# Patho-Genetic Analysis of Invasive Mucinous Adenocarcinoma of the Lung

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $631,889

## Abstract

Despite recent progress in the development of molecularly-targeted therapy and immunotherapy, lung cancer is
still the leading cause of cancer death since such therapies are not applicable for more than half of lung cancer
patients. Lung adenocarcinoma is the major pathological type of lung cancer. Lung adenocarcinoma has been
further subdivided based on both genetic alterations (e.g., KRAS or EGFR mutations and ALK fusions) and
differentiation state (including histopathologic subtypes such as acinar, lepidic, papillary, solid and mucinous).
In most cases, such genetic alterations do not strictly correlate with the histopathologic subtypes of lung
adenocarcinomas. However, genetic and molecular pathways that lead to the development of invasive mucinous
adenocarcinoma of the lung (IMA) have been revealed by our team and others in the past several years (e.g.,
HNF4A pathway), suggesting that such molecular pathways can be targeted to treat IMA for which there is
currently no effective therapy. Notably, the histology of IMA resembles that of mucus-producing cancers found
in the gastrointestinal tract (e.g., pancreatic cancer), which hampers efforts to properly diagnose IMA from lung
metastases originating from other mucus-producing organs. A biomarker to distinguish IMA from lung
metastases has not been established. Our long-term goal is to identify a therapy for IMA. The objective here is
to 1) determine whether HNF4A and its downstream genes that are specifically expressed in IMA but not in
normal lung can be therapeutic targets for IMA and 2) comprehensively identify therapeutic targets and
biomarkers using novel technologies such as single-cell mRNA-seq and 3D tumoroid (organoid) culture with a
large number of IMA specimens (>200). The central hypothesis is that IMA is driven by distinct molecular
pathways that can be therapeutically targeted. The rationale is based on our previous and preliminary studies
indicating that 1) the HNF4A pathway is required for the growth of IMA and 2) such a pathway creates a specific
tumor microenvironment that influences tumor-associated cells, which presents specific therapeutic targets and
biomarkers. This hypothesis will be tested in the following specific aims: 1) determine whether HNF4A and/or
its downstream genes can be therapeutic targets for IMA, 2) analyze the heterogeneity of IMA at a single-cell
level, and 3) discover diagnostic biomarkers for IMA. The approach is innovative because it will focus on
molecular pathways that have not been explored as therapeutic targets for IMA. The proposed research will: 1)
utilize model mice for IMA (GEMM and PDX) and human specimens of IMA and lung metastases and 2)
determine whether small molecular inhibitors and therapeutic antibodies can reduce the growth of IMA. The
proposed research is significant because our team, comprised of a number of IMA researchers from several
institutes, will bring their knowledge and expertise together to develop a novel therapy for IM...

## Key facts

- **NIH application ID:** 10129917
- **Project number:** 5R01CA240317-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Yutaka Maeda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $631,889
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129917

## Citation

> US National Institutes of Health, RePORTER application 10129917, Patho-Genetic Analysis of Invasive Mucinous Adenocarcinoma of the Lung (5R01CA240317-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129917. Licensed CC0.

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