# IAP inhibition as a therapeutic strategy to target therapy-resistant leukemia initiating cells

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $387,630

## Abstract

Acute myeloid leukemia (AML) is a devastating malignancy with dismal outcomes for patients, particularly in the
elderly where most cases occur. The recent approval of the BCL2 inhibitor venetoclax (Ven) in combination with
a hypomethylating agent (HMA; such as azacytidine/Aza) for the treatment of AML in elderly/unfit adults has
substantially improved outcomes for these patients. Still, about a third of patients treated with Ven/HMA exhibit
poor responses to therapy, and most patients who do respond will eventually relapse with Ven/HMA resistant
disease. Moreover, patients whose AML contains mutations in the TP53 gene are refractory to Ven/HMA and all
other forms of chemotherapy. The central premise of this project is that intra-patient heterogeneity of the
leukemia initiating cell (LIC) population is a key driver of therapy resistance/failure. At least two distinct forms of
LSCs can be found in AML patients, one with a more primitive phenotype (p-LIC) and one with a monocytic
phenotype (m-LIC). While Ven-based therapies are an effective means to eradicate the p-LSCs in newly
diagnosed AML patients, m-LIC are resistant to Ven/Aza and can mediate relapse. The goal of this work is to
identify and characterize distinct LIC subtypes and their vulnerabilities to design more effective and more durable
therapies. We have further shown that m-LIC exhibit upregulation of Inhibitor of Apoptosis Proteins (IAP) and
that IAP inhibition using drugs called SMAC mimetics (SMACm) potently sensitizes AML cells to Ven/Aza-
induced apoptosis in vitro and in vivo, particularly for the monocytic subpopulation highly resistant to Ven/Aza
alone. Intriguingly, SMACm therapy is also highly effective at eradicating TP53 mutant/deleted AML cells, which
are generally refractory to currently available therapies. Thus, varying subtypes of AML LIC are vulnerable to
targeting by distinct strategies. Mechanistically, we show that SMACm in combination with Ven/Aza induces
noncanonical NF-B signaling and high levels of TNF, which causes cell death by apoptosis. Here, we propose
to characterize the molecular phenotypes and therapeutic vulnerabilities of different LIC subpopulations in order
to design more effective therapies. In the first aim, we will characterize the pathways and molecular mechanisms
that mediate differential vulnerabilities of resistant LIC subtypes, with a focus on monocytic and TP53 mutant
subtypes. The second aim will leverage in vitro and in vivo models to gain a thorough understanding of the clonal
heterogeneity of different primary AML specimens, the phenotypes of the various subclones, and how distinct
LIC subclones differentially respond to Ven/Aza and SMACm therapy. Finally, in Aim 3, a clinical trial will assess
the safety and efficacy of combining a SMACm drug, tolinapant, with Ven/Aza in the relapsed/refractory AML
setting. Samples from this trial will be used to determine whether and how tolinapant sensitizes LICs to Ven/Aza
therapy, thereby inducin...

## Key facts

- **NIH application ID:** 10940217
- **Project number:** 1R01CA292432-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James V Degregori
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,630
- **Award type:** 1
- **Project period:** 2024-07-03 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940217

## Citation

> US National Institutes of Health, RePORTER application 10940217, IAP inhibition as a therapeutic strategy to target therapy-resistant leukemia initiating cells (1R01CA292432-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10940217. Licensed CC0.

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