Thursday, March 17 2016 | Source: BUSM
A new study provides insight on the potential role played by RNA (ribonucleic acid) editing in cancer.
The findings, which appear online in the journal Scientific Reports, may further our understanding of an emerging mechanism implicated in tumor initiation and progression, and may thus lead to the development of better treatment options in the future.
In every healthy human cell, the genetic information hard-wired into the DNA is transcribed into messenger RNA, which is in turn translated into proteins, the workhorses of all body tissues and organs. The prevailing view is that most malignancies are caused by DNA mutations, which can lead to the aberrant activation or inactivation of the corresponding protein products and to the consequent out-of-control growth and proliferation of malignant cells. RNA editing, the process by which ‘mutations’ of the RNA sequence are introduced post-transcriptionally, has the potential to impact a variety of cellular processes yet the precise mechanism of how has been poorly understood until now.
Previous studies have shown that more than one million sites in the genome are edited to various degrees. Despite the fact that a majority of these editing sites fall within regions that are not translated to protein, it has been shown that the differences in RNA editing levels between tumor and normal tissues are associated with different clinical outcomes. Currently, only a few coding RNA editing sites have been functionally characterized. However, it is still a puzzle whether and how the majority of the RNA editing events in the untranslated regions affect tumor growth.
Researchers from Boston University School of Medicine (BUSM) analyzed 14 tumor types, and identified more than 2,000 genes showing significant changes in RNA editing level between tumor and normal tissues.
“This study suggests that RNA editing may serve as an important epigenetic mechanism of cellular regulation beyond the genetic/DNA level,” explained corresponding author Stefano Monti, PhD, associate professor of medicine at BUSM. “We show that the effect of one epigenetic component can be offset by changes in another epigenetic component. Thus, it is important to have a comprehensive picture of changes in the cancer genome, which may point to vulnerabilities amenable to targeted treatment,” added lead author Liye Zhang, PhD, postdoctoral fellow at BUSM.
Funding for this study was provided by the MGHPCC Seed Fund program, the Evans Center for Interdisciplinary Biomedical Research ARC on “Etiology and Pathogenesis of Oral Cancer (EPOC)”, and the NIH National Heart Lung and Blood Institute (1R01HL124392-01).
Press Release: May 18, 2015 | Written by Lenny Bernstein – The Washington Post
When a suspicious lesion shows up in the lungs on a CT scan, the first thing your doctor wants to know is whether it’s cancerous. A specialist will pass a long, thin bronchoscope into your airway in the hope of grabbing a few cells of the growth so they can be examined under a microscope.
But some of these lesions or nodules are deep in the small branches of the lungs, out of reach of the bronchoscope, which is about the diameter of a pen. Other times, the results are inconclusive. That has left only two ways to determine whether the abnormality is cancerous: inserting a needle through the chest wall and into the tumor, or surgically opening a patient’s chest to find it (and remove it if necessary).
The first procedure carries a 15 percent risk of collapsing a lung (pneumothorax), as well as infection. The second is serious surgery that requires general anesthesia and results in the loss of lung tissue. Both are in-patient procedures that carry the cost and other risks of hospitalizations. In about a third of the surgeries, the growth turns out to be benign, meaning the surgery was unnecessary.
But now, according to a study published Sunday in the New England Journal of Medicine, there appears to be a new, much less invasive way of determining whether a growth is malignant. Researchers at Boston University have discovered that the thin epithelial cells that line the entire airway show changes that indicate whether a growth is malignant. With small brushes on the bronchoscope, they can take some of those cells and, using genomic testing that has been available only in recent years, reach a conclusion.
The study released Sunday showed that the tests were about 97 percent accurate on 639 subjects. A private company has purchased the technology and is making it available to hospitals across the country.
“Even though lung cancer tends to develop deep in your lung, all the cells that line your airway are exposed,” said Avrum Spira, a professor of medicine at Boston University who led the research. “They have changes in their genome.”
Spira’s test focuses on messenger RNA, the molecules that express genes’ instructions to cells. He called the technology “a canary in the coal mine” for lung cancer, which kills about 160,000 people in the United States each year.
