Early detection

Identification of biomarkers for the detection of small cell lung cancer

2013

Early Detection Research Award

Ignacio I. Wistuba, MD

University of Texas MD Anderson Cancer Center

Houston

Humam Kadara, PhD

University of Texas MD Anderson Cancer Center

Houston

Dr. Wistuba and his colleague Dr. Humam Kadara are identifying biomarkers that could ultimately lead to the fist test to detect small cell lung cancer in its earliest and most treatable stages.

Research Summary

There is a lack of strategies for detection of small cell lung cancer (SCLC), a difficult-to-treat lung cancer subtype, which we believe is due to our poor understanding of the molecular development of the disease. Moreover, while screening by clinical measures reduces lung cancer mortality, the detected lung cancers are less likely to be SCLCs warranting the need for additional detection methods (e.g., biological).

Our earlier work revealed cancer-associated markers and profiles in “normal” (to the “eye”) airways close to lung tumors, an effect we refer to as “molecular field cancerization,” in which there is field around the tumor that is enriched with malignant properties. We found field effects in “normal” airways that increased with time following tumor removal were different between patients with and without lung cancer or different subtypes of the disease, and were present in other respiratory tract compartments, including the nose.

Although we previously found that airways near SCLCs display excessive genetic abnormalities, the molecular field effect in SCLC and its relevance to detection of the disease is unknown. The proposed project aims to characterize, by high-throughput technologies, the molecular makeup of cells lining the nose and airways and of tumors from the SCLC patients compared to molecular profiles of samples from patients with benign disease or other lung cancer types, and then test these markers for their capacity to detect SCLC in easily accessible sites. We expect by using such unique resources and approaches to delineate novel markers for SCLC detection.

Technical Abstract

Small cell lung cancer (SCLC) exhibits aggressive clinical behavior and poor outcome and response to therapy. Moreover, there are no effective strategies for early detection of SCLC. Therefore, there is an urgent need to identify new strategies and markers for SCLC detection. We recently characterized the molecular airway field cancerization (FC) in non-small cell lung carcinoma (NSCLC) patients and identified airway profiles that varied spatially (n=1165) and with time (n=1395) following surgery. Moreover, we characterized the adjacent airway FC in NSCLC (n=1606 genes), a subset of which (n=299) significantly distinguished airways of smokers with lung cancer from those of healthy smokers and another (n=208) separated airways of different NSCLC subtypes. Although we previously showed that SCLCs and adjacent airways are characterized by higher level of allelic losses compared to those of NSCLC cases, the global airway FC in SCLC and its relevance to detection has not been explored. We hypothesize that the molecular airway FC in SCLC is different compared to that in NSCLC or benign lung disease and comprises biomarkers specific for early detection of SCLC. We will 1) perform global expression profiling of the airway FC and tumors or nodules in patients with SCLC, NSCLC, and benign disease for identification of airway markers specific to SCLC and 2) test identified airway mRNA markers for SCLC detection in bronchial and nasal compartments in patients with suspect lung cancer. We anticipate that our proposal, due to its unique resources and approaches, will identify novel markers for SCLC detection.

Key words

Adenocarcinoma

Biomarker or biomarker testing

Early detection

Molecular profile or molecular testing

Non-small cell lung cancer (NSCLC)

Risk profile

Screening

Small cell lung cancer (SCLC)

Squamous cell lung cancer

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Sputum biomarkers for the early detection of lung cancer

2013

Early Detection Research Award

This grant was funded in part by Upstage Lung Cancer.

Feng Jiang, MD, PhD

University of Maryland

Baltimore

Sanford Stass, MD

University of Maryland

Baltimore

Dr. Jiang is identifying sputum biomarkers that could improve the process of detecting early-stage lung cancer by contributing to development of a non-invasive test that complements low-dose computed tomography (CT) scans and improves the accuracy of diagnosis.

Research Summary

Cigarette smoking is a major cause of lung cancer. Finding lung cancer earlier in smokers by using low-dose CT followed by appropriate treatments can save lives. However, low-dose CT always causes overdiagnosis. The overdiagnosis requires additional medical evaluation and has negative consequences such as anxiety, additional medical costs, and other harms to the individuals who don’t have cancer. Therefore, noninvasive methods that can improve CT for accurately finding early lung cancer are urgently needed. To this end, we previously developed a panel of sputum-biomarkers (NBC News and AACR Breaking News) that can improve CT’s performance for lung cancer early detection. Yet these biomarkers are still not efficient for clinical use. Herein, we will use the most advanced technique to develop new and effective biomarkers to improve CT for finding lung cancer at early stages in smokers. Future use of the biomarkers together with CT will enable effective treatments to be immediately initiated for lung cancer, and hence decrease lung cancer deaths. It will also avoid harmful treatments to individuals without cancer and cut the tremendous burden of lung cancer on patients, families, and societies. Therefore, this project will strongly support the mission of LUNGevity Foundation.

Technical Abstract

Screening smokers with CT can detect lung cancer at relatively early stages, and thus reduce mortality. However, CT screening for lung cancer has a poor specificity, often resulting in unnecessary treatments to smokers who have benign diseases. The objective of this proposal is to develop genomic- and non-coding RNA (ncRNA)-based biomarkers in sputum that can complement CT for lung cancer early detection in smokers. Proposed aim 1 is to define sputum ncRNA signatures of early-stage lung cancer using next-generation sequencing (NGS). Proposed aim 2 is to optimize a panel of sputum ncRNA biomarkers with CT for the early detection of lung cancer. Proposed aim 3 is to integrate our previously identified genomic biomarkers and the newly optimized panel of ncRNA biomarkers with CT for the early detection of lung cancer in independent case-control series. Future use of the biomarkers in clinical practice for screening smokers for lung cancer will increase CT’s specificity, and hence reduce harmful and unnecessary treatments to many smokers who have benign diseases. Integrating the biomarkers with CT could assist making decisions for the management of abnormal findings in the lungs and enabling effective treatments to be immediately initiated for lung cancer. The study will translate the strengths of novel ncRNA profiling data developed from NGS into clinical settings by using a simple and cost-effective approach, and thus bridge the gap between basic research and patient care.

Key words

Adenocarcinoma

Biomarker or biomarker testing

Early detection

Molecular profile or molecular testing

Non-small cell lung cancer (NSCLC)

Risk profile

Stage I

Stage II