Toronto (Press Release) – Clinical researchers at Princess Margaret Cancer Centre have discovered why multiple myeloma, an incurable cancer of the bone marrow, persistently escapes cure by an initially effective treat­ment that can keep the disease at bay for up to several years.

The reason, explains research published online today in Cancer Cell, is intrinsic resistance found in im­ma­ture pro­gen­i­tor cells that are the root cause of the disease – and relapse – says principal investigator Dr. Rodger Tiedemann, a hematologist specializing in multiple myeloma and lym­phoma at the Princess Mar­garet, University Health Network (UHN). Dr. Tiedemann is also an Assistant Professor in the Faculty of Medi­cine, University of Toronto.

The research dem­onstrates that the pro­gen­i­tor cells are untouched by mainstay ther­apy that uses a protea­some inhibitor drug ("Velcade") to kill the plasma cells that make up most of the tumour. The 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 Dr. Tiedemann. "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.

(Dr. Tiedemann talks about his findings: http://www.youtube.com/watch?v=yy2HKCZYbBc .)

In tackling the dilemma of treat­ment failure, the researchers identified a cancer cell maturation hierarchy within multiple myeloma tumors and dem­onstrated the critical role of myeloma cell maturation in protea­some inhibitor sensitivity. The implication is clear for current drug research focused on devel­op­ing new pro­te­a­some inhibitors: targeting this route alone will never cure multiple myeloma.

Dr. Tiedemann says: "If you think of multiple myeloma as a weed, then pro­te­a­some inhibitors such as Velcade are like a persnickety 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 research team initially analyzed high-throughput screen­ing assays of 7,500 genes in multiple myeloma cells to identify effectors of drug response, and then studied bone marrow biopsies from patients to further under­stand their results. The process identified two genes (IRE1 and XBP1) that modulate response to the pro­te­a­some inhibitor Velcade and the mech­a­nism under­lying the drug resistance that is the barrier to cure.

Dr. Tiedemann is part of the latest generation of cancer researchers at UHN build­ing on the inter­na­tional legacy of Drs. James Till and the late Ernest McCulloch, who pioneered a new field of science in 1961 with their discovery that some cells ("stem cells") can self-renew repeatedly.

The science has con­tinued to ad­vance unabated ever since, and notably with key discoveries by Dr. John Dick of cancerstem cells first in leukemia and next in colon cancer.  Dr. Tiedemann's new findings under­score the clin­i­cal importance of under­stand­ing how cells are organized in the disease process.

The research was funded by the Canadian Cancer Society, the Molly and David Bloom Chair in Multiple Myeloma Research, the Arthur Macaulay Cushing Estate and The Princess Margaret Cancer Foundation.

About the Princess Margaret Cancer Centre, University Health Network

The Princess Margaret Cancer Centre has achieved an inter­na­tional reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five inter­na­tional cancer research centres, is a member of the University Health Network, which also in­cludes Toronto General Hospital, Toronto Western Hospital and Toronto Rehabilitation Institute. All are research hospitals affiliated with the University of Toronto. For more in­for­ma­tion, go to www.theprincessmargaret.ca or www.uhn.ca .

Source: The University Health Network.