Experimental Drug Combination Selectively Destroys Lymphoma Cells
Laboratory experiments conducted by researchers at Virginia Commonwealth University Massey Cancer Center suggest that a novel combination of the investigational agent ibrutinib and bortezomib (Velcade) could potentially be an effective new therapy for several forms of blood cancer, including diffuse large B-cell lymphoma and mantle cell lymphoma.
The study, published in the British Journal of Hematology, showed that the experimental drug combination killed cancer cells through apoptosis, but was relatively nontoxic to normal, healthy cells. Ibrutinib is an inhibitor of Bruton’s tyrosine kinase that inhibits the B-cell receptor (BCR) signaling complex, which plays an important role in the survival of malignant B-cells. It has shown very promising initial results in the treatment of patients with B-cell malignancies, including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and mantle cell lymphoma. The synergistic interaction of the two drugs proved lethal even to lymphoma cells that had become resistant to bortezomib alone.
“Bortezomib is currently used to treat mantle cell lymphoma and multiple myeloma, but, unfortunately, many patients develop resistance to the drug,” says principle investigator Steven Grant, MD, Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, Associate Director for Translational Research, Program Co-leader of Developmental Therapeutics and Cancer Cell Signaling research member at VCU Massey Cancer Center. “We are hopeful that this combination therapy may circumvent such resistance and eventually help fill an urgent need for more effective therapies for patients with these uncommon blood disorders.”
High Level of Synergism between Ibrutinib and Bortezomib
With cultured diffuse large B-cell lymphoma and mantle cell lymphoma cells in laboratory experiments spearheaded by Girija Dasmahapatra, PhD, lead author of the study’s manuscript and Instructor in the Department of Internal Medicine at VCU School of Medicine, the researchers found that ibrutinib blocked several molecular pathways that the cancer cells use for growth and survival. When ibrutinib was combined with bortezomib, the scientists observed a high level of synergism between the two drugs that resulted in profound cell death due to DNA damage, culminating in apoptosis. The research findings suggest that the effectiveness of the combination therapy against bortezomib-resistant lymphoma cells may stem from ibrutinib’s ability to block signaling pathways used by the cancer cells to survive bortezomib exposure.
Specifically, exposure of diffuse large B-cell lymphoma and mantle cell lymphoma cells to ibrutinib blocked the cancer-promoting NF-κB, AKT, and ERK1/2 signaling pathways. These signaling pathways provide cells with the ability to adapt to otherwise harmful environmental stimuli by transmitting messages from receptors located at the cell’s surface to proteins within the cell that trigger a variety of biological processes. In particular, NF-κB, AKT, and ERK1/2 have been shown to carry out many functions that allow cancer cells to survive and proliferate. Significantly, each of these pathways has been implicated in the development of resistance to proteasome inhibitors such as bortezomib.
Promising New Agent
“We have provided a framework for understanding how an agent like ibrutinib might be employed to enhance the activity of an established anticancer agent like bortezomib,” says Dr. Grant. “We are currently working with representatives from the pharmaceutical industry and the National Cancer Institute to develop a new treatment strategy in which ibrutinib will be combined with proteasome inhibitors like bortezomib for the treatment of patients with lymphomas and potentially other blood cancers.”
This research was supported by National Institutes of Health grants CA63753, CA93738, and CA100866; Lymphoma SPORE award 1P50 CA130805; award R6059-06 from the Leukemia and Lymphoma Society of America; the Multiple Myeloma Research Foundation; Myeloma Spore grant P50CA142509; the V Foundation; and, in part, by funding from VCU Massey Cancer Center’s NIH-NCI Cancer Center Support Grant P30 CA016059.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
