Abstract CT103: Low-dose daunorubicin to target leukemia stem cells in newly diagnosed and relapsed/refractory AML

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13_Supplement), p.CT103-CT103
• Main Authors: Lin, Tara L., Perry, John M., He, Xi, Reed, Gregory, Zhang, Na, Weir, Scott, McGuirk, Joseph, Li, Linheng
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-CT103

Background: Chemotherapy-resistant leukemia stem cells (LSC) are responsible for disease relapse in many patients with Acute Myeloid Leukemia (AML). The Wnt/β-catenin and PI3K/Akt pathways are frequently activated in cancer and interact to stimulate stem cell expansion through phosphorylation of β-catenin by Akt (pS552-β-catenin). We hypothesize that targeting pS552-β-catenin may inhibit chemoresistant LSCs. High-throughput screening identified that anthracyclines doxorubicin (DXR) and daunorubicin (DNR) inhibit Akt:β-catenin interaction at significantly lower doses than conventionally used. Using a mouse leukemia model, we repurposed DXR as a targeted therapy for pS552-β-catenin inhibition rather than a broadly cytotoxic agent. In contrast to the typical dose, which may stimulate expansion of resistant LSC, targeted/low-dose DXR inhibited chemoresistant LSC expansion and significantly reduced LSC tumorigenic potential. AML patients typically receive high-dose DNR but often relapse due to persistence of therapy-resistant LSCs, which frequently express pS552-β-catenin. Here, we use a metronomic approach to test the ability of low-dose anthracycline therapy to target therapy-resistant LSCs. Methods: A proof of concept trial (NCT02914977) was designed to measure the ability of low dose DNR to inhibit pS552-β-catenin in LSCs of adult relapsed/refractory AML patients. A protocol amendment added a second cohort of patients with newly diagnosed AML undergoing standard chemotherapy with DNR and cytarabine (7+3 induction). Treatment in each cohort consisted of DNR given at a dose of 6.75mg/m2/day x 5 days. Patients with relapsed/refractory AML had bone marrow aspiration pre-treatment prior to day 1, followed by DNR on days 1-5, and a post-treatment bone marrow aspiration on day 8. Patients with newly diagnosed AML were treated with conventional 7+3 chemotherapy. A sample from the day 14 bone marrow was collected. DNR was given on days 15-19. Bone marrow aspiration was performed with blood count recovery and samples sent for LSC marker assessment. In this study, we will determine the safety, pharmacokinetics, and pharmacodynamic effects of low dose DNR. The LSC population and phosphorylation status of β-catenin will be measured pre- and post-treatment. Two or more prior induction attempts are required for study entry for refractory patients; relapsed patients require only one prior induction. The trial has enrolled 14 patients: 11 in the relapsed cohort and 3 in the