-risk individual might develop lung cancer.

Research Summary

Lung cancer accounts for more than 28 percent of all cancer deaths each year and is the leading cause of cancer related mortality in the United States causing more deaths than prostate, colon and breast cancers combined Despite focused research in conventional therapies, the five-year survival rate remains only 15 percent. Due to anti-tobacco initiatives the number of active smokers in the US is steadily declining, however recent studies suggest that individuals who quit smoking continue to have an elevated risk of lung cancer that may not return to baseline risk for as much as 30 years following smoking cessation. Owing to the lack of reliable early diagnostic techniques, most patients are being diagnosed with advanced stage disease that his inoperable and therefore they have a poor prognosis. Thus, there are more than 100 million current and former smokers in the US who have elevated risk for lung cancer and may benefit from a non-invasive test for early detection.

Patients at risk for lung cancer may have undetected disease for years prior to diagnosis. The clinical challenge is therefore to develop lung cancer detection methods that are effective during this window of opportunity to increase the rate of early detection and thereby spur early treatment and improve lung cancer patient outcomes. During tumorigenesis, the developing tumor forms a microenvironment that is comprised of many components and cell types. These complex cellular populations produce many soluble factors that could be important for tumor initiation and growth and thus potentially serve as lung cancer biomarkers. Small tumors, initiated in this environment, may remain undetected; however, the profile of soluble factors produced by the tumor mircorenvironment will be altered in the peripheral blood of cancer patients and could therefore have utility for the development of a diagnostic panel for early lung cancer detection. Because the blood vessels in the lungs comprise approximately 50% of the body’s total vasculature, the peripheral blood is expected to serve as a non-invasive biospecimen that reflects even small variations in lung cancer biomarkers. We hypothesize that interactions between tumor cells and host cells recruited into the local tumor microenvironment will result in the production of a unique biomarker signature composed of proteins and microRNA (miRNA) important for cancer progression.

Over the past decade, our laboratory has gathered substantial data supporting the analysis of soluble mediators of lung carcinogenesis including inflammatory, growth and angiogenic factors and miRNA. Additionally, since our early investigations, a considerable literature has developed describing the contribution of these factors to lung carcinogenesis. Based on these findings, in our preliminary studies we have developed a plasma protein-based biomarker panel that accurately distinguishes smokers with and without lung cancer. Our predictive model provided 97% sensitivity.

Technical Abstract

Despite focused research in conventional therapies, the 5-year survival rate of lung cancer patients remains only 15%. Due to the lack of reliable early diagnostic techniques, most patients are diagnosed with advanced-stage disease and therefore have a poor prognosis. There are more than 100 million current and former smokers in the US who have elevated risk for lung cancer and may benefit from a non-invasive test for early detection. Patients at risk may have subclinical disease for years prior to diagnosis. Therefore the clinical challenge is to develop lung cancer detection methods that are effective during this window of opportunity to increase the rate of early detection and thereby spur early treatment and improve lung cancer patient outcomes. During tumorigenesis, the developing tumor forms a complex cellular microenvironment that produces many soluble mediators, such as proteins and miRNAs, which are important for tumor initiation and growth and thus can serve as lung cancer biomarkers. Because the pulmonary vascular bed comprises approximately 50% of the body’s total vasculature, the peripheral blood is expected to reflect even small variations in lung cancer biomarkers.

Over the past decade, our laboratory has gathered substantial data supporting the analysis of soluble mediators of lung carcinogenesis including inflammatory cytokines, growth and angiogenic factors, and miRNA. Additionally, a considerable literature has developed describing the contribution of these factors to lung carcinogenesis. Based on these findings, in our preliminary studies we have developed a plasma protein-based biomarker panel that accurately distinguished between lung cancer patients and at-risk control subjects. Our predictive model provided 97% sensitivity, 77% specificity, and an area under the ROC of .93 for stage 1 vs. high-risk controls. Because recent studies demonstrated that circulating miRNA can serve as robust and specific diagnostic biomarkers, we developed a panel of 17 miRNAs relevant to lung carcinogenesis. In our preliminary studies utilizing this miRNA panel, we were able to detect miRNAs that are differentially expressed in the plasma of lung cancer patients as compared to high-risk controls. We hypothesize that the proteins and miRNA profiles will each contribute unique information and thus, an integrated panel of protein and miRNA markers may provide higher sensitivity for early lung cancer detection than either platform alone.

Specific aims for the current proposal include: 1) to identify protein profiles in plasma associated with early-stage lung cancer, 2) to identify plasma miRNA profiles associated with early stage lung cancer, and 3) to integrate miRNA and cytokine biomarkers established in Aims 1 and 2 to improve early-stage lung cancer detection. The first and second aims address the clinical problems of patients at risk for lung cancer who present with a suspicious pulmonary nodule of indeterminate significance that has be further evaluated.

