Little is known about the molecular mechanisms underlying early carcinogenesis of lung adenocarcinoma
(ADC), the most common subtype of lung cancer. Atypical adenomatous hyperplasia (AAH) is the only
recognized preneoplasia. AAH is postulated to progress to adenocarcinoma in situ (AIS), minimally invasive
adenocarcinoma (MIA), and eventually invasive ADC. However, the molecular landscape of these lesions has
not yet been well characterized and the definition and management of these lesions remain controversial. Our
preliminary data have demonstrated a progressive increase in genomic complexity and immunosuppression
with neoplastic progression from AAH, to AIS, MIA, and invasive ADC indicating continuous genomic evolution
and “immunoediting”. This work led to our recently approved immunoprevention trial, “IMPRINT-Lung:
Randomized phase II trial of immunotherapy for the prevention of non-small cell lung cancers using
pembrolizumab”. We herein hypothesize: 1) Immune escape contributes to progression of lung preneoplasia;
2) Higher levels of molecular complexity are associated with less effective cancer immunosurveillance; and 3)
Immune checkpoint blockade at pre- and early neoplastic stages prevents or delays the development of
invasive ADC. We will investigate our hypotheses in the following aims. In Aim 1, we will utilize a large, unique
cohort of resected AAH, AIS, MIA and invasive ADC to define and compare the molecular and immune profiles
to identify molecular and immune features that characterize specific lung preneoplasia stages and subsequent
progression. Next, in Aim 2, we will leverage the valuable specimens from the IMPRINT-Lung trial
to a) determine molecular and immune features associated with progression or regression of high-risk IPNs
and identify biomarkers to select patients suitable for observation versus immunoprevention; b) discover novel
targets and strategies for lung cancer prevention. Finally in Aim 3, we will develop and characterize human-
relevant lung ADC preneoplasia murine models by a) defing the molecular and immune landscapes of lung
preneoplasia in EGFR-mutant, KRAS/TP53-mutant and KRAS/LKB1-mutant genetically engineered murine
models (GEMMs); b) determining whether PD1/PDL1 blockade prevents invasive lung ADC in GEMMs; and c)
test potential novel targets for lung cancer prevention using lung preneoplasia GEMMs based on insights
gained from Aims 1 and 2. I have a proven track record of productivity in defining the molecular heterogeneity
and evolution of early stage lung adenocarcinomas and have assembled a team with expertise in genomics,
bioinformatics, immunology, translational research, genetically engineered mouse models, and pathology to
tackle these specific aims.
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