Thursday, Aug. 28, 2014
While many scientists are trying to prevent the onset of a cancer defense mechanism known as autophagy, researchers at Virginia Commonwealth University Massey Cancer Center are leveraging it in a new therapy that causes the process to culminate in cell death rather than survival. The novel treatment strategy targets the p62 protein, which is often referred to as the “Trash Man” due to its role in disposing unwanted cellular proteins during autophagy. Results from preclinical experiments suggest this experimental treatment approach could be particularly effective against multiple myeloma and potentially other forms of blood cancers.
Cancer therapies cause unwanted proteins to accumulate in cancer cells, which can trigger a form of cell suicide known as apoptosis. To survive, the cells break down the excess proteins through autophagy, from a Greek term meaning “self eating.” In a study recently published in the journal Molecular and Cellular Biology, scientists induced autophagy using the anti-tumor drug obatoclax while simultaneously blocking the production of p62 using a drug known as a cyclin-dependant kinase (CDK) inhibitor. Several experiments involving animal models and cultured multiple myeloma cells demonstrated that blocking p62 disrupted autophagy and killed far more cancer cells than administering the anti-cancer agents alone.
“Therapies that are designed to block the early stages of autophagy do not offer the possibility of exploiting its potentially lethal effects,” said Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. “Our strategy turns autophagy from a protective process into a toxic one, and these results suggest it could increase the effectiveness of a variety of cancer therapies that induce autophagy.”
Critical to the success of this therapy is Bik, a protein that plays a significant role in governing cell death and survival. During cancer treatments, Bik accumulates in cancer cells until it triggers apoptosis. Normally, the cancer cells would induce autophagy and p62 would rid the cells of Bik by loading the proteins into degradation chambers known as auotophagosomes for disposal. However, blocking p62 production results in an inefficient form of autophagy and the accumulation of Bik eventually causes the cancer cells to undergo apoptosis.
This research builds upon more than a decade of work by members of Grant’s laboratory investigating novel treatment strategies and combination therapies that selectively kill multiple myeloma and other blood cancer cells. The technology in his study has been made available for licensing through the VCU Office of Research.
“We are now working to identify additional CDK inhibitors that can be used to disrupt autophagy,” Grant said. “The ultimate goal will be to translate these findings into a clinical trial to test the therapy in patients with various blood cancers.”
Grant collaborated with the study’s lead co-authors, Yun Dai, M.D., Ph.D., and Shuang Chen, M.D., Ph.D., who spearheaded this work, as well as Liang Zhou, Yu Zhang, Ph.D., Xinyan Pei, M.D., Ph.D., and Hui Lin, M.D., all from the Department of Internal Medicine at the VCU School of Medicine; Yun Leng, M.D., from the Multiple Myeloma Research Center of Beijing; and Richard Jones, Ph.D., and Robert Orlowski, M.D., from MD Anderson Cancer Center.
This research was supported by National Institutes of Health grants P50 CA142509-01, CA100866 and CA93738; the Multiple Myeloma Research Foundation; the Leukemia and Lymphoma Society of America; and, in part, by National Cancer Institute Cancer Center Core Grant P30CA016059 and Center Core Grant 5P30NS04743.
The full manuscript of this study is available online at: http://mcb.asm.org/content/early/2014/07/01/MCB.01383-13.full.pdf+html.
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 one of only 68 National Cancer Institute-designated institutions in the country that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, Massey 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 offers the most cancer clinical trials in Virginia and serves patients at 10 locations. Its 1,000-plus 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 cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information.