Lab research suggests clinical trial may be especially effective against rare mantle cell lymphoma
A multi-institutional Phase I clinical trial testing the effects of a new combination of chemotherapies on rare forms of lymphoma is poised to begin at Virginia Commonwealth University Massey Cancer Center. As the trial prepares to open, new laboratory research from Massey scientists suggests that the novel therapy may warrant particular attention in patients with mantle cell lymphoma (MCL), a relatively rare form of non-Hodgkin’s lymphoma.
The study’s findings, originally published in the journal Molecular Cancer Therapeutics, demonstrate for the first time synergistic interactions between the histone deacelytase inhibitor (HDACI) vorinostat and the proteasome inhibitor carlfizomib in multiple MCL types as well as in patient-derived MCL cells. When combined, the agents were active in killing MCL cells resistant to bortezomib, a proteasome inhibitor currently used to treat multiple myeloma and MCL. Additionally, the regimen displayed relatively little toxicity toward normal human bone marrow cells. Proteasome inhibitors such as carlfizomib act by blocking the action of proteasomes, which are large protein complexes that help destroy proteins no longer needed by the cell. HDACIs such as vorinostat modify the expression of genes in cancer cells involved in the regulation of cell death and differentiation.
The lead author of this study was Girija Dasmahapatra, Ph.D., of the Department of Internal Medicine at the VCU School of Medicine. The work was carried out in the laboratory of Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. For more than eight years, Grant and his colleagues have been investigating synergistic interactions between proteasome inhibitors and HDACIs in various malignant blood cancers. These efforts have resulted in several recent Phase I clinical trials testing combinations of HDAC and proteasome inhibitors in patients with relapsed or refractory blood cancers.
“Currently, there are no treatment regimens for MCL that significantly prolong survival,” says Grant. “While the clinical trial was already open to patients with mantle cell lymphoma, our research further supports their inclusion. We hope to see responses in patients analogous to our laboratory findings.”
Led by Beata Holkova, M.D., Harrison Endowed Scholar in Cancer Research and hematologist-oncologist at VCU Massey, the trial is currently enrolling patients at VCU Massey Cancer Center and the James P. Wilmot Cancer Center at the University of Rochester in Rochester, N.Y. The trial is being conducted under the aegis of a Lymphoma SPORE (Specialized Program of Research Excellence) award, which also includes the Arizona Cancer Center at the University of Arizona. The goal of the trial is to determine the maximum tolerable dose of these two targeted agents in patients with diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma and mantle cell lymphoma.
“The patients in our study suffer from forms of lymphoma which are resistant to conventional therapies,” says Holkova. “While it is difficult to predict how effective a new treatment will be in patients, we are excited by these recent laboratory findings and hope they will be validated in the clinic, ultimately leading to a more effective therapy for this difficult-to-treat disease.”
The full research manuscript is available online at:
In addition to Dasmahapatra and Holkova, Grant collaborated on this work with Dimitry Lembersky, M.P., and Elisa Attkisson, both from VCU Massey and VCU School of Medicine; Paul Dent, Ph.D., Universal Corporation Distinguished Professor for Cancer Cell Signaling at VCU Massey and professor and vice chair of research in the Department of Neurosurgery at the VCU School of Medicine; and Richard Fisher, M.D., and Jonathan Friedberg, M.D., from the University of Rochester.