Risk profile

Liquid biopsy

Squamous cell lung cancer

Screening

Stage I

Stage II

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Early detection and prognosis of lung cancer using bioengineered implants

2023

Pierre Massion Young Investigator Award for Early Detection Research

Ramon Ocadiz Ruiz, PhD

University of Michigan

Ann Arbor

Dr. Ocadiz Ruiz proposes to develop a bioengineered scaffolding and test it in mouse models. If successful, this research could progress to a phase 1 clinical trial and lay the groundwork for a new technology to be used in individuals with increased risk of lung cancer. This technology has to potential to make biopsies and consequently, early detection, easier.

Research Summary

Lung cancer is the leading cause of cancer related deaths, resulting in 1.8 million deaths annually. The current lung cancer detection and monitoring modality is primarily focused on imaging, which unfortunately identifies disease only after it has reached a detectable size that represents significant burden of disease. Therefore, new affordable and efficient lung cancer diagnostic and monitoring approaches are needed. We propose the use of a subcutaneous implant that acts as a surrogate for the lung, which can capture tumor and immune cells at early stages of the disease, providing critical information about cancer cells and their environment. This device collects cells within the device, which can be biopsied without significant risk to the patient. With this technology we will detect and monitor cancer cells prior to overt symptoms and avoiding invasive lung biopsies that have significant associated risks. The information collected with this technology will help the clinician identify disease while the burden is low, and the analysis of the tumor cells can be used to select targeted therapies to improve patient outcomes.

Technical Abstract

Lung cancer is the leading cause of cancer related death among women and men and the second most diagnosed cancer in the world, causing 1.8 million deaths annually. Surgical resection of the primary tumor is the standard of care whenever possible. However, 90% of lung cancer deaths are caused by metastases months-to-years after surgery. Current screening tools such as high-resolution Computed Tomography (CT) and Positron Emission Tomography (PET) can only identify tumors that have reached a detectable size, that often correlates with advanced disease. However, this technology carries side problems, including the false positive rate that led to follow-up tests and invasive procedures that confers additional risks to patients.

Therapeutic strategies targeting specific driver mutations have emerged in recent years for the treatment of metastatic non-small cell lung cancer and have improved survival, yet the initial identification of these molecular alterations depends on biopsies of metastatic lesions after the resection of the primary tumor. For biopsy, the metastatic lesion must be large enough to be detectable by clinical imaging tools, and this large lesion indicates a relatively advanced stage of disease. Biopsy of these lesions is often difficult from both location and patient-safety perspective. An emerging option is a blood draw or liquid biopsy to obtain circulation tumor DNA (ctDNA) for mutation analyses, yet the ctDNA is not abundant in circulation until relatively large metastases have already formed.

Therefore, novel, efficient, and affordable approaches are needed for disease surveillance. We propose a high sensitive, minimally-invasive and efficient cell capture device for easy isolation of tumor cells at early stages of disease, whose analysis can identify targeted therapeutics that can be applied while the disease burden and heterogeneity are low. Furthermore, this technology would increase the coverage of the eligible population and reduce the clinical costs by using histopathology analysis of the sentinel implant. This device is a porous biomaterial scaffold that, when implanted, is vascularized, and infiltrated by immune cells and subsequently cancer cells, acting as a synthetic sentinel niche that provides information about the disease development and progression. Our previous studies in breast and pancreatic cancer models have demonstrated that tumor cells are detectable early after tumor initiation and during the progression of the disease. A comparative analysis of scaffolds and ctDNA showed that the implant captured and therefore detected cancer cells before positive detection of ctDNA.

We will determine the genomic and transcriptomic prolife of inoculated lung cancer cells in PDX’s murine model at early time points. We anticipate that the tumor cells captured by the scaffolds will recapitulate the genotype of the parental PDX. The scaffold safety will be investigated in a Phase I clinical study of metastatic lung cancer patients implanted with our scaffold, with biopsy and subsequent removal to analyze captured cells. Sequencing analysis will be applied to captured cancer cells to assess their genomic and transcriptomic profile. We foresee the use of these bioengineered implants for surveillance in high-risk lung cancer patients, with analysis of the collected cells employed to identify personalized therapeutic strategies to improve patient outcome.