Protect Your Lungs/ LUNGevity Foundation Research Grant; funded in part by A Breath of Hope Foundation

Samir Hanash, MD, PhD

Fred Hutchinson Cancer Research Center, Seattle, WA

Gary Goodman, MD

Fred Hutchinson Cancer Research Center, Seattle, WA

Christopher Li, MD, PhD

Fred Hutchinson Cancer Research Center, Seattle, WA

Blood Tests for the Early Detection of Lung Cancer

Never-smokers with lung cancer represent 15% of all lung cancer patients. However, never-smokers do not undergo computed tomography (CT) for screening. Dr. Samir Hanash and his team are identifying biomarkers in the blood of low-risk people. Their ultimate aim is to develop a blood test to screen never-smokers.

Research Summary

Improvements in outcomes for cervix cancer and bowel cancer provide support for the concept that early diagnosis has the greatest promise to improve cancer outcomes. Unfortunately our improved understanding of the molecular basis of lung cancer has not translated into effective means for early detection. There is at the present time a substantial need for simple but accurate non-invasive tests to detect lung cancer before it is advanced to the point that treatment is rendered ineffective. Blood based biomarker tests provide an ideal approach given that asymptomatic subjects have blood drawn at the time of routine check-ups. The public health impact of the development of effective blood based tests for the detection of lung cancer are quite substantial, given the millions of subjects who are at risk for lung cancer due to current smoking or due to a past history of smoking. Additionally there is a need to develop tests to identify subjects at risk for developing lung cancer who are never-smokers given that never smokers with lung cancer represent some 15% of cases and lung cancer among never smokers is number 7 on the top ten list of cancer killers. This two-year program of research builds on the identification of candidate markers for lung cancer by a team of three PI’s at the Fred Hutchinson Cancer Research Center with expertise in Thoracic Oncology, Cancer Epidemiology and Prevention, and Molecular Diagnostics. Our goals are to develop blood tests to 1- identify never smoker subjects at increased risk of developing lung cancer (C. Li, PI); 2- detect lung cancer before onset of symptoms (G. Goodman, PI); and 3- distinguish between benign and malignant lesions identified by CT scans (S. Hanash, PI). If successful this research program will result in a paradigm shift in our approach to lung cancer screening.

Technical Abstract

Three independent principal investigators at the Fred Hutchinson Cancer Research Center with combined expertise in thoracic oncology, cancer epidemiology and prevention, and molecular diagnostics are joining efforts to respond to the Protect Your Lungs RFA. The proposed research program is focused on developing novel blood-based tests to 1) identify never-smoker subjects at increased risk of developing lung cancer (C. Li, PI), 2) detect lung cancer before onset of symptoms (G. Goodman, PI), and 3) distinguish between benign and malignant lesions identified by CT scans (S. Hanash, PI). The research questions address important public health issues in lung cancer and build on discoveries of candidate markers by the applicant group for which we propose validation studies in this proposal. Validation studies to be conducted will take advantage of the availability to the investigators of pertinent bio-specimens consisting of samples derived from two large cohort studies (The Women’s Health Initiative and the Beta Carotene and Retinol Efficacy Trial (CARET)) and samples derived from CT screening studies. The samples available are sufficient to meet the needs of the proposed studies. The collaborative nature of the proposed research will ensure synergism and efficiency of scale to meet study objectives and fast-track the development of clinically relevant applications.

2009

Early Detection Research Award

LUNGevity Foundation - Canary Foundation Research Grant

Canary Lung Cancer Early Detection Initiative

Canary Foundation, Palo Alto, CA

Development of simple blood and imaging tests that can identify and isolate lung cancers at their earliest stages

The Initiative is developing a panel of blood-based biomarkers that will improve the reliability of different imaging approaches. It is also exploring markers that will predict the recurrence of lung cancer.

LUNGevity Foundation/Uniting Against Lung Cancer Research Grant

William P. Bennett, MD

Beckman Research Institute at the City of Hope, Duarte, CA

DNA Methylation Changes in Peripheral Blood Mononuclear Cells as Biomarkers of Lung Cancer

Dr. Bennett is evaluating potential biomarkers for their use in identifying lung cancer patients by comparing blood samples taken from patients with lung cancer and from patients without lung cancer. His goal is to build a panel of biomarkers that will aid in diagnosis.

LUNGevity Foundation/Partnership for Cures Research Grant

Peter J. Mazzone, MD, MPH, FRCPC, FCCP

The Cleveland Clinic Foundation, Cleveland, OH

Identification and validation of exhaled breath biomarkers for the detection of early stage lung cancer

Dr. Mazzone is identifying exhaled breath biomarkers for the detection of early-stage lung cancer. This breath biomarker work may also lead to a new way to characterize lung cancers, determine their prognosis, and predict and monitor their response to therapy.

