Findings provide insights for new, targeted cancer ther­a­pies in clin­i­cal trials

Scottsdale, AZ (Press Release) - Researchers have discovered why multiple myeloma, a dif­fi­cult to cure cancer of the bone marrow, frequently recurs after an initially effective treat­ment that can keep the disease at bay for up to several years.

Working in col­lab­o­ration with colleagues at Princess Margaret Cancer Centre in Toronto, researchers from Mayo Clinic in Arizonaand the Translational Genomics Research Institute (TGen) in Phoenix were part of the team that conducted the study published in the Sept. 9 issue of Cancer Cell.

The research team initially analyzed 7,500 genes in multiple myeloma cells to identify genes which when suppressed made cancer cells resistant to a common class of drugs called pro­te­a­some inhibitors such as bor­tez­o­mib or car­filz­o­mib. Then, the team studied bone marrow biopsies from patients to further under­stand their results. The process identified two genes (IRE1 and XBP1) that control response to the pro­te­a­some inhibitor and the mech­a­nism under­lying the drug resistance that is the barrier to cure.

The findings showed recurrence was due to an intrinsic resistance found in immature tumor progenitor (mother) cells is the root cause of the disease and also spawns relapse. The research dem­onstrates that although the visible cancer cells that make up most of the tumor are sensitive to the pro­te­a­some inhibitor drug, the under­lying progenitor cells are untouched by this ther­apy. These progenitor cells then proliferate and mature to reboot the disease process, even in patients who appeared to be in com­plete remission.

"Our findings reveal a way forward to­ward a cure for multiple myeloma, which involves targeting both the progenitor cells and the plasma cells at the same time," says Rodger Tiedemann, M.D., a hematologist specializing in multiple myeloma and lym­phoma at Princess Margaret and lead investigator of the study. "Now that we know that progenitor cells persist and lead to relapse after treat­ment, we can move quickly into clin­i­cal trials, measure this residual disease in patients, and attempt to target it with new drugs or with drugs that may already exist."

"Some myeloma cells are too immature to be caught by the drugs and thus hide underground only to reemerge later," says Keith Stewart, M.B., Ch.B., Dean for Research at Mayo Clinic in Arizona and contributor to the study. "This study has wide implications in the search for a cure of this common blood cancer as this 'progenitor cell' will have to be targeted."

Jonathan Keats, Ph.D., head of TGen's Multiple Myeloma Research Laboratory, said: "This study, which leverages data generated at TGen as part of the Multiple Myeloma Genomics Initiative, shows how mutations acquired by multiple myeloma tumors can make a tumor resistant to specific ther­a­pies and highlights the importance of TGen's precision medicine ap­proaches."

Dr. Tiedemann says: "If you think of multiple myeloma as a weed, then pro­te­a­some inhibitors are like a goat that eats the mature foliage above ground, producing a remission, but doesn't eat the roots, so that one day the weed returns."

The study — Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma — was funded by the National Cancer Institute, Multiple Myeloma Research Foundation, Leukemia and Lymphoma Society and Canadian Cancer Society, the Arthur Macaulay Cushing Estate and The Princess Margaret Cancer Foundation

Dr. Tiedeman is the Molly and David Bloom Chair in Multiple Myeloma Research, at the University of Toronto, Dr. Stewart is the Anna Maria and Vasek Pollack Professor of Cancer Research at Mayo Clinic. Dr. Keats is an Assistant Professor in TGen's Integrated Cancer Genomics Division.

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research to­wards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Work­ing with col­lab­o­rators in the scientific and medical communities literally world­wide, TGen makes a sub­stan­tial con­tri­bu­tion to help our patients through efficiency and effectiveness of the translational process. For more in­for­ma­tion, visit:http://www.tgen.org.

About Mayo Clinic

Mayo Clinic is a nonprofit world­wide leader in medical care, research and education for people from all walks of life. For more in­for­ma­tion, visit MayoClinic.com or MayoClinic.org/news.

Source: Mayo Clinic.