If the test is negative, its accuracy will allow doctors to wait and watch a lesion. If it shows a malignancy, a biopsy still would be needed to confirm the cancer. “There will still be a small number of biopsies,” Spira said. “But we’re going to reduce them significantly.”
Other research is being conducted to find markers for lung cancer, though much of it focuses on substances that can be found in the blood, Spira said. With the vast majority of lung cancer victims being smokers, the epithelial cells show changes that could be tracked once the technology became available, he said.
The next logical question is whether those changes might be detected early enough to predict and prevent lung cancer. Spira said his team already is working on research to determine whether that’s possible.
The current advance was a long time in coming and shows the difficulty of bringing research from the lab to the consumer. Spira said the initial discovery was made 12 years ago, but he couldn’t find any private group willing to put up the millions of dollars needed to conduct studies, work through the government and academic regulatory process and bring his idea to market.
Seven years ago, he formed his own company, raised venture capital and eventually proved that his idea worked. Now his company has been purchased by Veracyte, which will take over the production and marketing of the “Bronchial Genomic Classifier.”
“We were adding 30 seconds to a minute” to the length of a bronchoscopy, Spira said. “. . . Even then, the regulatory hurdles were significant. We got over them all, but they were significant.”
Press Release from July 24th 2014
A new study has shown that it is possible to predict long-term cancer risk from a chemical exposure by measuring the short-term effects of that same exposure. The findings, which currently appear in the journal PLOS ONE, will make it possible to develop simpler and cheaper tests to screen chemicals for their potential cancer causing risk.
Despite an overall decrease in incidence of and mortality from cancer, about 40 percent of Americans will be diagnosed with the disease in their lifetime, and around 20 percent will die of it. Currently fewer than two percent of the chemicals on the market have been tested for their ability to induce cancer.
Using an experimental model, researchers from Boston University School of Medicine (BUSM), Boston University School of Public Health, the BU Bioinformatics Program and the National Toxicology Program at the National Institute of Environmental Health measured the effects on healthy tissue from few days of exposure to a given chemical and assessed the effects on the gene expression response in the liver. “By comparing the responses to known chemical carcinogens and non-carcinogens, we were able to extract a “signature” and an associated predictive model capable of discriminating with high accuracy between the two,” explained corresponding author Stefano Monti, PhD, associate professor of medicine at BUSM and a member of the BU Superfund Research Program. “Furthermore, by inspection of the coordinated set of genes driving the response to chemical exposure, we were able to zoom in to the potential mechanisms driving cancer induction,” he added.
According to the researchers there is growing recognition that the role played by environmental pollutants in human cancer is under-studied and that more formal approaches to the analysis of the biological consequences of prolonged exposure to pollutants are needed. “This work has confirmed that it is possible to predict the long-term cancer risk by measuring the short term effects,” said Monti. “As a result of our findings we expect that accurate and cost-effective screening for evaluating the carcinogenic potential of the more than the 80,000 chemicals currently in commercial use soon will be a reality.”
Publication: Daniel Gusenleitner, Scott S. Auerbach, Tisha Melia, Harold F. Gómez, David H. Sherr, Stefano Monti. Genomic Models of Short-Term Exposure Accurately Predict Long-Term Chemical Carcinogenicity and Identify Putative Mechanisms of Action. PLoS ONE, 2014; 9 (7): e102579 DOI:10.1371/journal.pone.0102579
Story Source: The above story is based on materials provided by Boston University Medical Center. Note: Materials may be edited for content and length.
Press Release: From October 28th 2013
Written by Jenny C Leary
Researchers at Boston University School of Medicine (BUSM) have discovered a molecule that could help lead to the non-invasive detection of lung cancer as well as its treatment. Using RNA sequencing, the team looked at airway epithelial cells and identified a regulatory molecule that was less abundant in people with lung cancer and inhibits lung cancer cell growth. The findings, which are published in the Proceedings of the National Academy of Sciences, suggest that this molecule may aid in diagnosing lung cancer in earlier stages and could potentially, when at healthy levels, aid in treating the disease.
