NEW YORK (Reuters Health) Sep 17 - Multiple myeloma responds to current drug treatments, but can't yet be cured, and new findings published in Cancer Cell may explain why.
Proteasome inhibitors (PIs) such as bortezomib (Velcade) target the most mature multiple myeloma cell populations, but don't get at the less-mature, harder to identify progenitor cells, Dr. Rodger Tiedemann told Reuters Health. "These drugs work well to suppress the bulk of the tumor cells, but fail to get at the roots of the disease," he said in an interview.
In studies of multiple myeloma cell lines and bone marrow extracted from patients, Dr. Tiedemann of the Princess Margaret Cancer Centre in Toronto and his team showed the existence of tumor B cells and pre-plasmablast progenitors that lacked expression of the XBP1 gene. These progenitor cells survived PI exposure because they had not yet matured into immunoglobulin-secreting plasma cells, which are vulnerable to PIs.
The work suggested that the tumor progenitor cells were less dependent than secretory plasma cells on proteasome activity to manage stress developed during immunoglobulin production, rendering them less responsive to PI.
"What's clear is that these progenitor cells have many of the same genetic hallmarks of the later-stage tumor cells," Dr. Tiedemann explained. "They have a potential to become mature tumor cells via the normal B cell maturation pathway and therefore to cause relapse of clinical disease. We need to work out what's involved in regulating that maturation process."
While some of the progenitor B cells are CD20 positive, meaning they could be targeted with rituximab, others including pre-plasmablasts are CD20 negative, the researcher noted. "It seems that we are going to have to target a spectrum of tumor cells of different phenotypes to achieve a really deep response," he said.
Dr. Tiedemann and his colleagues are now conducting drug screening and RNA interference studies to identify strategies for targeting the progenitor cells. Because they have figured out how to identify these cells, he noted, it will now be possible to measure the effectiveness of future treatments against progenitor cell residual disease in patients. "That will allow us to move more rapidly forward with clinical studies," he said
SOURCE: http://bit.ly/1emD46Q
Cancer Cell 2013.
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