Key words

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Integration of Liquid Biopsy Assays for the Early Detection of Lung Cancer

2023

Early Detection Research Award

Maximilian Diehn, MD, PhD

Stanford University

Stanford

Lung cancer is the number one cause of cancer-related deaths in the US because it is often found only after it has spread to other organs in the body, decreasing the likelihood of surviving at least 5 years after diagnosis. Only 21% of patients are diagnosed then their lung cancer is early stage, when it is most treatable. The goal of this project is to create a new way to screen for lung cancer using a blood sample that can find early stage disease when patients can still be treated and/or cured. In preliminary work, Dr. Diehn has developed a blood test that can identify tiny amounts of DNA from lung cancer cells and in this study he will improve this test and apply it to patients and healthy controls. If successful, Dr. Diehn’s work has the potential to significantly improve early detection of lung cancer and improve outcomes for patients.

Research Summary

Lung cancer is the number one cause of cancer-related deaths in the U.S. and can affect both smokers and non-smokers. Lung cancer is often deadly because it is usually found after it has spread to other organs like the brain, liver, or bones, at which point it is no longer possible to cure the disease in most patients. But if caught early when the cancer cells are still confined to the lung, it can often be cured with surgery or radiation. Screening for lung cancer in current or former smokers using CT scans has been proven to reduce the number of patients who die from lung cancer by catching the disease early. Although insurance covers it in the U.S., only about 15% of those who qualify actually get screened. Some reasons for this low rate of screening include worries about false positives from CT scans and difficulty accessing radiology facilities. Our goal is to create a new way to screen for lung cancer using a blood sample that can find early stage cancers when they can still be cured. Our method looks for tiny amounts of DNA in the blood that comes from lung cancer cells. We have completed initial tests that show our idea could work. Now, we plan to further improve our test and to apply it to several hundred lung cancer patients and healthy controls. If our experiments are successful, our blood test could eventually be used alongside CT scans to cut down on unnecessary follow-up tests or even replace CT scans as the main way to screen for lung cancer. If so, this work could contribute to saving lives of patients with lung cancer.

Technical Abstract

Lung cancer is the leading cause of cancer in the U.S., with over 238,000 new cases and more than 125,000 deaths expected in 2023. Early detection is crucial for improving prognosis, and low-dose computed tomography (LDCT) scans are recommended for high-risk populations. However, LDCT screening has limitations, including a significant false positive rate and low compliance. New approaches are therefore needed to enhance early detection in high-risk individuals. Liquid biopsy assays that can detect circulating tumor DNA (ctDNA) represent a promising alternative early detection approach. Our group has developed three state-of-the-art liquid biopsy techniques that each have the potential to detect lung cancer noninvasively, including a somatic mutation approach (Lung-CLiP), a methylation-based approach (meCAPP-Seq), and a fragmentomic-based approach (EPIC-Seq). We hypothesize that combining mutation-, methylation-, and fragmentomic-based ctDNA analysis will maximize sensitivity for detecting early stage lung cancers. Our proposal includes three specific aims. In the first aim, we will compare the clinical sensitivity and specificity of meCAPP- Seq, EPIC-Seq, and Lung-CLiP for early lung cancer detection. In the second aim, we will determine the analytical limits of detection for the three methods, which is important for future regulatory considerations. In the third aim, we will develop an integrated liquid biopsy assay that combines meCAPP-Seq, EPIC-Seq, and/or Lung-CLiP. We will test if combining two or all three assays can improve performance over the best- performing single assay. The deliverable of this project will be the identification of the combination of liquid biopsy assays that achieves the best performance for early lung cancer detection. If successful, our work has the potential to significantly improve early lung cancer detection which would lead to improved outcomes for lung cancer patients.

Key words

Liquid biopsy

Squamous cell lung cancer

Screening

Stage I

Stage II

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The Germline-Somatic Interaction in Young-Onset Lung Cancer

2023

Career Development Award

This grant was funded in part by Lung Cancer Initiative

Jaclyn LoPiccolo, MD, PhD

Dana-Farber Cancer Institute

Boston

Although the average age at diagnosis is 70, thousands of new patients under 45 are diagnosed with lung cancer every year, most of whom have never smoked. Dr. LoPiccolo hypothesizes that these patients may share inherited genetic changes that predispose them to developing lung cancer at a younger age. In a preliminary analysis of young-onset lung cancer patients, Dr. LoPiccolo has found that approximately 30% of these patients carry rare mutations in known cancer-associated genes. In this study, Dr. LoPiccolo will investigate whether these mutations affect response to targeted or immune-based therapies. This insight is likely to identify risk factors among young lung cancer patients, which could lead to improved screening and treatment options for this population.

