Multiple myeloma is a cancer involving antibody-producing cells in the bone marrow, and, in most cases, is incurable. Targeted therapies work by interfering with biological and biochemical functions critical for cancer cell survival and proliferation.
The new treatment strategy from VCU Massey combines Src inhibitors, which block the activity of an important group of proteins that regulate cancer cell behavior, with Chk1 inhibitors, which interfere with cancer cells' ability to undergo cell cycle arrest and repair DNA damage.
"Chk1 inhibitors are currently used primarily in conjunction with conventional DNA-damaging chemotherapeutic agents," says the study's lead investigator Steven Grant, M.D., associate director for translational research, Shirley Carter and Sture Gordon Olsson Chair in Oncology Research and professor of internal medicine at VCU Massey Cancer Center. "By combining Chk1 inhibitors with another targeted agent, such as Src inhibitors, we were able to induce cell death in multiple myeloma cells while sparing healthy, normal cells."
When multiple myeloma cells are subjected to DNA-damaging agents, or even when they are undergoing normal DNA replication, their DNA is subject to breakage. To survive, they must slow down their progression through the cell cycle in order to repair the DNA, or, if the damage is too severe, undergo a form of cell suicide.
Chk1 is an enzyme that allows cells to undergo cell cycle arrest, a process required to repair the DNA damage. When cancer cells are exposed to Chk1 inhibitors, they experience DNA damage and, as a consequence, launch another defense mechanism by activating a protein known as ERK1/2.
"The activation of ERK1/2 explains why multiple myeloma cells are able to survive the lethal effects of Chk1 inhibitors," says Grant. "Therefore, we used Src inhibitors to block the activation of ERK1/2." The results were more promising than even the researchers had hoped.
Grant's team discovered that Src inhibitors not only blocked ERK1/2 activation, but also synergized with Chk1 inhibitors to trigger a dramatic increase in cell death. In addition, the combined treatment greatly reduced blood vessel formation, which plays an important role in the maintenance of many tumors, including multiple myeloma. Significantly, the treatment exerted virtually no effects on healthy, normal cells.
"We found tumors treated with the combined regimen were noticeably smaller and showed signs of a lack of blood supply when compared to tumors from the control group or those treated only with Chk1 inhibitors," says Grant. "This study is not only the first to demonstrate that Src inhibitors can dramatically increase the effects of Chk1 inhibitors, but it is also the first to show that preventing blood vessel formation may contribute to the effectiveness of this combination strategy."
This study builds upon more than seven years of research by Grant's team investigating cell signaling in relation to DNA damage repair and survival pathways involving Src and ERK1/2 proteins. The researchers are now developing more complex experiments as a prelude to clinical trials in multiple myeloma patients. "We're hopeful the approach of combining targeted agents will open up the possibility of developing entirely new therapies for patients with multiple myeloma and potentially other blood cancers," says Grant.
Co-investigators included the study's first author, Yun Dai, M.D., Ph.D., Shuang Chen, M.D., Ph.D., and Xinyan Pei, M.D., all from the VCU Department of Internal Medicine; and Paul Dent, Ph.D., Universal Distinguished Professor in Cancer Cell Signaling at VCU Massey. Funding for the study was provided by grants from the National Cancer Institute, the Multiple Myeloma Foundation, the V Foundation for Cancer Research and a Specialized Programs of Research Excellent (SPORE) award.
The full journal article is available online at: http://bloodjournal.hematologylibrary.org/cgi/content/short/blood-2010-06-291146v1.
About VCU Massey Cancer Center
VCU Massey Cancer Center is one of only 66 National Cancer Institute-designated institutions in the country that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information.
About VCU and the VCU Medical Center
Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 32,000 students in 211 certificate and degree programs in the arts, sciences and humanities. Sixty-nine 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 compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.
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