Chronic myeloid leukemia (CML) is a cancer of white blood cells that is driven by a constitutively active oncogenic tyrosine kinase. Tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec), revolutionized the treatment of CML and remain a major therapeutic strategy for CML patients. However, dormant leukemic stem cells that are resistant to tyrosine kinase inhibitors and may be responsible for CML resistance and recurrence, are protected from therapy-induced cell death by the bone marrow microenvironment and in particular, by bone marrow stromal cells. Therefore, novel drugs are needed that can target leukemic stem cells in the bone marrow.
The study, led by Prof. Arnon Nagler, Director of the Hematology Division and Bone Marrow Transplantation Center at Sheba Medical Center, Israel, assessed the effect of BL-8040 alone, and in combination with imatinib, on the proliferation of human CML cells in culture and on human CML tumors that were engrafted in mice. Results of the study show that the BL-8040 treatment directly inhibited cancer cell growth and induced apoptotic cell death of CML cells in-vitro. Furthermore, BL-8040 had a synergistic effect with imatinib, enabling use of imatinib at low doses. In mice engrafted with CML tumors, the combination of BL-8040 with low-dose imatinib markedly inhibited tumor growth, achieving a 95% suppression. Most importantly, the novel drug reversed the protective effect of the bone marrow stroma on CML cells, effectively promoting their apoptosis.
"We are very pleased with the results of this study, which show that BL-8040 has the potential to be an important addition to the drug arsenal for CML," stated Prof. Nagler. "BL-8040 shows two intriguing properties. First, it can directly suppress CML cell proliferation, and second, it can sensitize CML cells that hide in the bone marrow to therapy-induced apoptosis. The second property mainly stems from the ability of this drug to flush out cancer cells from the bone marrow into the peripheral blood."
Dr. Kinneret Savitsky, Chief Executive Officer of BioLineRx, commented, "These encouraging results support the rationale for BL-8040 therapy, in combination with tyrosine kinase inhibitors, to override drug resistance and suppress residual disease. The study shows that BL-8040 has the potential to treat CML patients who have developed resistance to Gleevec. BL-8040 is currently undergoing a Phase 2 trial for AML and is expected to enter a Phase 1 trial for stem cell mobilization in the second quarter of this year, with top-line results for both of these studies expected in the fourth quarter of 2014. We have high hopes that this promising drug will realize its potential to help cancer patients, both as a stand-alone therapy and in combination with other therapies in the foreseeable future."
Results of the study were recently published in Molecular Cancer Therapeutics.