Granulocyte-Macrophage colony-Stimulating factor receptor-Targeted therapy of chemotherapy- and radiation-Resistant human myeloid leukemias

John P. Perentesis Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Anne E. Bendel Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Yu Shao Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Berta Warman Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Stella M. Davies Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Chang H. Yang Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Mridula Chandan-Langlie Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Kevin G. Waddick Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

Fatih M. Uckun Biotherapy Institute, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA; Departments of Pediatrics, Therapeutic Radiology-Radiation Oncology, Biochemistry, Pharmacology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA

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Abstract

Contemporary therapies for acute myeloid leukemia (AML) commonly fail to cure patients because of the emergence of drug resistance. Drug resistance in AML is multifactorial but can be associated with the overexpression of transmembrane transporter molecules, including P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP), or associated with inactivation of the p53 tumor suppressor gene, as well as overexpression of the anti-apoptotic protein bcl-2. We are investigating if novel recombinant biotherapeutics can circumvent these resistance mechanisms to effectively treat refractory AML. To target the lethal action of diphtheria toxin (DT) to high affinity granulocyte-macrophage colony-stimulating factor (GMCSF) receptors on AML blasts, we have produced a recombinant chimeric fusion toxin, DT_ctGMCSF. Since DT_ctGMCSF enters and kills its target cells by unique mechanisms (GMCSF-receptor binding and protein synthesis inhibition) and is not similar in structure to Pgp or MRP substrates, we postulated that it would be an active agent against therapy-resistant AML. DT_ctGMCSF was selectively cytotoxic (IC₅₀ 1–10ng/ml) to GMCSF-receptor positive AML cells expressing the Pgp- or MRP-associated multi-drug resistant phenotypes, despite high level resistance to conventional chemotherapeutic agents. DT_ctGMCSF also efficiently killed AML cells deficient in p53 expression, as well as radiation-resistant AML cells and mixed lineage leukemia cells expressing high levels of bcl-2. In addition, DT_ctGMCSF killed>99% of primary leukemic progenitor cells from therapy-refractory AML patients under conditions that we have previously found to not adversely affect the proliferative capacity or differentiation of pluripotent normal hematopoietic progenitor cells. DT_ctGMCSF may prove useful in treating myeloid leukemias that are otherwise resistant to a wide range of conventional therapies.

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Granulocyte-Macrophage colony-Stimulating factor receptor-Targeted therapy of chemotherapy- and radiation-Resistant human myeloid leukemias

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Granulocyte-Macrophage colony-Stimulating factor receptor-Targeted therapy of chemotherapy- and radiation-Resistant human myeloid leukemias

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