Research Database

As a mechanism of resistance to EGFR inhibitors, cancers can change histology from adenocarcinoma to small cell or squamous cell lung cancer. Once this happens, EGFR inhibitors are no longer effective treatment; there are no strategies currently available to prevent or reverse transformation after it has occurred. Dr. Yu will use advanced molecular techniques to identify genetic changes that contribute to transformation. Understanding these genetic changes will identify biomarkers that can be utilized to develop treatments to prevent and reverse transformation.

Dr. Arbour will test a combination treatment regimen (MRTX849 for KRAS G12C and TNO155 for SHP2) in specialized mouse models of KRAS-mutant lung cancer, as well as analyze blood samples from patients who are currently receiving the MRTX849 drug to proactively monitor how these patients are developing resistance to MRTX849. Her ultimate goal is for new drugs, such as TNO155, to be added to the treatment regimen for KRAS-positive patients to combat acquired resistance. Dr. Arbour is the recipient of the Kristie Rolke Smith/LUNGevity Career Development Award, generously funded by the Rolke family in memory of their daughter, Kristie.

Dr. Gay and his team will test an immunotherapy-DNA damage response (DDR) inhibitor combination therapy in SCLC patients and validate a biomarker profile. Dr. Gay’s research aims to develop a new drug therapy combination and determine which patients are likely to benefit from it. 

Dr. Pitroda and his team will develop a biomarker signature that can predict which patients are the most likely to benefit from an immunotherapy-radiation therapy combination. The ultimate goal is to determine which patients are likely to benefit from this combination treatment.

The lung cancer treatment landscape is rapidly evolving with the advent of immunotherapy. Now, three checkpoint inhibitors are available in the first-line and second-line settings for certain subsets of patients with advanced-stage NSCLC. Despite this promise, a large subset of patients treated with immunotherapy will not respond to these drugs. This lack of response may be attributed to immune suppressive mechanisms, such as interferon signaling.

Dr. Joshua Bauml’s laboratory is studying pathways that block interferon signaling, such as the JAK-STAT pathway. He proposes to conduct a phase II combination clinical trial (the immunotherapy drug pembrolizumab with the JAK-STAT pathway inhibitor itacitinib) in patients with advanced-stage NSCLC. Dr. Bauml postulates that the combination regimen will remove the immune suppressive effects of interferon signaling and enhance the action of pembrolizumab. He will also be collecting tumor and blood samples during the course of the trial and characterize these samples to identify molecular predictors of response in patients.

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.