Research Database

Small cell lung cancer (SCLC) comprises 15% of all diagnosed cases of lung cancer. It usually responds to initial chemotherapy; however, it inevitably becomes resistant to the chemotherapy and progresses. Identifying strategies to reverse chemoresistance in SCLC continues to be an unmet need.

SCLC cells produce high amounts of a protein called EZH2. This protein helps SCLC cells escape the effects of chemotherapy. DS-3201b is a drug that blocks the effects of EZH2. Dr. Lai will conduct a phase 1 clinical trial with DS-3201b in patients with extensive-stage SCLC receiving chemotherapy. The goal of the trial is to determine whether addition of DS-3201b to chemotherapy prevents the development of chemoresistance in SCLC patients. 

Currently, three immune checkpoint inhibitors are approved by the FDA for the treatment of advanced-stage NSCLC. Recently, an immunotherapy-chemotherapy combination regimen has shown to be effective in both advanced-stage squamous and non-squamous NSCLC patients. Despite this promise, immunotherapy works only in a subset of patients with advanced-stage NSCLC. There remains an unmet need to improve immunotherapy modalities such that a larger patient population may benefit from this novel treatment regimen. One hypothesis is that current checkpoint inhibitors do not work in all patients because specialized immune cells called T-cells (the target of immune checkpoint inhibitors) are unable to home in on their tumors (these tumors are referred to as “cold” tumors).

Dr. Aaron Lisberg is studying a novel combination immunotherapy approach—administering a checkpoint inhibitor, pembrolizumab, with genetically modified immune cells derived from a patient. Dendritic cells are immune cells that help other immune cells such as T-cells in identifying and homing in on a cancer. Dr. Lisberg’s laboratory will genetically manipulate a patient’s dendritic cells to artificially produce a protein called CCL21 (CCL21-DCs). He proposes that combining these CCL21-DCs will help recruit T cells to a patient’s tumor and make them responsive to the immune checkpoint inhibitor (turning a cold tumor into a hot one).

Checkpoint inhibitors, a type of immunotherapy, are now available in the first-line and second-line settings for certain subsets of NSCLC patients. Furthermore, the U.S. Food and Drug Administration recently approved an immunotherapy-combination treatment regimen for the treatment of a subset of advanced-stage NSCLC patients. While we are making progress in combining and sequencing immunotherapy with other conventional treatments, it is still unclear which patients will respond to these combinations. Dr. Kellie Smith’s laboratory is studying immune cells in blood samples from patients who have received the recently approved combination therapy. She postulates that immune cells from patients receiving the combination behave very differently from immune cells from patients who have received single-agent immunotherapy. Dr. Smith’s team will identify and exploit these differences to develop a blood test that will help predict which patients may benefit from combination therapies, thereby sparing patients the exposure to ineffective treatments.

Currently, three immune checkpoint inhibitors are approved by the FDA for the treatment of a subset of advanced-stage NSCLC. However, immunotherapy is a costly treatment regimen and comes with a unique side effect profile because of the inhibitors’ ability to cause inflammatory tissue damage. At present, the PD-L1 protein is used as a biomarker to predict which patients may respond to immunotherapy. Unfortunately, presence or absence of PD-L1 protein may not be an accurate predictor of response. Dr. Jeffrey Thompson is studying how we can develop more accurate biomarker signatures that may not only predict response to immunotherapy but may also determine which patients will develop treatment-related side effects. He will develop a novel blood-based liquid biopsy approach that will enable doctors to predict which patients will respond to immunotherapy drugs.

Currently,  computed tomography (CT) is available as a tool for the early detection of lung cancer in high-risk individuals. Unfortunately, it has a high false-positive rate: less than 5% of people with nodules found through CT actually have lung cancer. Apart from the distress associated with false positives, individuals may have to undergo invasive procedures, such as a biopsy, to rule out lung cancer.

Circulating tumor DNA (ctDNA) is DNA released from dying cancer cells into the bloodstream. Individuals with early-stage lung cancer may have ctDNA in their blood, even when the cancer is localized. CRISPR-Cas technology is a novel DNA modifying tool that can be used to develop sensitive, specific, and economic ctDNA assays. Dr. Edwin Yau will develop a CRISPR-Cas-based blood test to detect ctDNA in the blood of individuals suspected of having lung cancer. While the immediate goal of the project is to evaluate this blood test in individuals who have already undergone a CT scan, the ultimate goal of the project is to develop a blood test for screening all individuals.

Side effects associated with immunotherapy (immune-related adverse events or irAEs) with checkpoint inhibitors are different from those seen in other treatment approaches, such as chemotherapy, radiation therapy, and targeted therapies. Their onset is unpredictable, so irAEs require different side-effect management strategies. Dr. Altan is studying how we can predict which patients will develop irAEs so that the best therapy can be selected and symptom management can be proactive.