Research Summary

Lung cancer is the most common cause of cancer death in both men and women. Although the average age at lung cancer diagnosis is 70, thousands of new lung cancers occur in patients under 45 years old, most of whom have never smoked. There have been few efforts to analyze potential causes of young-onset lung cancer, particularly looking for inherited genetic changes, which are present in all cells in the body, that are shared among these patients and might predispose to developing lung cancer at a young age. To investigate whether inherited genes cause lung cancer in young patients, we collected blood samples from more than 350 lung cancer patients aged 45 and under at diagnosis and sequenced their genomes. In a preliminary analysis of 243 patients, we found that roughly 30% of young lung cancer patients carry rare, harmful inherited mutations in known cancer-associated genes, higher than many cancers known to have a strong genetic component. In addition to predicting cancer risk, inherited mutations that are present in every cell may influence how a tumor behaves and responds to treatment. We hypothesize that understanding the inherited contribution to tumor development may affect the response of cancer to targeted or immune-based therapies. Additionally, finding genetic risk factors could identify a group of people eligible for yearly CT screening and early detection of lung cancer (currently only used only for patients over 50 years old with heavy smoking histories), and/or guide therapies for lung cancer patients in the future.

Technical Abstract

Lung cancer is the most common cause of cancer-related mortality in North America. Although the average age at diagnosis is 70, thousands of new lung cancers are diagnosed each year in patients under 45 years over 45 years old (median age of diagnosis = 67). The work proposed here will further define this difference in a larger cohort, and address whether the identified variants or genes affect tumor evolution and treatment outcomes. The aims of our study are to identify a population of young lung cancer patients with elevated germline risk, and to investigate the mechanism of the germline-somatic interaction in young lung cancer. The young lung cancer population also provides a lens through which to better understand oncogene-driven lung cancer that occurs in non-smokers – increasingly important as global smoking rates decline.old, most of whom have never smoked. Given that younger patients develop lung cancer decades earlier and without known environmental insults, we hypothesized that underlying germline genetic variation predisposes to developing lung cancer at a young age. Here, we assembled a cohort of over 350 patients diagnosed with lung cancer at age 45 or younger and performed germline whole-genome sequencing (WGS). Preliminary data from 243 patients with median diagnosis age of 37 showed at least 30% of patients carry clinically actionable pathogenic germline alterations in cancer-associated genes, at rates exceeding those seen in many other cancer types – with key age-specific differences when compared to ancestry-matched lung cancer patients from The Cancer Genome Atlas diagnosed over 45 years old (median age of diagnosis = 67). The work proposed here will further define this difference in a larger cohort, and address whether the identified variants or genes affect tumor evolution and treatment outcomes. The aims of our study are to identify a population of young lung cancer patients with elevated germline risk, and to investigate the mechanism of the germline-somatic interaction in young lung cancer. The young lung cancer population also provides a lens through which to better understand oncogene-driven lung cancer that occurs in non-smokers – increasingly important as global smoking rates decline.

Key words

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Optimizing biomarker based strategies for lung cancer screening

2021

Early Detection Research Award

Anil Vachani, MD

University of Pennsylvania

Philadelphia

Currently, low-dose computed tomography (LDCT) is the only tool for the screening and early detection of lung cancer in individuals who meet screening criteria. LDCT is not very sensitive; often, abnormalities identified in an LDCT scan turn out to be benign. However, ruling out cancer requires an invasive biopsy. Dr. Vachani is testing whether a biomarker signature can be integrated into LDCT screening to improve the sensitivity of LDCT so that patients may be spared unnecessary biopsies.

Research Summary

Lung cancer remains the leading cause of cancer-related mortality in the US and globally accounting for 1.8 million deaths annually. Use of low-dose CT (LDCT) for lung cancer screening has been shown to save lives and is recommended for individuals at high-risk of lung cancer. However, LDCT has potential risks including a high rate of false positive findings, which may result in additional testing and potentially harmful invasive procedures. Several blood and imaging biomarkers have emerged as potentially useful complementary tools for lung cancer screening (LCS). Our proposed research will use a computational framework to estimate the population level impact of biomarker-based tests and identify the optimal strategy for integration of these emerging tools into LCS and pulmonary nodule evaluation.