According to the National Cancer Institute (NCI), lung cancer is the leading cause of cancer death among both men and women in the United States, and 90 percent of lung cancer deaths among men and approximately 80 percent of lung cancer deaths among women are due to smoking. The NCI also estimates that approximately 373,489 Americans are living with lung cancer and its treatment costs approximately $10.3 billion in the United States each year.
MicroRNA’s are a new class of molecules classified as important regulators of the activity of other genes. In this study, the research team used a next-generation RNA sequencing technology and identified that a microRNA named miR-4423 in epithelial airway cells plays a major role in how these cells develop. In epithelial cells from the airway of smokers with lung cancer, levels of miR-4423 were decreased.
“These results suggest measuring the levels of microRNAs like miR-4423 in cells that line the airway could aid in lung cancer detection through a relatively non-invasive procedure,” said Avrum Spira, MD, MSc, the Alexander Graham Bell professor of medicine and chief of the division of computational biomedicine at BUSM, one of the study’s senior authors.
Using experimental models in vitro and in vivo, the research team demonstrated that miR-4423 can both promote the development of the normal airway cells and suppress lung cancer cell growth. This suggests that miR-4423 plays a major regulatory role in cell fate decisions made by airway epithelial cells during maturation and low levels of miR-4423 contributes to lung cancer development. Interestingly, throughout the body, miR-4423 seems only to be present in high levels in the airway epithelium, suggesting this could be a very specific process occurring only in the lungs.
“Our findings open up the option to study whether returning the levels of miR-4423 to normal in the airway could help stop cancer growth and potentially be a way to treat lung cancer,” said Catalina Perdomo, PhD, a researcher in the division of computational biomedicine at BUSM who is the paper’s lead author.
“Interestingly, when we examined the genomes of other species for microRNAs that might function like miR-4423, we did not find anything in non-primates,” said Marc Lenburg, PhD, an associate professor in computational medicine and bioinformatics at BUSM who is one the study’s senior authors. “It makes us wonder what it is different about lung development in primates and excited that this could be a very specific process to target for lung cancer treatment.”
This study was funded in part by the National Institutes of Health’s National Cancer Institute Early Detection Research Network under grant award numbers R01 CA 124640 and U01 CA152751; the National Science Foundation Integrative Graduate Education and Research Traineeship under grant award number P50CA58184; and Merit Review grants 5I01BX000359 and R43HL088807-01.
Journal Reference: Perdomo C, Campbell J.D., Gerrein J, Tellez C, Garrison C.B., Walser T.C., Drizik E, Si H, Gower A.C., Vick J, Anderlind C, Jackson G.R., Mankus C, Schembri F, O’Hara C, Gomperts B.N., Dubinett S.M., Hayden P, Belinsky S.A., Lenburg M.E., Spira A (2013) MicroRNA 4423 is a primate-specific regulator of airway epithelial cell differentiation and lung carcinogenesis. Proc Natl Acad Sci USA, 10.1073/pnas.1220319110 PMID: 24158479
Please click here to download editorial.
Press Release: From April 11, 2013
Written By Jenny C Leary
BUSM researchers have pinpointed a genetic signature for chronic obstructive pulmonary disease (COPD) from airway cells harvested utilizing a minimally invasive procedure. The findings provide a novel way to study COPD and could lead to new treatments and ways to monitor patient’s response to those treatments. The study is published online in the American Journal of Respiratory and Critical Care Medicine.
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that leads to the loss of lung function primarily caused by cigarette smoking. It causes coughing, wheezing, shortness of breath, chest tightness and other symptoms that make it difficult to breathe. While there are treatments and lifestyle changes that can help people cope with COPD, there currently is no cure and there are no effective therapies to reduce the rate of lung function decline. According to the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI), which partially funded the study, COPD is the third leading cause of death in the United States, resulting in approximately 135,000 deaths each year.
