A team of researchers at Princess Margaret Cancer Centre have determined that the intrinsic resistance found in progenitor cells, which initially cause multiple myeloma, could also be the reason the resistance can eventually overcome the effects of treatment.
The results, published in the Cancer Cell (2013:24;289-304), show that in patients with multiple myeloma, progenitor cells remain untouched by the proteasome-inhibitor drugs (such as bortezomib) used to kill the plasma cells that make up most of the tumor. The data also show that those progenitor cells can eventually proliferate and reboot the disease, even in patients who appear 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,” the principal investigator, Rodger Tiedemann, MD, PhD, a hematologist at Princess Margaret, said in a news release.
“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.”
He and his colleagues (first author was Chungyee Leung-Hagesteijn, MSc) analyzed high-throughput screening assays of 7,500 genes in myeloma cells to identify effectors of drug response—and then studied bone marrow biopsies from patients to further understand the results. Two genes (IRE1 and XBP1) were identified that modulate response to bortezomib and ultimately cause myeloma tumor cells to become resistant to such therapy.
RODGER TIEDMANN, MD, PHD
Tiedemann further explained via email: “IRE1-XBP1 signaling acts to protect cells from endoplasmic reticulum stress, which can be very severe in professional secretory cells such as plasma cells (the principal cell type found in multiple myeloma tumors). We found, however, that IRE1-XBP1 signaling in myeloma cells actually promoted bortezomib-induced cell death, whereas suppression of this pathway rescued myeloma cells—the exact opposite of what might have been predicted.
“Further data showed that a second function of IRE1-XBP1 signaling was to promote the maturation of B cells to plasma cells. We found that XBP1s-negative cells lack secretory maturation and produce less immunoglobulin—and are therefore less dependent on the proteasome to help manage endoplasmic reticulum stress, rendering them less susceptible to proteasome inhibition. We then demonstrated the existence of XBP1s-negative tumor progenitor subpopulations in bone marrow samples from multiple myeloma patients, which confirmed that these cells preferentially survive clinical bortezomib treatment. These cells—in a sense—represent a previously unrecognized pool of minimal residual disease in multiple myeloma patients.”
The persistence of the tumor progenitor subpopulation accounts for the failure to cure multiple myeloma with proteasome inhibitor-based treatment strategies, even if complete response is attained within the plasma cell compartment, the authors concluded in the paper.
And, said Tiedmann, “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.”