Technical Abstract

Lung cancer remains the leading cause of cancer related mortality in the US and globally— responsible for ~1.8 million deaths annually. Randomized trials of low dose CT (LDCT) for lung cancer screening have demonstrated a clear mortality benefit and are recommended by the United States Preventive Services Task Force (USPSTF). However, most individuals currently eligible for screening do not have lung cancer and many at risk populations are not candidates for screening. Additionally, LDCT has a relatively high rate of false positives leading to potentially harmful tests and invasive procedures. Moreover, early experience suggests that LCS outcomes in clinical practice may differ from those observed in randomized trials. Given the concerns with the performance of LDCT, the use of blood and imaging biomarkers to complement the screening process has the potential to enhance its efficacy and effectiveness. Biomarkers could be employed at two different steps of the screening process – as the initial test for cancer screening, to better define the best candidates for screening, or following a positive LDCT scan, to inform lung nodule evaluation and management. While several screening and diagnostic biomarkers have been developed, they have not been formally evaluated in prospective comparative effectiveness trials, nor have they been subjected to cost-effectiveness analyses. More importantly, their impact on lung cancer burden at the population level is still unknown. Our proposed research will inform the following areas of LCS and biomarker discovery: 1) generate a computational framework to estimate and compare the population impact of emerging screening and diagnostic biomarkers, 2) identify the optimal strategy of integrating biomarker tests into LCS, and 3) highlight and identify the characteristics of biomarkers (sensitivity and specificity for histological subtypes, etc.) which are critical for cost-effective biomarker applications.

Key words

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Pilot study of SGLT2 in the characterization of early lung adenocarcinoma

2021

Early Detection Research Award

Claudio Scafoglio, MD, PhD

University of California, Los Angeles

Los Angeles

The protein SGL2 seems to be produced in higher quantities on abnormal lung cells than on normal lung cells. Dr. Scafoglio is testing whether SGL2 can be used to image lung cancer cells by using a new imaging technology.

Research Summary

Lung cancer claims around 140,000 lives in the United States every year; there is great need for early diagnosis strategies, and an attractive target is cancer metabolism. Cancer cells require more glucose than normal tissues for their unregulated growth; glucose cannot enter the cells freely, but needs to be transported by specific proteins called glucose transporters.

We have recently discovered that early-stage and pre-cancerous lesions rely on a specific glucose transporter to satisfy their metabolic needs: sodium-dependent glucose transporter 2 (SGLT2). We have introduced a new probe, Me4FDG, which can be used for positron emission tomography (PET) to detect accumulation of glucose in the patient’s tissues through a whole-body scan. We have started a pilot trial of Me4FDG PET in patients diagnosed with lung cancer as proof of principle that this diagnostic technique can be used for early lung cancer diagnosis. We propose to perform more thorough and systematic studies to evaluate the feasibility of Me4FDG PET as a novel diagnostic imaging technique for early stage lung cancer.

Technical Abstract

Lung cancer is the leading cause of cancer-related death in US, and lung adenocarcinoma (LUAD) is the most frequent histology. Early diagnosis is crucial. High-resolution CT has increased the discovery of solitary lung lesions, many of which are benign, whereas some progress to invasive cancer; the identification of novel biomarkers to predict the malignant potential of these lesions is of paramount importance. We found that sodium-dependent glucose transporter 2 (SGLT2) is expressed in human pre-malignant and early-stage LADC, and is required for progression of LUAD. SGLT activity can be measured by PET imaging with methyl-4-[18F] fluorodeoxyglucose (Me4FDG). Importantly, we identified SGLT2 activity in FDG-negative, early-stage lesions in mouse models and in human lung nodules.

Specific aims of the study are: 1. To assess the safety and efficacy of Me4FDG in patients with lung cancer, via a pilot study in 60 patients (30 with pathological diagnosis of LUAD, 30 with a clinical diagnosis of benign nodule); 2. To evaluate the prognostic significance of SGLT2 expression in early lung adenocarcinoma, through SGLT2 staining of 674 samples embedded in tissue microarrays.

The proposed research is likely to introduce a novel diagnostic tool for early diagnosis of lung adenocarcinoma, and further define the prognostic role of SGLT2 in lung cancer. If successful, this pilot trial will open the way for larger clinical studies where we will evaluate the ability of Me4FDG PET to predict the malignant behavior of indeterminate subsolid lung nodules. This will improve the early diagnosis of lung cancer.

Key words

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Genome Alterations Associated With Airway Premalignant Lesion Progression

2016

Career Development Award

Joshua Campbell, PhD

Boston University

Boston

One of the challenges for early detection and prevention of squamous cell lung cancer, a type of non-small cell lung cancer (NSCLC), is the lack of understanding of how premalignant lesions develop and progress to lung cancer. Dr. Campbell is studying how normal lung cells acquire changes in their DNA to form premalignant lesions. His ultimate goal is to develop a biomarker to predict development of squamous cell lung cancer.