LUNGevity Foundation/The University of Kansas Cancer Center Research Grant

Sitta Sittampalam, PhD

University of Kansas Medical Center, Kansas City, KS

Chao Huang, MD

Developing Novel Biomarkers and Targets to Address Small Cell Lung Cancer

Dr. Sittampalam is determining whether circulating tumor cells can be a useful blood-based tumor marker in untreated patients with extensive-stage small cell lung cancer who are planning to receive chemotherapy. He is also exploring the feasibility of genomic profiling using circulating tumor cells.

Targeted Therapeutics Research Award

Funded equally by LUNGevity Foundation and the National Lung Cancer Partnership

Prasad Adusumilli, PhD

Memorial Sloan Kettering Cancer Center, New York, NY

Regional Delivery of Targeted Immunotherapy for Lung Cancer in the Pleura

Dr. Adusumilli is studying patients who underwent surgery for early-stage lung cancer but whose lung cancer returned because of a condition in which the cancer extends to the pleural membrane covering the lung cancer. Using genetic engineering, Dr. Adusumilli is modifying the patient’s own immune cells in a way that may not only eliminate the spread of tumor cells to the pleura but may also treat the spread of the cancer by tumors too small to be detected.

Funded equally by LUNGevity Foundation and the Upstate Medical University at State University of New York

Jing An, MD, PhD

SUNY Upstate Medical University, Syracuse, NY

Development of new radiosensitizers for human lung cancers

Radiation therapy is used for the treatment of lung cancer. Sometimes, the cancer does not respond to radiation. Dr. An is developing new drugs to make lung cancer cells sensitive to radiation. The primary goal of the research is to provide lung cancer patients with a customized combination treatment of the drugs and radiation therapy.

LUNGevity Foundation/Respiratory Health Association of Chicago Research Grant

Jeffrey A. Borgia, PhD

Rush University Medical Center, Chicago, IL

Molecular signatures to predict response in neoadjuvant chemoradiation therapy of Stage III NSCLC patients

Dr. Borgia is developing a process based on biomarkers derived from tissue and clinical factors such as age, smoking history, histology, and stage of diagnosis of lung cancer. This process will identify which patients with advanced-stage lung cancer will respond to medical treatment and thus qualify for surgery that potentially could cure the cancer.

Funded equally by LUNGevity Foundation and The CHEST Foundation

Johann C. Brandes, MD, PhD

Emory University, Atlanta, GA

CHFR methylation as novel predictor for chemotherapy response in NSCLC

The CHFR gene is a gene that has undergone changes in its DNA. Dr. Brandes is studying how the CHFR gene predicts a non-small cell lung cancer patient’s response to chemotherapy.

LUNGevity Foundation/Uniting Against Lung Cancer Research Grant

Johan C. Brandes, MD, PhD

Emory University, Atlanta, GA

Targeting CHFR through PARP-inhibition: A novel strategy to overcome taxane resistance in adenocarcinomas of the lung

The PARP protein is a protein that protects cancer cells from being killed by chemotherapy. Dr. Brandes is determining how drugs that stop the PARP protein can be used for targeted therapy of non-small cell lung cancer.

Funded by LUNGevity Foundation and Arkansas Respiratory Health Association, Breathe California of Los Angeles County, Breathe California of the Bay Area, Breathe New Hampshire, and Respiratory Health Association of Metropolitan Chicago

Navdeep Chandel, PhD

Feinberg School of Medicine, Northwestern University, Chicago, IL

Notch signaling regulates lung cancer

Dr. Chandel is working to identify novel pathways underlying KRAS-driven lung cancer. He is testing two pathways, to determine how mitochondria (powerhouses of the cell) and Notch signaling (a pathway often activated in lung cancer that relays information from outside the cell to inside) behave differently in cancer and non-cancer cells.

Funded equally by LUNGevity Foundation and the American Lung Association

John Eaton, PhD

University of Louisville, Louisville, KY

A Broad Spectrum Lung Cancer Stem Cell Vaccine

Previous work of Dr. Eaton and colleagues has demonstrated that mice vaccinated with certain stem cells are 80%-90% protected against the growth of lung tumors injected into the mice as well as protected against the development of lung cancer caused by administration of a carcinogen. The current research is determining whether lung cancer stem cells are selectively destroyed by lymphocytes (immune cells) from vaccinated mice. Dr. Eaton is also determining whether stem cell vaccination affects the growth of lung tumors in mice that have been genetically engineered to spontaneously develop lung cancer.

Funded equally by LUNGevity Foundation and the Illinois Chapter of the American Cancer Society

Federico Innocenti, MD, PhD

University of Chicago Department of Medicine, Chicago, IL

Molecular signatures of angiogenesis in NSCLC and their prognostic role

The key proteins driving the growth of new blood vessels in tumors are the vascular endothelial growth factor (VEGF) and its main receptors. Dr. Innocenti is studying how the level of these factors varies in the tumors of non-small cell lung cancer patients. He is also determining whether there is a genetic basis for the difference in their levels and what the role of these proteins in helping patients live longer is.