The lung cancer treatment landscape is rapidly evolving with the advent of immunotherapy. Checkpoint inhibitors, a class of immune-targeted agents, are now available in both the first-line and second-line settings for certain subsets of lung cancer patients. However, the fraction of patients achieving a durable response remains low and, even among patients who respond, the majority develop resistance. Dr. Valsamo Anagnostou is using a comprehensive approach employing genome-wide and functional immune analyses to identify mechanisms of resistance to immune checkpoint blockade. In addition, she is developing a blood-based molecular assay utilizing serial blood samples of lung cancer patients to more accurately predict response and resistance to these therapies.

Targeted therapies have become a mainstay of treatment for non-small cell lung cancer patients whose tumors test positive for a targetable driver mutation. The EGFR mutation is one such targetable mutation. New third-generation EGFR inhibitors have recently entered the clinic and can be very effective therapies for some patients who develop resistance to first- and second-generation EGFR inhibitors. Unfortunately, we are now seeing that cancer cells can also learn how to outsmart these third-generation inhibitors, and new and more effective treatments are needed. Dr. Zofia Piotrowska is studying how lung cancer cells become resistant to third-generation EGFR inhibitors, such as osimertinib, and how the heterogeneity of EGFR-mutant lung cancers can contribute to resistance to drugs like osimertinib. During the period of this award, Dr. Piotrowska will also be conducting a clinical trial testing a novel drug combination developed to prevent or delay the development of drug resistance among patients with EGFR-mutant lung cancer.

The SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Dream Team, led by LUNGevity SAB member Dr. Avrum Spira, is developing a combination of diagnostic tools, such as non-invasive nasal swabs, blood tests, and radiological imaging, to confirm whether lung abnormalities found on chest imaging are benign lung disease or lung cancer.

The SU2C-LUNGevity Foundation-American Lung Association Lung Cancer Interception Translational Research Team, headed by LUNGevity Scientific Advisory Board (SAB) member Dr. Lecia Sequist, is developing a lung cancer interception assay (LCIA) that can be used in conjunction with low-dose CT scans. This assay will be based on an integration of several blood-based assays that examine circulating tumor cells and circulating tumor DNA.

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.

A tissue biopsy is often required to make a definitive diagnosis of lung cancer. However, because of small size and inadequate biopsy yield, early-stage lung cancer is often difficult to diagnose. Dr. Hariri is using a novel imaging technique called optical coherence tomography (OCT) to develop tools to guide tissue biopsy sampling to improve tissue yield. These tools will also provide additional diagnostic information.

Chemotherapy has been the mainstay for treatment of small cell lung cancer (SCLC)—a highly aggressive subtype of lung cancer—for the past three decades. SCLC responds well to initial treatment but inevitably comes back. No targeted therapy is currently available for patients with SCLC. Dr. Lehman is studying how SCLC becomes resistant to chemotherapy. His research will further our understanding of chemotherapy resistance and identify novel targets for SCLC treatment.

Cells in the respiratory tract are usually stacked in an orderly fashion. As lung cancer develops, the cells get “un-stacked” and their shapes change, giving them the ability to grow and spread to other parts of the body. Dr. Vadim Backman from Northwestern University is utilizing a new technology called Partial Wave Spectroscopy for seeing those cells. With the LUNGevity Early Detection Award, he will check how cells taken from the cheeks of stage I lung cancer patients reflect these early changes with the ultimate goal of using partial wave spectroscopy technology for early detection of lung cancer.

Drs. Byers and Gibbons have discovered that lung cancer cells acquire the ability to hide from the immune system during epithelial-to-mesenchymal transition—a process through which cancer cells develop the ability to spread to other parts of the body (metastasis). The LUNGevity award will help Drs. Byers and Gibbons study the effect of a new drug that can reverse the EMT process and make lung cancer cells more visible to the immune system.

Dr. Kulkarni is studying how circulating tumor cells (cancer cells that are released into the blood stream) can be used to develop a blood test for lung cancer early detection and treatment. Funding from LUNGevity will help him use a novel technology called the Vortex Chip to test two things: first, if lung cancer be detected early by identifying circulating tumor cells in the blood and second, if there are biomarkers in circulating tumor cells that can differentiate patients who will respond to immunotherapy or chemotherapy.

Dr. Lito is working with a new drug that works efficiently to stop the growth of lung cancer cells with a mutation in the KRAS gene. Funding from LUNGevity will provide resources to test the drug in mice that have KRAS-positive lung cancer. Dr. Lito’s ultimate aim is to develop a clinical trial for the drug for use in patients who test positive for a KRAS mutation.