Research Summary

Lung cancer remains the leading cause of death from cancer in the US, and lung squamous cell carcinoma is the second most common type of lung cancer. Many regions of abnormal cell growth can be identified via autofluorescence bronchoscopy in the airway of high-risk smokers. Many of these abnormal regions, which are called premalignant lesions, will resolve without any clinical intervention. However, a small subset will turn into lung squamous cell carcinoma. An ability to identify the lesions that are going to progress before they grow to invasive cancer would allow clinicians to intervene earlier and should reduce the number of deaths from this type of lung cancer. Over the past several years, DNA sequencing of tumors has revealed many mutations in important genes that cause cells to grow and proliferate uncontrollably. In this study, DNA sequencing will be used to identify mutations in premalignant lesions from the airways of high-risk smokers that have been sampled over time. It will be determined whether the presence or types of mutations can predict progression or regression of these lesions and use this knowledge to build a test to rapidly identify the mutations associated with progression. This test could have utility in the setting of lung cancer screening to stratify patients into chemoprevention trials.

Technical Abstract

One of the challenges for early detection and prevention of lung squamous cell carcinoma is the lack of understanding of the molecular and cellular changes that cause initiation and progression of this disease. Airway premalignant lesions are the precursors of lung squamous cell carcinoma and can be detected and monitored by autofluorescence bronchoscopy. However, many of these lesions will regress without clinical intervention, and only a subset will progress to invasive carcinoma. The goal of this study is to characterize the landscape of somatic mutations in airway premalignant lesions and to develop an early detection biomarker using targeted DNA sequencing that can predict risk of lesion progression. Ultra-deep whole-exome sequencing will be performed on a previously collected cohort of airway premalignant lesions from high-risk smokers that have been sampled over time, characterized histologically, and classified into those that are stable, regress, or progress. Significantly mutated genes, recurrent copy number changes, and mutational signatures will be identified, and a determination will be made whether they are associated with lesion histology or progression or regression status. Finally, the findings from this study will be combined with the driver genes from The Cancer Genome Atlas (TCGA) to build a targeted DNA sequencing panel. This panel will serve as a rapid and relatively inexpensive method for monitoring premalignant lesions from patients over time and can be used in a clinical trial to assess the ability of autofluorescence bronchoscopy in combination with molecular profiling to stratify patients and serve as a companion diagnostic in chemoprevention trials.

Key words

Molecular profile or molecular testing

Mutation profile

Squamous cell lung cancer

Screening

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Circulating miRNA as a biomarker in lung cancer

2007

Early Detection Research Award

Funded by LUNGevity Foundation and The CHEST Foundation

S. Patrick Nana-Sinkam, MD

The Ohio State University

Columbus

Dr. Nana-Sinkam is delineating the role of microRNA expression profiling in the diagnosis, management, and prognosis of lung cancer. He is testing whether microRNA expression profiles are detectable in the blood of lung cancer patients. He will compare individuals with lung cancer with current and former smokers without lung cancer.

Key words

Molecular profile or molecular testing

Stage - all

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Autoantibody biomarkers for the detection of lung cancer

2008

Early Detection Research Award

Funded equally by LUNGevity Foundation and the American Lung Association

Michael Tainsky, PhD

Wayne State University, Karmanos Cancer Institute

Detroit

Dr. Tainsky has developed a technology that takes advantage of the responses of the human immune system to identify cancer-associated proteins that bind to antibodies present in the blood of cancer patients but not in the blood of healthy subjects or those with benign diseases. Dr. Tainsky is working to develop a non-invasive screening test for the early detection of lung cancer by using cancer-associated antigens as biomarkers.

Key words

Stage I

Stage II

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Diagnostic Test Development for Non-Small Cell Lung Cancer: Early Detection of Lung Cancer

2008

Early Detection Research Award

Funded by LUNGevity Foundation and Partnership for Cures

Jeffrey A. Borgia, PhD

Rush University Medical Center

Chicago

Dr. Borgia is working to develop new biomarkers to strengthen the capabilities of the existing blood test for identifying the presence of metastatic progress in non-small cell lung cancer that he has developed. He plans to adapt the blood test to a diagnostic card format so that high-risk individuals can put blood droplets on diagnostic cards at home and mail them to a test facility where the blood will be extracted and tested for the biomarkers in the panel.

Key words

Molecular profile or molecular testing