“There have been limited molecular studies of COPD given the inaccessibility and invasiveness of obtaining lung tissue,” said Katrina Steiling, MD, MSc, assistant professor of medicine at BUSM who served as the study’s first author. The researchers hypothesized that while COPD primarily affects the tissue deep within the lung, the effects of COPD might be detectable in relatively accessible tissue throughout the respiratory tract. This echoes previous work they had done that found that cancer found deep in the lung could be detected by cancer-specific patterns of gene expression in the largest airways connected to the windpipe, far from the tumor.
To examine their hypothesis, the research team used airway cells obtained during a bronchoscopy, a procedure that involves putting a small camera into the airway through the nose or mouth. During the procedure, which can be done while a patient is awake under local anesthesia or moderate sedation, a cytology brush is used to gently scrape the sides of airways to collect cells.
They examined 238 samples from current and former smokers that had been collected by Stephen Lam, MD, a collaborator from the University of British Columbia. Eighty seven of the samples were from patients who had been diagnosed with mild to moderate COPD based on their lung function. The other 151 samples represented patients who did not have COPD based on these criteria.
When the researchers compared the airway samples from both groups, they found that 98 genes were expressed at different levels in those diagnosed with COPD compared to those without COPD. In order to determine how similar the airway cell changes were to lung tissue cells, the researchers compared their results with previously published findings on the gene expression changes associated with COPD in lung tissue. The results of the comparison demonstrate that the changes that occur in the airway cell samples in those diagnosed with COPD were similar to the changes in lung tissue cells of individuals with the disease despite the airway cells coming from regions of the lung not thought to be altered by disease.
“Our data shows that there are consistent gene-expression changes that occur in both airway and lung tissue cells in individuals with COPD,” said Avrum Spira, MD, MSc, Alexander Graham Bell professor of medicine and chief of the division of computational biomedicine at BUSM who served as one of the senior co-authors of the study. Spira also is a physician in the pulmonary, critical care and allergy department at Boston Medical Center.
To investigate the effects of treatment on the COPD-associated gene expression changes, the researchers collaborated with a team led by Maarten van den Berge, MD, PhD, from the University of Groningen Medical Center in the Netherlands that had collected airway cells from COPD patients before and after they started steroid therapy. They found that the expression of some genes that changed due to COPD reversed their expression after treatment and started to look more like the levels seen in current or former smokers without COPD.
“Part of the COPD ‘signature’ reverses with therapy, suggesting that examining airway cells might be a minimally invasive tool for monitoring the disease and evaluating the response to therapy more quickly in order to determine the best course of treatment for each individual patient,” said Marc Lenburg, PhD, associate professor in computational biomedicine and bioinformatics at BUSM and the study’s other senior co-author.
“Studying COPD using the large airway opens up some really exciting new avenues of research that could also improve care for patients with COPD,” said Spira. “While we are still at an early stage, I envision being able to examine airway cells from my patients with COPD to determine what is causing the disease and, from that information, recommend a more specific and effective treatment.”
Funding for this research was provided in part by the National Institutes of Health’s (NIH) NHLBI under grant award number 1R01 HL095388 (PI: Spira/Lenburg) and the NIH’s National Center for Advancing Translational Science through the Boston University Clinical and Translational Science Institute under award number KL2RR025770.
Journal Reference: K. Steiling, M. van den Berge, K. Hijazi, R. Florido, J. Campbell, G. Liu, J. Xiao, X. Zhang, G. Duclos, E. Drizik, H. Si, C. Perdomo, C. Dumont, H. O. Coxson, Y. O. Alekseyev, D. Sin, P. Pare, J. C. Hogg, A. McWilliams, P. S. Hiemstra, P. J. Sterk, W. Timens, J. T. Chang, P. Sebastiani, G. T. O’Connor, A. H. Bild, D. S. Postma, S. Lam, A. Spira, M. E. Lenburg. A Dynamic Bronchial Airway Gene Expression Signature of COPD and Lung Function Impairment. American Journal of Respiratory and Critical Care Medicine, 2013; DOI: 10.1164/rccm.201208-1449OC
Press Release: BioMed Central August 31, 2012
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is thought to affect almost three million people in the UK. New research published in BioMed Central’s open access journal Genome Medicine has identified genes whose activity is altered with increasing lung damage and, using a database of drug effects on gene activity (the Connectivity Map), finds that the compound Gly-His-Lys (GHK) affects the activity of these genes. When tested on human cells from lungs damaged by emphysema, GHK was able to restore normal gene activity and repair cell function.
