# Proximal Differentiation Therapy for K-Ras-Induced Lung Adenocarcinoma

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

ABSTRACT
Individualized therapeutics for K-RAS mutant lung adenocarcinoma are nonexistent. Recently, we have
described a unique interaction between activated K-Ras and the Type II cell that explains the unique
ability of the Type II cell to proliferate in response to K-Ras activation. The absence of the transcription
factor Sox2 allows Notch to be upregulated when K-Ras is activated. In addition, K-Ras is able to induce
a transcriptional program that dedifferentiates distal lung epithelial cells into distal progenitors that are
proliferative and multipotent during development. These distal stem cells express Sox9 as well as Ezh2.
In this proposal, we will examine the effects of proximalizing Type II cells with Sox2 activation and Notch
inhibition and Ezh2 inhibition on tumor initiation in Aim 1. This will involve inducible mouse transgenic
alleles and human cell lines and human cells and tumors. We will also test the efficacy of a novel Sox2-
mimetic compound, RepSox, for anti-tumor activity in K-Ras activated distal epithelial cells. In Aim 2, we
will test the hypothesis that proximalization of the Type II cells suppresses progression of established K-
Ras mutant adenocarcinomas. Finally, in Aim 3, we will assess the tumor suppression of Sox2 activation
and Notch inhibition in more genetically complex tumors (K-Ras mutant, p53 knockout). We hypothesize
that proximalization therapy will be tumor suppressive and potentially also chemosensitizing. Successful
completion of these aims could help tens of thousands of patients per year.
1

## Key facts

- **NIH application ID:** 9815433
- **Project number:** 5I01BX003262-03
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Mark Onaitis
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815433

## Citation

> US National Institutes of Health, RePORTER application 9815433, Proximal Differentiation Therapy for K-Ras-Induced Lung Adenocarcinoma (5I01BX003262-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815433. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*