Huntsman Cancer Institute Myeloma Program

Team of researchers comes to HCI to identify genes that make treating multiple myeloma a challenge

A team of scientists and research technicians led by Fenghuang Zhan, MD, PhD, have joined the Myeloma Program at Huntsman Cancer Institute directed by Dr. Guido Tricot. The major aim of their research is to identify the genes that make some myeloma cells resistant to chemotherapy. Their research could have a significant impact on the survival rates and quality of life of both newly diagnosed and relapsed multiple myeloma patients.

The myeloma researchers will utilize a powerful tool called gene expression profiling in their studies. Gene expression profiling, also known as microarray analysis, is a technique that enables scientists to measure the activity of thousands of genes in a single RNA sample all at once, which can reveal how a person’s myeloma cells are reacting to treatment.

The pioneering work of Zhan and his colleagues has already led to significant discoveries in the field of myeloma with respect to understanding the biology and genetics of this type of cancer. In 2002 after studying the bone marrow plasma cells of 74 newly diagnosed multiple myeloma patients, 5 patients with monoclonal gammopathy of undetermined significance, and 31 healthy volunteers, Zhan demonstrated how distinctly different multiple myeloma plasma cells are from normal plasma cells. He identified four distinct subgroups of myeloma plasma cells, setting the framework for a new classification system that identifies the genetic differences between these subgroups.

In 2003, Dr. Zhan and his colleagues demonstrated the role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma and published their results in the New England Journal of Medicine.

In 2005, Zhan published the results of his study that identified how the dysregulation of a type of gene known as the cyclin D gene can be responsible for transforming normal plasma cells into myeloma tumor cells.

Recently, a genetic analysis of more than 400 newly diagnosed patients with multiple myeloma identified seven subtypes of the disease that had a bearing on a patient’s prognosis and offered the potential for targeted treatments. The article on this study, “The molecular classification of multiple myeloma,” was published in the Sept. 15, 2006, issue of Blood.

Using purified myeloma cells taken from 532 newly diagnosed patients, Dr. Zhan and his colleagues screened more than 54,000 gene expression tags found in the human genome. The researchers have determined that the activity of as few as 17 genes of the more than 25,000 analyzed could determine if a patient had a high or low probability of early death due to their illness. About 13 percent of all the patients they studied fit into the high-risk category. The gene expression–based high-risk signature may guide therapeutic interventions. These results were also published in Blood 2007 and 2008.

In addition to gene expression microarrays, Dr. Zhan and his team are using new technologies such as RNA interference and lentivirus vectors to knock down or over-express high-risk disease related genes in myeloma cells in order to investigate if these genes influence tumor growth or relate to drug sensitivity in vitro and in vivo.

Zhan and his team will continue to try to establish correlations between genetic abnormalities in myeloma patients and the outcome of their disease. In his current study, the team is comparing the gene expression profiles of myeloma patients who have not yet started treatment to their gene expression profile at the time their disease comes back after treatment and at the time when they are identified as having minimal disease.

The team will use this data to identify the genes that are making the myeloma cells resistant to treatment. Once identified, these genes can be targeted and their function can be blocked so that therapeutic regimens can be more effective.

Gene expression profiling is a powerful tool in molecular biology today and will lead to more customized and individualized methods of treatment for various groups of multiple myeloma patients.

MORE ABOUT FENGHUANG ZHAN, MD, PHD

Fenghuang Zhan received his MD and PhD at Hunan Medical University in China. He did postdoctoral fellowships at the University of Louisville in Kentucky and the Myeloma Institute for Research and Therapy in Arkansas. Now he is an associate professor in the University of Utah.

Selected Publications:

Zhan F, Barlogie B, Mulligan G, Shaughnessy Jr. J, and Bryant B. A Gene Expression-Based Risk Stratification Model for Newly Diagnosed Multiple Myeloma Treated with High Dose Therapy Is Predictive of Outcome in Relapsed Disease Treated with Single Agent Bortezomib. Blood, 2008;111 (2): 968.

Xiong W, Shaughnessy Jr. J, Wu X, Starnes S, Johnson SK, Haessler J, Wang S, Chen L, Barlogie B, and Zhan F. An Analysis of the Clinical and Biological Significance of TP53 Loss in Multiple Myeloma and the Identification of Potential Novel Transcriptional Targets of TP53. Blood, 2008 Mar 13.

Zhan F, Colla S, Wu X, Chen B, Stewart JP, Kuehl WM, Barlogie B, Shaughnessy JD Jr. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood. 2007;109(11):4995.

Shaughnessy Jr JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, Stewart JP, Kordsmeier B, Randolph C, Williams DR, Xiao Y, Xu H, Epstein J, Anaissie E, Krishna SG, Cottler-Fox M, Hollmig K, Mohiuddin A, Pineda-Roman M, Tricot G, van Rhee F, Sawyer J, Alsayed Y, Walker R, Zangari M, Crowley J, Barlogie B. Deregulated Expression of Chromosome 1 Genes Defines High-Risk Multiple Myeloma. Blood, 2007;109(6):2276.

Zhan F, Barlogie B, Arzoumanian V, Huang Y, Dhodapkar M and Shaughnessy Jr. J. A gene expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood 2007 ;109(4):1692.

Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, Epstein J, Yaccoby S, Sawyer J, Burington B, Hollmig K, Pineda-Roman M, Tricot G, van Rhee F, Walker R, Zangari M, Crowley J, Barlogie B, Shaughnessy Jr JD. The molecular classification of multiple myeloma. Blood. 2006 Sep 15;108(6):2020.