P01CA257906

Deciphering LKB1-Associated Immunotherapy Resistance in Lung Adenocarcinoma (LUAD) - Summary

Lung cancer is the leading cancer killer in the United States. Our team proposes to develop novel personalized therapeutic strategies by exploiting vulnerabilities and opportunities created by alterations in tumor suppressors in lung cancer.

Specifically, we focus on the tumor suppressor LKB1, which is one of the most commonly mutated genes in lung adenocarcinoma (LUAD). LKB1 mutations are detected in 15-25% of LUAD, representing a major subpopulation of lung cancer patients. Despite the frequency, upward trajectory of incidence, and aggressive nature of the disease, patients with LKB1-mutant LUAD not only have no targeted therapeutics available but also show poor response to immune checkpoint inhibitors, demanding urgent development of effective therapeutic options.

To address this critical gap, our revised application will capitalize on our integrated understanding of LKB1-loss-evoked tumor growth regulatory mechanisms and suppression of anticancer immunity to develop innovative clinical approaches for the treatment of patients with LKB1-mutant LUAD.

New preliminary data from our team showed that:
1) LKB1 loss allows metabolic dysregulation, such as glutamate dehydrogenase (GDH) activation by FAK, leading to increased regulatory T cells and immune suppression;
2) LKB1-loss-triggered inhibition of STING, a key innate immunity regulator, can be reversed by an IAP inhibitor, leading to reactivated immune response and its potent in vivo immune-dependent anticancer effect; and
3) FAK is activated in LKB1-deficient cancer cells and supports cell invasion and inhibits immune infiltration.

These results lead to our central hypothesis that mutated LKB1 may exert its immune suppression function through a dysregulated anti-cancer immunity cycle mediated by key metabolic, innate immunity, and stromal regulatory factors. Targeting these factors may lead to novel approaches to re-activate anticancer immunity for effective therapeutic development in LUAD.

We will address this hypothesis through three highly integrated projects.
Project 1 will examine the role of the FAK-GDH1 axis in immunotherapy resistance and tumor progression of LKB1-mutant LUAD.
Project 2 will exploit our recently discovered LKB1-regulated IAP-JAK-STING signaling in LUAD to reverse immune suppression with an IAP inhibitor to enhance immunotherapy effect.
Project 3 will focus on targeting FAK-mediated primary tumor progression in LKB1-mutant LUAD by performing a clinical trial with the combination of a FAK inhibitor and an immune checkpoint inhibitor coupled with mechanistic studies.

The projects are supported by three cores, whose functions are administrative (Core 1), molecular pathology and immunology (Core 2), and bioinformatics and biostatistics (Core 3). This highly integrated effort builds on new discoveries from our established lung cancer team with more than 100 co-publications and with strong institutional support.

We expect to advance lung cancer treatment strategies by new agent discovery (GDH1 inhibitors), new application of clinical stage IAP inhibitors, and a new phase II clinical trial of a FAK-targeted combination approach to overcome immunotherapy resistance of LKB1-mutant LUAD and bring treatment options to this patient population.

Emory University

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Atlanta, Georgia 30322 United States

Single Zip Code

National Cancer Institute Program Project Applications (P01 Clinical Trial Optional) (PAR-20-077)

Amendment Since initial award the End Date has been extended from 05/31/27 to 05/31/28 and the total obligations have increased 189% from $2,229,253 to $6,449,718.