# Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2021 · $163,237

## Abstract

Project Summary/Abstract
 Acute myeloid leukemia (AML) is an aggressive blood cancer that encompasses a variety of genetically
distinct sub-types. AML patients overall, display one of the lowest overall 5-year survival rates (<25%) of all
cancer diagnoses and currently ranks as the deadliest form of leukemia. These unsatisfactory outcomes are
largely the result of the ineffectiveness and toxicities of existing chemotherapies and highlight the urgent need
for more-effective therapies that either replace or improve the effectiveness these chemotherapies.
 The development of more-effective therapies begins by identifying the molecular mechanisms that
underpin AML pathogenesis and chemotherapy ineffectiveness. We recently discovered that the two
transcription factors (TFs) TFs, ATF4 and XBP1s, which are components of the signal transduction network,
the unfolded protein response (UPR), are key mediators of AML cell survival and disease progression.
Specifically, we have found that inhibition of ATF4 or XBP1s antagonizes AML cell survival and disease
progression in multiple in vitro and in vivo models of AML. We also found that small-molecule inhibitors of
PERK and IRE1α, which are upstream activators of ATF4 and XBP1s, respectively, antagonizes AML cell
survival and enhances the effectiveness of first-line chemotherapies.
 The collective goals of this proposal aim to address two key unanswered questions: 1. What are the
downstream transcriptional targets of ATF4 and XBP1s that support AML biology and 2. What are the
molecular nodes of the UPR that can be targeted with chemical strategies? With respect to the first question,
we have identified two candidates, DDIT4 and SREBF1, which are known regulators of autophagy and
cholesterol biology, respectively. We will use a combination of established genetically engineered mouse
models of AML and patient-derived AML samples to assess the functional roles of DDIT4 and SREBF1 in AML
as well as their relationship to the UPR. Additionally, we will assess the contribution of DDIT4 and SREBF1 –
as well as the downstream-regulated processes contribute to the pro-leukemia functions of ATF4 and XBP1s.
 Second, we will assess therapeutic strategies for targeting the UPR, autophagy and cholesterol biology
either alone or simultaneously in experimental models of AML. The results of these studies will provide new
insight on the molecular mechanisms that support the pathogenesis and chemotherapy responses of AML and
establish a platform for developing novel therapeutic strategies. Moreover, components of the UPR support the
pathophysiology of many other tumor settings and thus results from our proposed studies will likely have
implications for other forms of human cancers.

## Key facts

- **NIH application ID:** 10144402
- **Project number:** 5R01CA227830-03
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Stephen Matthew Sykes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,237
- **Award type:** 5
- **Project period:** 2019-05-07 → 2021-08-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144402

## Citation

> US National Institutes of Health, RePORTER application 10144402, Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance (5R01CA227830-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144402. Licensed CC0.

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