# Adaptive resistance to HIF1a inhibition in hypoxia

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $352,232

## Abstract

Project Summary
Patients with advanced and metastatic cancer have limited treatment options and face grim outcomes. There is
an urgent need for novel and effective treatments. Hypoxia is a universal pathological feature of solid tumors.
Hypoxic tumor cells acquire metastatic and lethal phenotypes primarily through the activities of hypoxia-
inducible factor 1 alpha (HIF1α). Therefore, HIF1α is considered as a promising therapeutic target. To date,
while several HIF1α inhibitors have been discovered and validated in preclinical studies, the clinical
translations of these agents have been less successful. The robust antitumor effects seen in preclinical models
are not observed in clinical trials. The reasons for the poor clinical efficacy are unclear. Thus, the long-term
goal of this proposal is to understand how tumor cells adaptively respond and develop resistance to
HIF1α inhibition, and harness this knowledge to translate HIF1α inhibitors into clinically effective and
sustainable treatments. In preliminary studies, we specifically inhibited HIF1α using stable shRNA in multiple
human tumor cell lines. We found that although tumor cells were initially sensitive to the antitumor activities of
HIF1α inhibition, they quickly developed resistance in hypoxia in vitro and in xenografts in vivo even though
HIF1α remained inhibited. Mechanistically, we observed that tumor cells adaptively responded to HIF1α
inhibition by increasing the stability of oncogenic protein ID1 in hypoxia, and we found that silencing ID1
restored sensitivity to HIF1α inhibition, while overexpressing ID1 conferred resistance. In this proposal, we will
test the hypothesis that HIF1α inhibition induces adaptive resistance via compensatory stabilization of
oncogenic protein ID1 in hypoxia, which in turn supports the hypoxic growth of HIF1α-inhibited
tumors. We further hypothesize that silencing ID1 or ID1-mediated oncogenic pathways will block the
resistance and enhances the antitumor efficacy of HIF1α inhibition. We will use molecular biology and
preclinical animal models to test this hypothesis in three specific aims. Aim 1: Determine the role of ID1 in
conferring resistance to HIF1α inhibition in vitro and in vivo. Aim 2: Elucidate the mechanism by which ID1
protein is regulated by HIF1α in hypoxia. Aim 3: Determine the mechanism by which ID1 confers resistance to
HIF1α inhibition in hypoxia. The successful completion of these aims may deepen our understanding of the
role of HIF1α in cancer biology and therapy, may provide a rational approach to the clinical translation of
HIF1α-inhibitory agents, and may lead to novel and lifesaving treatments for patients with advanced and
metastatic disease.

## Key facts

- **NIH application ID:** 9966904
- **Project number:** 5R01CA207377-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Zheng David Qian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,232
- **Award type:** 5
- **Project period:** 2016-08-12 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966904

## Citation

> US National Institutes of Health, RePORTER application 9966904, Adaptive resistance to HIF1a inhibition in hypoxia (5R01CA207377-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9966904. Licensed CC0.

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