# Effect of Cyclical Intermittent Hypoxia on Lung Cancer Progression

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2021 · —

## Abstract

Objective: Lung cancer continues to have a very poor prognosis, with Veterans having a higher incidence of
lung cancer and worse outcome compared to civilians.1 Obstructive sleep apnea (OSA) has been associated
with higher cancer incidence2-5 and mortality,2, 6-8 and again, Veterans have a higher prevalence of OSA that is
more severe compared to civilians.9 Our overarching objective is to determine how cyclical intermittent hypoxia
(CIH), a major underlying pathology of OSA, promotes lung cancer progression. Our hypothesis is that CIH
increases the differentiation of immature immune cells to suppressor immune cells which then, inadvertently,
protects the cancer. We have published that CIH accelerates primary lung cancer progression in Triple
Transgenic KrasG12D+; p53fl/fl; myristolated p110fl/fl ROSA-gfp (TT-Kpp) mice (funded by VA CPPF grant). This
grant is the next step - to explore mechanisms of HOW CIH promotes cancer progression. Research Design:
The technical innovation of this grant is that we will be the first to measure the effect of mild, moderate and
severe CIH on cancer progression in TT-Kpp mice (Aim 1). The conceptual innovation of this grant is that we
will be the first to use this TT-Kpp model to explore whether systemic CIH increases production, differentiation
and recruitment of suppressor immune cells to primary lung cancer. Methodology: Aim 1: TT-Kpp mice
injected with Ad5CC10Cre virus will be exposed to one of 4 conditions: sham (room air), mild CIH (CIH15,
(drops in FiO2 0.21 to FiO2 0.15 [SaO2 nadir of 82%]) moderate CIH (CIH10, (drops in FiO2 0.21 to FiO2 0.15
[SaO2 nadir of 61%]) or severe CIH (CIH5; drops in FiO2 0.21 to FiO2 0.05 [SaO2 nadir of 37%]). Primary
outcome will be quantitative tumor volumes (monthly microCT scans); secondary outcome will be survival. Aim
2: Assess the effect of CIH5 (vs Sham) on production, differentiation and recruitment of suppressor immune
cells in mice with and without cancer. Primary outcome will be quantitative M-MDSC/TAM/Tregs in bone
marrow, spleen, thymus, left lung and right lung at early (2 weeks) and late (4 months) time points; secondary
outcome will be functional assays of suppressor immune cells. Exploratory Aim 3: Develop a clone cancer cell
from lung cancer of TT-Kpp mice. Also, assess the effect of CIH5 (vs Sham) regulating (1) chemokine/cytokine
genes within lung cancer cell (via PCR panel at early and late time point) and (2) other genes (via RNA-seq at
one time point). Together, the PCR and RNA-seq information will be utilized in a future grant where we will use
CRISPR editing of significant genes within clone cells and inject them into a wild type mouse (syngeneic
orthotopic model) to further understand mechanism of effect of CIH on cancer progression. Findings: First
submission. Clinical Relationships: We may provide evidence that CIH, a major pathology of obstructive sleep
apnea, is a modifiable risk factor that can improve lung cancer survival. Impact/Significance: Po...

## Key facts

- **NIH application ID:** 10092810
- **Project number:** 7I01BX004872-02
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Diane C Lim
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092810

## Citation

> US National Institutes of Health, RePORTER application 10092810, Effect of Cyclical Intermittent Hypoxia on Lung Cancer Progression (7I01BX004872-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10092810. Licensed CC0.

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