Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia

Abstract

Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program) were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have measurable cytotoxicity against leukemia cells, and among these, 12 were effective against all five MLL-rearranged cell lines (IC₅₀ [half maximal inhibitory concentration] < 1 μM). These 12 agents include cladribine, dactinomycin, daunorubicin, docetaxel, etoposide, gemcitabine, mitomycin C, mitoxantrone, teniposide, topotecan, triethylenemelamine, and vinblastine. We show that the Approved Oncology Drug Set II contains a number of agents with potent antileukemic activity in the tested cell lines. As approved drugs, these agents have been used in clinical settings for many years for other malignancies, thus their toxicity profile, pharmacokinetics, and other properties are readily available. Further evaluation of their use in future clinical trials for pediatric leukemia with MLL abnormalities should be considered.

Keywords:

• drug screening
• therapeutic repertoire

Supplementary material

Figure S1 Comparison of cell survival measurements by the Celigo™ cytometer and alamarBlue^®. W1 leukemia cells were incubated with imatinib (A), gefitinib (B), sorafenib (C), or sunitinib (D) for 96 hours then measured using the Celigo cytometer, followed by alamarBlue. Survival compared with control DMSO-treated cells is shown, with data points and error bars representing the mean and standard error, respectively.

Abbreviation: DMSO, dimethylsulfoxide.

Table S1 IC₅₀ values after incubation with drugs from the Approved Oncology Drug Set II

Acknowledgments

This work was supported by grants from the Kids Cancer Care Foundation of Alberta and the Alberta Children’s Hospital Foundation. RJA was funded in part through an endowed King Fahd Chair.

Disclosure

The authors have no conflicts of interest to declare.