UH3CA244697

Intercepting progression from pre-invasive to invasive lung adenocarcinoma - Abstract

Despite advances in therapeutic strategies, non-small cell lung cancer remains a deadly disease. An improved understanding of the biology of lung cancer is needed to intercept the disease at an early point in its progression.

Our project, which is inspired by that challenge, focuses on events transpiring in the earliest radiographically-detected manifestation of lung cancer: the computerized tomography (CT)-detected non-solid nodule, of which as many as 40% harbor frankly invasive adenocarcinoma. Thus, despite conventional wisdom that CT-detected non-solid nodules represent pre or minimally invasive malignancy, clearly transition to more invasive histologies occurs in a significant proportion of these nodules.

Understanding the cellular and molecular changes within non-solid nodules that drive progression will provide unique and novel insights into the fundamental mechanisms of lung carcinogenesis. We hypothesize that alterations in cells of the tumor microenvironment (TME) have a role in initiating and supporting this progression. In agreement with that proposal, our preliminary multiplex immunofluorescence (IF) studies suggest that progression to a more invasive phenotype is associated with the development of a strong immunosuppressive TME.

In this project, we test our hypothesis using multidimensional methods to profile the TME and to determine the crosstalk between cancer cells and the TME in pre-invasive to invasive human lung non-solid adenocarcinomas. Comparative analysis of the cellular and molecular events associated with the distinct histological stages will lead to identification of the critical events triggering progression and thereby identify targets to intercept disease progression.

We will use appropriate mouse models in pre-clinical studies to develop these targets as strategies to intercept progression of pre-invasive to invasive cancer. In the first phase of these studies (UG3 phase), we will define TME alterations associated with progression of lung nodules using RNAseq profiling and image-based methods (multiplex IF and imaging CyTOF) in studies of our archival tumor samples. These studies will generate a comprehensive catalogue of the cellular and molecular events that trigger progression of indolent lesions to frankly invasive cancers, with a strong focus on immune mechanisms. These analyses will provide novel and detailed insights into how the composition and activity of the TME changes with progression.

In the second phase (UH3 phase), we will leverage mouse models to explore interception strategies to target immune mechanisms and prevent progression. The proposed cohort satisfies the RFA's focus on high-risk cohorts for cancer-immunoprevention studies, since lung nodules are premalignancies highly prevalent in smokers.

Weill Medical College Of Cornell University

TO PROVIDE SUPPORT FOR INITIATIVES FUNDED UNDER THE 21ST CENTURY CURES ACT TO SUPPORT CANCER RESEARCH, SUCH AS THE DEVELOPMENT OF CANCER VACCINES, THE DEVELOPMENT OF MORE SENSITIVE DIAGNOSTIC TESTS FOR CANCER, IMMUNOTHERAPY AND THE DEVELOPMENT OF COMBINATION THERAPIES, AND RESEARCH THAT HAS THE POTENTIAL TO TRANSFORM THE SCIENTIFIC FIELD, THAT HAS INHERENTLY HIGHER RISK, AND THAT SEEKS TO ADDRESS MAJOR CHALLENGES RELATED TO CANCER.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

New York United States

State-Wide

Immuno-Oncology Translation Network (IOTN): Cancer Immunoprevention Research Projects (UG3/UH3) (RFA-CA-19-012)

Amendment Since initial award the End Date has been extended from 08/31/24 to 02/28/25 and the total obligations have increased 247% from $845,268 to $2,931,434.