Researchers at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, have discovered why multiple myeloma, an incurable cancer of the bone marrow, ultimately and persistently escapes cure by an initially effective treatment that can keep the disease from advancing for up to several years.
A research report published online September 9 in the journal Cancer Cell, explains that the reason has been found in intrinsic resistance of the immature progenitor cells that are the disease’s root cause and subsequent relapse — according to principal investigator and article corresponding author 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. Dr Tiedemann’s lab within the Ontario Cancer Institute located at The Princess Margaret Cancer Centre is focused on the development of novel therapeutic strategies for multiple myeloma from a comprehensive understanding of myeloma tumor biology and myeloma genomics. Dr. Tiedemann discusses his team’s research in a video here:
Multiple Myeloma (MM) is a malignancy of differentiated plasma cells that and the second most prevalent blood cancer after non-Hodgkin’s lymphoma. accounting for 15% of all hematological cancer, Approximately 76,000 people in the United States and Canada are killed by multiple myeloma every year. The disease is characterized by excessive numbers of abnormal plasma cells in the bone marrow. Symptoms often include bone pain, fatigue, unusual bleeding (usually from the nose and gums), frequent infections and fevers, thirst, weight loss and nausea or vomiting. Multiple myeloma may also cause renal abnormalities and structural bone damage resulting in painful fractures. The goal of multiple myeloma treatment is to rapidly relieve symptoms, avoid complications and prolong life.
However, despite recent advances in treatment, MM remains incurable at present, and is over represented in cancer death rate. In the Cancer Cell article abstract, the researchers note that Proteasome inhibitor (PI) resistance mechanisms in MM remain controversial, but report that they have found the existence of a progenitor organization in primary multiple myeloma that recapitulates maturation stages between B cells and plasma cells, and thereby contributes to clinical PI resistance. The Xbp1s tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of multiple myeloma before the plasmablast stage enables the disease to progress during PI treatment. They note that mechanistically, suppression of Xbp1s in multiple myeloma is shown to induce resistance to the drug bortezomib via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in multiple myeloma and help explain the failure to cure multiple myeloma with currently employed therapies.
The researchers observe that Proteasome inhibitors including bortezomib and carfilzomib, are mainstay therapy of multiple myeloma treatment, and can extend survival time, but these drugs fail to cure, reporting results revealing that MM progenitor cells are untouched by the proteasome inhibitor drug “Velcade” (bortezomib), which is used to kill the plasma cells that make up most of the tumor. By blocking the proteasome, Velcade disrupts processes related to the growth and survival of cancer cells. The proteasome is a structure that exists in all cells and plays an important role in breaking down proteins that control how the cell lives and grows.
However, Dr. Tiedemann’s research team 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 Velcade, and the mechanism underlying the drug resistance that is the barrier to cure, determining that he progenitor cells tolerate XBP1 inactivation, which contributes to therapeutic resistance, allowing them to proliferate and mature to reboot the disease process after about four years, even in patients who appeared to be in complete remission, suggesting that IRE1 inhibitors may prove ineffectual in multiple myeloma, and that to achieve cure, treatment strategies must better address early MM progenitors.
“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 in a UHN 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.”
In a report, Everyday Health Staff Writer Amir Khan cites Dr. Robert Orlowski, MD, PhD, professor of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, noting that the Canadian research may help onchology clinicians better understand which patients will respond well to treatment, noting that “Patients with myeloma have these different mixtures of cell types. “The more mature ones are sensitive to treatment, the less mature are not. This means that if you can profile patient’s genes before you treat them, you can see if they have a lot of these immature cells and know that they are less likely to respond to treatment.” In the Everyday Health article, Dr. Orlowski goes on to observe that patients with myeloma are automatically started on Velcade, commenting that “Right now, we use the drug on everyone and see what happens,” but that “The problem with that is that it can take up to two months to see if it’s working, and in the meantime, you’re exposing the patient to the side effects of therapy. It also wastes their money.” Consequently, since testing for the number of immature myeloma cells is easy, if the Canadian study’s findings can be verified over a five-year period, they could amount to a major breakthrough in multiple myeloma treatment.
Velcade is approved in more than 90 countries and has been used to treat more than 300,000 patients worldwide. On June 24, 2013 Health Canada issued approval of expanded indication for Velcade in the treatment of multiple myeloma, and with this approval, Velcade is indicated as part of a medically recognized combination therapy for induction treatment of patients with previously untreated multiple myeloma who are suitable for stem cell transplantation, making it the first time this novel agent will be available for use in all front-line patients.
However, as fore-noted, in addressing the dilemma of treatment failure, the UHN researchers identified a cancer cell maturation hierarchy within multiple myeloma tumors and demonstrated the critical role of myeloma cell maturation in proteasome inhibitor sensitivity, and say the implication is clear for current drug research focused on developing new proteasome inhibitors that targeting this route alone will never cure multiple myeloma.
“If you think of multiple myeloma as a weed, says Dr. Tiedemann says in the UHN release, “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.”
Consequently, one of Dr. Tiedemann’s research interests is to define all essential and potentially ‘druggable’ survival genes required by myeloma tumor cells. He and his team are attempting to do this by conducting large-scale RNA interference genetic screens in a range of myeloma cells using pooled lentivirus libraries containing 80,000+ shRNA targeting the genome. To capture the genetic heterogeneity of myeloma tumors in our results, they are screening a panel of hypo- or hyper-diploid tumor lines bearing common t(4;14), t(11;14) or t(14;16) translocations and 13q or 17p deletions. Previously, we have used smaller scale RNA interference studies, including a 17,000 siRNA screen, to identify critical Achilles heel vulnerabilities within a portion of the genome in myeloma cells.
A second research interest is to identify molecular targets within the genome whose inhibition is what synergistically sensitizes myeloma cells to the most potent anti-myeloma drugs currently available, with the objective of developing highly synergistic drug combination strategies for patients, and to identify all genes whose loss is associated with drug protection, in order to investigate drug resistance mechanisms.
A third research goal is evaluation of critical molecular vulnerabilities within myeloma tumor cells as prospective drug targets, using various experimental models. To short-list genes for evaluation the researchers are combining various ‘omics’ datasets to determine the role of critical tumor genes in promoting myeloma development and progression and to identify molecular targets that may be selectively vulnerable in myeloma cells.
From early siRNA screens they have previously identified G-protein coupled receptor kinase 6 (GRK6) as a tumor-selective drug target in myeloma and are currently collaborating with others at UHN to develop small molecule inhibitors of this kinase for exploration as novel therapeutics.
Photos courtesy Princess Margaret Cancer Center, MD Anderson Cancer Center