Echinomycin has been used unsuccessfully in the treatment of solid tumors but not previously evaluated in the patients with haematological malignancies. OncoImmune’s founders have demonstrated that echinomycin is highly effective at selectively targeting leukemia stem cells (LSCs) and we are developing novel formulations of Echinomycin for the treatment of Acute myeloid leukemia (AML).
AML is a fast-growing form of cancer of the blood and bone marrow, and the most common type of acute leukemia. Treatment of AML is usually divided into 2 chemotherapy (chemo) phases: Remission Induction which is aimed at getting rid of as many leukemia cells as possible, and Consolidation (post-remission therapy) which aims to destroy any remaining leukemia cells and prevent a relapse. However, while current therapy can result in complete remission (CR) in the majority of AML cases, relapsed AML (rAML) occurs in >50% patients within two years of CR. Among them, more than 60% succumb to AML within two years of relapse and is generally resistant to chemotherapy. Recent studies suggest that leukemia stem cells (LSC) are highly resistant to conventional chemotherapy and thus likely responsible for relapse. Therefore, therapeutic elimination of LSC may offer a new strategy for the treatment of rAML.
Echinomycin is a DNA intercalating cyclic peptide which belongs to a member of quinoxaline antibiotics originally isolated from Streptomyces echinatus. Because of its anti-neoplastic activities against murine tumors, echinomycin was brought into clinical development for solid tumors by the National Cancer Institute (NCI) in multiple phase I and phase II studies. However, the dose-limiting toxicity (DLT) in all trials, regardless of schedule, was severe and often protracted and echinomycin was not consistently effective for adult patients with solid tumors. Accordingly, clinical development of echinomycin was discontinued.
Using a transgenic mouse model of lymphoma/leukemia, OncoImmune’s founders identified a subset of cells with stem cell like self renewing properties. This cell population was found to be particularly susceptible to the HIF-1a inhibitor, echinomycin, whereas inhibitors of other pathways had little to no effect on cell viability. Furthermore, the lymphoma CSCs were approximately 100-fold more sensitive than normal hematopoeitic progenitor cells (HPCs) and echinomycin treatment results in long-lasting elimination of lymphoma CSCs as demonstrated by a complete lack of recurrence in treated mice. The HIF-1a -Notch pathway was determined to be essential for the maintenance of these cancer stem cells (CSCs) in hematological malignancies under normoxia.
Leukemia stem cells (LSCs) from AML display a similar increase in HIF-1a expression. The inhibitory effect of echinomycin was demonstrated in 7 independent primary AML samples taken from the bone marrow (BM) or peripheral blood (PB). In the xenogeneic model of human AML, short-term treatment by echinomycin prevented serial transplantation of AML, supporting the use of echinomycin as a therapeutic agent for AML.
The major limitation of echinomycin as a drug product, is the narrow therapeutic window due to its short half life. OncoImmune is developing new formulations of echinomycin with increased half life and we have received orphan drug designation from the FDA for the treatment of AML.