Massey researchers first to show that a specific protein inhibitor successfully kills multiple myeloma tumor cells
Cyclin-dependent kinase inhibitor 7 (CDK7) is a protein that regulates cell cycle progression. However, it also plays a key role in controlling transcription of three genes that help tumor cells proliferate and survive in patients with multiple myeloma, a form of plasma cell cancer.
Researchers at VCU Massey Cancer Center, led by principal investigator Steven Grant, M.D., and supported in part by grants from the National Cancer Institute, found that a CDK7 inhibitor, THZ1, effectively reduced and suppressed the transcription of the three genes — MCL-1, BCL-xL, and c-Myc — and potently led to induction of tumor cell death, or apoptosis.
In the study, published in July in the journal Clinical Cancer Research, THZ1 showed activity against primary patient-derived multiple myeloma cells and was effective in animal models of multiple myeloma. THZ1 also significantly increased the activity of several approved agents used in the treatment of multiple myeloma, such as proteasome inhibitors. Myeloma cells produce several proteins that are not useful to the body, but which can promote myeloma cell survival. By blocking the transcription of genes encoding these proteins, agents such as THZ1 can promote myeloma cell death.
The Massey study is the first to demonstrate the activity of CDK7 inhibitors in multiple myeloma and show that THZ1 is active in animal models while enhancing the activity of approved anti-myeloma agents, such as proteasome inhibiters.
The results may serve as a basis for including inhibitors in the toolkit of multiple myeloma therapies. Indeed, efforts are underway at Massey to develop a clinical protocol combining a clinically relevant CDK7 inhibitor with an approved proteasome inhibitor for patients with relapsed and refractory multiple myeloma.
"These findings lay the foundation for developing a novel therapeutic approach involving CDK7 inhibitors for the treatment of patients with multiple myeloma who are resistant to currently available therapies," said Grant, the Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, co-leader and member of the Developmental Therapeutics research program at Massey and a professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.
Multiple myeloma and other plasma cell cancers are diseases in which the body makes too many plasma cells. Plasma cells develop from B lymphocytes (B cells), a type of white blood cell made in bone marrow.
Normally, when bacteria or viruses enter the body, some B cells convert to plasma cells. The plasma cells make specific antibodies to fight each type of bacteria or virus that enters the body, helping stop infection and disease.
Plasma cell neoplasms are diseases in which too many plasma cells, or myeloma cells, are produced that are unable to function normally in the bone marrow. In patients with multiple myeloma, these cells accumulate in the bone marrow, forming tumors in multiple bones of the body and preventing bone marrow from producing healthy blood cells.
In addition to Grant, the study was co-authored by Yu Zhang, laboratory manager in the Department of Internal Medicine at the VCU School of Medicine. Additional contributors include Liang Zhou, instructor in the VCU Department of Internal Medicine; Dipankar Bandyopadhyay, Ph.D., director of the Biostatistics Shared Resource and member of the Cancer Prevention and Control research program at Massey as well as professor in the VCU Department of Biostatistics; Kanika Sharma, science technician in the VCU Department of Internal Medicine; Alexander Joseph Allen from the VCU Division of Hematology, Oncology and Palliative Care; and Maciej Kmieciak, Ph.D., from the VCU Department of Microbiology and Immunology.
This study was supported by awards CA205607 and UH2TR001373 (SG) from the National Cancer Institute and R6508-18 from the Leukemia and Lymphoma Society. Services and products in support of the research project were generated by the Virginia Commonwealth University Cancer Mouse Models Core Laboratory, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.