Our multiple myeloma research
Our researchers have collaborated internationally with many other research groups to study various areas of multiple myeloma including its mechanisms and new therapies using different targets. The Bone Biology Lab lead by Prof Peter Croucher along with the Intravital Microscopy Lab lead by A/Prof Tri Phan have been the key drivers in multiple myeloma research at the Garvan.
We have studied dormant multiple myeloma cells which are responsible for causing relapses to discover what causes their reactivation and the genes that are responsible for this behaviour. We have also looked in to why bone gets broken down when they are affected by multiple myeloma leading to easily fractured bones and possible treatments to prevent this as well as encourage bone growth.
Another key area is finding new targets to aim for in the development of novel therapies for multiple myeloma.
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Key areas of investigation
Dormant cell awakening and targeting
Dormant cells in multiple myeloma and other cancers are able to hide within the body and come back later to cause a relapse after treatment. Our research in this area first looked at how dormant myeloma cells are reactivated within the body and found that osteoclasts are one of the main causes. Osteoclasts are special bone cells that are responsible for breaking down bone ready for remodelling and can be overactive in brittle bone diseases. We were also able to show that melphalan, a chemotherapy used for multiple myeloma, increased osteoclast formation which in turn activated dormant myeloma cells.
Further research revealed certain genes in the dormant cells that were “switched off” in active myeloma cells. It was also shown that when the myeloma cells were in contact with osteoblast (bone forming) cells, these genes were “switched on” inducing dormancy. Knowing which genes are active in the dormant state is incredibly useful when developing new treatments. A treatment targeted towards those active genes could be developed to eradicate dormant myeloma cells along with the active myeloma cells, decreasing the possibility of a relapse in the future.
Rebuilding and strengthening bones in multiple myeloma
Bone pain and frequent fractures are symptoms of those with multiple myeloma caused by the increased breakdown of bone compared to bone formation. Treatments for multiple myeloma called bisphosphonates stop this bone loss from occurring but do not encourage bone regrowth leaving the patient constantly at risk for new fractures.
Garvan researchers showed that using antibodies to target sclerostin, a protein that aids bone breakdown by pausing bone formation, increased bone growth making them stronger. Furthermore, this anti-sclerostin treatment can be combined with bisphosphonates for an even better result in bone regrowth and strength. This treatment has the potential to improve the quality of life and reduce the mortality rate of those with multiple myeloma.
Discovering potential targets for treatment
Targeted treatments with greater specificity can increase the efficiency of the treatment while decreasing unnecessary damage to other parts of the body. Researchers at the Garvan have highlighted some potential targets for multiple myeloma.
One of these targets is the chemokine receptor CCR1 which is regulated by hypoxia-inducible factor 2alpha (HIF-2alpha). HIF-2alpha encourages the distribution of myeloma cells within the body by increasing the expression of CCR1 in these cells. It was found that patients who had multiple myeloma with increased CCR1 expression generally had a poorer prognosis and had increased numbers of myeloma cells in circulation. Targeting and inhibiting CCR1 in multiple myeloma may prevent the dissemination of myeloma cells, therefore reducing the spread of the disease and lowering the risk of a future relapse.
Another target that has been studied are special macrophages called CD169+ macrophages which reside in the bone marrow. The role of CD169+ macrophages is still unclear, but they have been implicated in the progression of multiple myeloma as well as in resistance to therapies. A/Prof Croucher, in collaboration with various researchers from the University of Adelaide and South Australian Health and Medical Research Institute, was able to show that using clodronate-liposome to deplete CD169+ macrophages suppressed myeloma progression and reduced the number of tumour cells in mice models with multiple myeloma. This shows that targeting CD169+ macrophages in multiple myeloma has great potential in future treatments.