The strongest cause of COPD is smoking, and at least 25% of smokers will develop this disease. Tobacco smoke and other irritants cause oxidative stress and chronic inflammation, which over time results in emphysema, the destruction of lung alveolar cells. Without these cells, the lungs are not able to efficiently exchange oxygen for carbon dioxide, leaving the patient continuously short of breath and with low levels of oxygen in their blood.
In a ground breaking, multi-centre, study funded by the National Institute of Health (NIH), researchers used cells taken from lungs donated by patients undergoing double lung transplant, whose own lungs were irrevocably damaged by COPD. Profiling of these samples showed that 127 genes had changes in activity that was associated with worsening disease severity within the lung. As would be expected from the nature of the disease, several genes associated with inflammation, such as the genes involved in signalling to B-cells (the immune system cells which make antibodies), showed increased activity.
In contrast genes involved in maintaining cellular structure and normal cellular function, along with the growth factors TGFβ and VEGF, were down-regulated and showed decreased activity. This included genes which control the ability of the cells to stick together (cell adhesion), produce the protein matrix which normally surrounds the cells, and which promote the normal association between lung cells and blood vessels.
Dr Avrum Spira and Dr Marc Lenburg, who co-led this study from the Boston University School of Medicine, explained, “When we searched the Connectivity Map database, which is essentially a compendium of experiments that measure the effect of therapeutic compounds on every gene in the genome, we found that how genes were affected by the compound GHK, a drug known since the 1970s, was the complete opposite of what we had seen in the cells damaged by emphysema.”
Dr Joshua Campbell explained, “What got us especially excited was that previous studies had shown that GHK could accelerate wound repair when applied to the skin. This made us think that GHK could have potential drug’s as a therapy for COPD.”
Prof James Hogg, from the University of British Columbia continued, “When we tested GHK on cells from the damaged lungs of smokers with COPD, we saw an improvement in the structure of their actin cytoskeleton and in cell adhesion, especially to collagen. GHK also restored the ability of cells to reorganise themselves to repair wounds and construct the contractile filaments essential for alveolar function.”
GHK is a natural peptide found in human plasma, but the amount present decreases with age. While more testing needs to be done on its effects in COPD, these early results are very promising. Therapeutic studies with GHK in animal models of COPD are now underway with the ultimate goal of moving this compound into clinical trials. As more gene activity signatures are discovered, this method of matching drug to disease may provide a rapid method for discovering potential uses for existing drugs and compounds.
A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK
Joshua D Campbell, John E McDonough, Julie E Zeskind, Tillie L Hackett, Dmitri V Pechkovsky, Corry-Anke Brandsma, Masaru Suzuki, John V Gosselink, Gang Liu, Yuriy O Alekseyev, Ji Xiao, Xiaohui Zhang, Shizu Hayashi, Joel D Cooper, Wim Timens, Dirkje S Postma, Darryl A Knight, Marc E Lenburg, James C Hogg and Avrum Spira
Genome Medicine 2012, 4:67
Please click here to download manuscript editorial published in Genome Medicine entitled, “Next-generation personalized drug discovery: the tripeptide GHK hits center stage in chronic obstructive pulmonary disease”.
Press Release: Dana-Farber Cancer Institute September 10, 2012
Researchers from Dana-Farber Cancer Institute, the Broad Institute, Boston University and colleagues have found a molecular “signature” in a common form of lymphoma that identifies patients unlikely to respond to standard chemotherapy, and who might benefit instead from treatment with certain experimental targeted drugs.
The discovery came from a massive, fine-grained analysis of DNA structure and gene expression in tumors from patients with diffuse large B cell lymphoma (DLBCL), a cancer of white blood cells. It is the most common form of non-Hodgkin lymphoma. The findings are published in the Sept. 11 issue of Cancer Cell.
