Targeting Grb2 with BP1001: A Promising Approach for Gleevec-Resistant Chronic Myelogenous Leukemia

The abstract discusses the role of the protein Grb2 in cancer cell signaling, particularly in chronic myelogenous leukemia (CML). Grb2 is involved in signaling pathways that lead to the activation of Ras and Erk1,2 proteins. The study suggests that Grb2 could be a therapeutic target for CML, and a treatment called BP1001, which is an antisense oligodeoxynucleotide encapsulated in a liposome, was developed to inhibit Grb2 expression.

The aim of the research was to explore BP1001's potential to curb the growth of CML cells that are resistant to Gleevec, a common treatment for CML. The study also investigated whether BP1001 could increase the effectiveness of another drug, dasatinib, in treating CML cells. The clinical study included a Phase I trial where BP1001 was administered intravenously to patients with CML.

The methods used in the study included the alamarBlue dye incorporation method and the CellTiter Glow method to measure cell viability, and flow cytometry to analyze cell cycling and Grb2 expression. The clinical study was structured as a standard dose-finding trial with BP1001 administered twice weekly for 28 days.

The results indicated that BP1001 reduced the proliferation of Gleevec-resistant CML cells in a dose-dependent manner and that pre-treatment with BP1001 significantly enhanced the inhibitory effects of dasatinib. The combination of BP1001 and dasatinib primarily induced cell death. In a clinical trial involving 39 patients with various hematologic malignancies, five CML patients showed a significant reduction in circulating blasts during treatment, particularly two patients with a T315I mutation.

BP1001 was found to decrease Grb2 levels by more than 25% in 10 out of 12 samples, with an average decrease of 49%, and similarly, it reduced phosphorylated Erk1,2 levels by more than 25% in 7 out of 12 samples, with an average decrease of 52%.

The conclusion of the study is that BP1001 shows promise in treating Gleevec-resistant CML cells and in enhancing the efficacy of dasatinib. Further research is planned in the form of a Phase I/II trial to evaluate the safety and effectiveness of BP1001 in combination with dasatinib for patients with advanced CML.