Tumor draining lymph node immunomodulation to decrease recurrence in NSCLC

Jonathan Villena-Vargas, MD
Weill Medical College of Cornell University
New York

Lymph nodes are small structures that work as filters for foreign substances, such as cancer cells and infections. These nodes contain infection-fighting immune cells that are carried in through the lymph fluid. This project will study the lymph node draining basin, which is involved in the spread of a tumor from the original location site to distant sites, and whether activating cancer-fighting T-cells can decrease recurrence in NSCLC.  Dr. Villena-Vargas will use animal models to investigate whether immune checkpoint inhibitors enhance lymph node T-cells memory, which increases their ability to recognize cancer cells in the bod and can prevent metastatic recurrence.

Therapeutic targeting of BRAF fusion altered lung cancer

Michael Offin, MD
Memorial Sloan Kettering Cancer Center
New York

Alterations in the BRAF gene can lead to the development of non-small cell lung cancer. BRAF fusions are a type of BRAF gene alterations. These fusions are powerful growth stimulators of lung cancer. Currently, no treatment exists for cancers that harbor these BRAF fusions. Dr. Offin will be testing a series of new drugs in preclinical cell line and animal models of lung cancer. The ultimate goal of his project is to identify new drugs that can be tested in clinical trials.

Targeting lineage plasticity to suppress DTP in RET-positive lung cancer

Grant title (if any)
RETpositive / LUNGevity Foundation Lung Cancer Research Award
Hideo Watanabe, MD, PhD
Icahn School of Medicine at Mount Sinai
New York

Despite an initial response to the newly approved RET inhibiting drugs, most RET-positive lung cancers become resistant to these drugs and the cancers relapse. Dr. Watanabe’s project will provide anti-relapse therapeutic strategies for RET-positive lung cancer that target newly identified “drug-tolerant persisters (DTPs)”. DTPs are a small population of cancer cells that do not respond to these drugs and therefore start growing, leading to the relapse of these cancers. The role of DTPs in RET-positive lung cancer is not well understood. Dr. Watanabe proposes therapeutic strategies, such as targeting the Wnt and Hippo signaling pathway to overcome the DTP adaptability and prevent relapse before these cells arise.

Identifying non-genomic mechanisms of RET TKI resistance

Grant title (if any)
Hamoui Foundation / LUNGevity Lung Cancer Research Award
Alexander Drilon, MD
Memorial Sloan Kettering Cancer Center
New York

Many RET-positive cancers become resistant to targeted therapy for reasons not clearly based on genetic changes alone. Dr. Drilon predicts that other causes of resistance include (1) chemical changes (in the “epigenome”) that turn cancer-causing genes on or off and (2) changes in how these cancers look under the microscope (“histology”) that affect cancer behavior. Because these changes affect cell states rather than mutations, this resistance is potentially reversible, defining a key opportunity to maintain, restore, and extend sensitivity to potent and specific RET inhibitors.

Investigating incidental pulmonary nodules in underserved communities

Neel Chudgar, MD
Montefiore Medical Center

How KRAS mutations affect gene expression in lung cancer

Harold Bien, MD, PhD
Stony Brook University/Northport VA Medical Center
Stony Brook

Molecular Characterization of Lineage Plasticity

Helena Yu, MD
Memorial Sloan Kettering Cancer Center
New York

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.

Mechanisms of resistance to direct KRAS G12C inhibition

Kathryn Arbour, MD
Memorial Sloan Kettering Cancer Center
New York

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.