Abstract 708: Phase I clinical trial to target oxidative phosphorylation and CREB for children and young adults with relapsed or refractory AML

The overall survival for pediatric AML is 60-70% and treatment includes intensive chemotherapy and stem cell transplantation, which are associated with significant morbidity and mortality. There are few therapies for relapsed/refractory pediatric AML. We previously demonstrated that the transcription factor CREB is overexpressed and activated in AML blasts and leads to increased proliferation and survival of AML cells. CREB overexpression was associated with an increased risk of relapse and decreased event-free survival in AML patients. Knockdown of CREB in mouse bone marrow transduction/transplantation assays did not affect engraftment of healthy hematopoietic stem or progenitor cells. Therefore, we hypothesized that CREB is a potential target for AML therapy.The CREB inhibitor, XX-650-23, disrupts CREB interaction with its binding partner, CBP/p300 (CREB Binding Protein), which is required for CREB function. Treatment of primary pediatric AML cells and xenograft mouse models demonstrated that XX-650-23 inhibits AML progress in vitro and in vivo. Since XX-650-23 is not a clinical candidate, we performed a virtual screen of FDA-approved drugs with known safety and pharmacokinetic profiles and similar structure to XX-650-23. Niclosamide is an orally bioavailable drug that was previously used to treat tapeworm in developing countries and is safe for both children and adults. We studied niclosamide in pediatric AML cells and pediatric AML xenograft mouse models. Niclosamide primarily acts through inhibition of oxidative phosphorylation and induces apoptosis of AML blast cells, including leukemia initiating cells, resulting in decreased progression and prolonged survival in mice. Combination of niclosamide and cytarabine showed synergistic effects with combination index of less than 1. Based on our preclinical data, a Phase I clinical trial was initiated for relapsed or refractory AML in children and young adults (clinicaltrials.gov, NCT05188170). The study is a single institution, open label, prospective, dose escalation study. The treatment is 2 weeks of oral niclosamide followed by 5 days of high dose cytarabine. Eligibility is between 2 and 30 years of age with relapsed or refractory AML. The primary objective is to identify and evaluate the safety for Phase 2 dose of niclosamide in combination with cytarabine for relapsed/refractory pediatric AML. The secondary objective is to determine the pharmacodynamic effects of niclosamide in AML cells. We are currently enrolling patients and at the first dose level have not observed any significant toxicities related to niclosamide. Preliminary data have demonstrated decreased AML blasts in the bone marrow. Our results suggest that repurposing niclosamide is potentially safe and effective for treatment of relapsed or refractory pediatric AML. Citation Format: Kailen Mark, Norman Lacayo, Kathleen M. Sakamoto. Phase I clinical trial to target oxidative phosphorylation and CREB for children and young adults with relapsed or refractory AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 708.