“We think that capturing this signature will identify a group of patients whose tumors have a genetic basis for deregulated cell growth,” said Margaret Shipp, MD, chief of the Division of Hematologic Neoplasia at Dana-Farber and senior author of the study. “These tumors are less likely to respond completely to standard chemotherapy. Because we now know the basis of this deregulated cell growth, these results suggests ways to target it.”
About 60 percent of patients with DLBCL can be cured with current therapy — a combination of a monoclonal antibody and four drugs – while the remaining 40 percent are not, and have an unfavorable prognosis. This study defines genetic and biological mechanisms that underlie the differing responses, said Shipp.
In many cancers, scientists have discovered major mutations that drive tumor growth and whose presence or absence can predict treatment outcome, as well as providing targets for selective drugs. Such dominant mutations are less common in DLCBL, which is “much more genetically complicated,” said Shipp, who is also the director of the Lymphoma Program at Dana-Farber. Until recently, oncologists assessed outcomes using a set of clinical features such as age, tumor size and pattern, and some easily measured parameters in blood tests. “But these don’t tell you about the basic biology of the disease or how you might treat it more effectively.”
Poorer response to chemotherapy has been linked to DLBCL tumors whose cells are proliferating rapidly, Shipp noted, though the reason wasn’t known.
In the new study, researchers used a new genomic platform, called high-density SNP arrays, to search for subtle changes on chromosomes known as copy number alterations (CNA). Unlike mutations that disable a gene or cause it to go into overdrive, CNAs change gene dosage by increasing or decreasing gene copy numbers. Advanced genomic methods are needed to detect these alterations.
The analysis provided “much higher resolution and a much more fine-grained map of the alterations” han previous studies,” said Shipp. In addition, the researchers measured variations in gene expression across the DLBCL genomes, and combined those results with the CNA map.
Together, these experiments revealed a complex pattern of CNAs and associated gene expression changes in DNA samples from patients who were poor responders to chemotherapy. By contrast, the analysis found “clean” genomes, with few CNAs or gene activity abnormalities, in samples from successfully treated patients.
Together, this pattern of structural alterations and changes in gene expression formed a molecular signature predicting an unfavorable outcome with chemotherapy for DLCBL, the researchers reported. Such a test could be combined with clinical factors to improve prognostic testing, Shipp said. In addition, scientists found that the CNAs in the DNA of poor responders caused disruption of two important molecular pathways often involved in cancer.
First, the CNAs reduced activity of the p53 gene, which protects cells against genetic instability that can ead to cancer. Second, the copy number alterations stimulated genes that control cell division, causing he increased proliferation of cells previously observed in poor-prognosis DLBCL.
For bad-prognosis patients, Shipp added, the good news is that experimental drugs exist that target protein kinases that regulate cell division, and might be successful in blocking excessive cell proliferation. She said one such drug, a “pan-cyclin kinase (CDK) inhibitor” called flavopiridol, showed “nice effectiveness” against lymphoma tumors grafted onto mice. Clinical trials of panCDK inhibitors in patients are being planned, she said.
The research was funded in part by a National Institutes of Public Health grant (PO1CA092625).
The paper’s joint first authors are Stefano Monti, PhD, formerly of the Broad Institute and now at Boston University of Medicine, and Bjoern Chapuy, MD, PhD, of Dana-Farber. The paper’s other authors, in addition to Shipp, are from Dana-Farber, the Broad Institute, Brigham and Women’s Hospital, and Dana- Farber/Children’s Hospital Cancer.
Please see below for manuscript reference or click here to download.
Monti S, Chapuy B, Takeyama K, Rodig SJ, Hao Y, T. Yeda KT, Inguilizian H, Mermel C, Curie T, Dogan A, Kutok JL, Beroukim R, Neuberg D, Habermann T, Getz G, Kung AL, Golub TR, Shipp MA. Integrative Analysis Reveals an Outcome-associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B-cell Lymphoma, Cancer Cell, 22(3):359-372, 2012.
Please click here to download related manuscript published in October issue of Cancer Cell entitled, “Metabolic signatures uncover distinct tarts in molecular subsets of diffuse large B cell lymphoma”.
Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.
For the journal article please click here.