Scientists Devise New Strategy to Destroy Multiple Myeloma

Researchers at Virginia Commonwealth University Massey Cancer Center are reporting promising results from laboratory and animal experiments involving a new combination therapy for multiple myeloma, the second most common form of blood cancer.

The study published online in the journal Cancer Research details a dramatic increase in multiple myeloma cell death caused by a combination of the drugs obatoclax and flavopiridol. The researchers, led by Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader and member of Developmental Therapeutics and member of the Cancer Cell Signaling program at VCU Massey Cancer Center, found that the two drugs worked together through different mechanisms to promote a form of cell suicide known as apoptosis.

“There is an urgent need for curative therapies for multiple myeloma,” says Grant. “Our hope is that this research will lay the foundation for new and more effective treatments for patients with multiple myeloma and potentially other blood cancers for which adequate therapies are lacking.”

Obatoclax is an experimental agent currently being investigated in various forms of blood cancers. It works by disabling proteins that prevent cancer cells from undergoing apoptosis. Flavopiridol is a member of a class of agents known as a cyclin-dependant kinase (CDK) inhibitors, and blocks the growth of cancer cells in addition to reducing levels of anti-apoptotic proteins.

In laboratory experiments, the novel drug combination dramatically increased multiple myeloma cell death. These results were confirmed in animal models where the drugs significantly improved the survival of immune-compromised mice with human multiple myeloma. An unexpected effect was also observed – flavopiridol, in addition to reducing levels of anti-apoptotic proteins, significantly increased the expression of apoptosis-inducing proteins such as Bim, a protein shown in previous studies to trigger cell death.

“This research builds on nearly a decade of work carried out by our laboratory that focuses on manipulating mechanisms that lead to apoptosis in hematological malignancies,” says Grant. “Our findings could have immediate implications for the design of clinical trials using combinations of these types of drugs. In fact, plans to develop such a trial at Massey are currently underway.”

Because the findings showed synergism between these two classes of drugs, the researchers plan to test other clinically-relevant CDK inhibitors in combination with obatoclax for multiple myeloma.

Grant collaborated with the study’s lead co-authors, Yun Dai, M.D., Ph.D., and Shuang Chen, M.D., Ph.D., from the VCU Department of Internal Medicine, who were key contributors to this work. Other collaborators included Xinyan Pei, M.D.,  Ph.D., also from the VCU Department of Internal Medicine; Paul Dent, Ph.D., Universal Corporation distinguished professor in cancer cell signaling and member of the Developmental Therapeutics program at VCU Massey; and Robert Orlowski, Ph.D., M.D., from M.D. Anderson Cancer Center.

The full manuscript of this study can be found at: http://cancerres.aacrjournals.org/content/early/2012/06/14/0008-5472.CAN-12-1118.long

This research was supported by NIH Research Project Grant (RO1) CA100866, a Multiple Myeloma SPORE award from the National Cancer Institute, the Multiple Myeloma Research Foundation, the Leukemia and Lymphoma Society of America and, in part, by funding from VCU Massey Cancer Center's NIH-NCI Cancer Center Support Grant P30 CA016059.

About VCU and VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 226 degree and certificate programs in the arts, sciences and humanities. Sixty-seven of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University comprise VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.

About the VCU Massey Cancer Center

VCU Massey Cancer Center is among the top 4 percent of cancer centers in the country to be designated by the National Cancer Institute to lead and shape America’s cancer research efforts. Working with all kinds of cancers, Massey conducts every form of cancer research, including basic science, translational, clinical and population sciences research; provides state-of-the-art cancer treatments and cutting-edge clinical trials; serves as a vital resource for oncology education, teaching and training; and promotes cancer prevention. Since 1974, Massey has been an internationally recognized center of excellence. Massey provides award-winning cancer care at multiple sites throughout Virginia by leading cancer sub-specialists and offers one of the largest selections of cancer clinical trials as well as a statewide network that brings trials to communities across the commonwealth. Its 1,000-plus researchers, clinicians and staff members are dedicated to improving the quality of human life by discovering, developing, delivering and teaching effective means to prevent, detect, treat and ultimately cure cancer. Visit Massey online atmasseycancercenter.org masseycancercenter.org or call 877-4-MASSEY for more information.

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Steven Grant, M.D.
Steven Grant, M.D.