Patients with myeloma could benefit from ‘designer’ drugs in the future after new genome-mapping technology has allowed scientists to identify a full genetic blueprint of the mutations which drive the bone marrow cancer.
In the largest study of its kind, US scientists at the Broad Institute and Dana-Farber Cancer Institute used ‘next generation sequencing’ to map the cancer cell genomes of 38 patients with myeloma, comparing them with their normal genomes.
The research, published in the journal Nature, showed that a small proportion of patients with myeloma, which is currently incurable, could benefit from a highly promising existing drug actually designed to fight skin cancer.
Given the duration, complexity and cost of the standard genome sequencing process, it has been rare to sequence the cancer genome of more than one patient. As a result, some of our understanding of various cancer genomes has been based on single or low numbers of individuals. While valuable, the difficulty of looking at single cases has been that it is not clear which mutations are unique to that individual and which represent real ‘targets’ for cancer drugs.
Myeloma is a cancer which affects the plasma cells, the cells in the immune system which normally produce antibodies to fight infections. It is a relatively common cancer that causes many complications, including kidney failure, anaemia and multiple painful bone fractures. Although the outlook has been improved by new treatments in recent years, 60% of patients die within five years of diagnosis.
The study, led by Dr Mike Chapman, who was funded by UK charity Leukaemia & Lymphoma Research, was able to gain unexpected insights into myeloma by using next generation sequencing. Notably, nearly half of patients with myeloma were found to have mutations in genes that control two fundamental cellular processes: how RNA is processed and proteins are folded. Two of these genes, DIS3 and FAM46C, appear to play important roles in the stability of RNA and hence its translation into protein. Researchers also found genes involved in blood clotting mutated in myeloma patients, a new and surprising discovery.
Understanding of the exact genes involved offers a significant opportunity to develop ‘designer’ anti-myeloma drugs, to target these mutated protein processing genes in certain patients.
Dr Chapman said: “Like other cancers, myeloma develops as a result of gene mutations – mistakes in the blueprints for constructing the proteins of the cell. While traditional methods for discovering these mutations have been laborious, slow and required prior clues as to which genes were involved, we have been able to completely map the myeloma genome, throwing up some entirely unexpected genetic pathways which can be targeted by new drugs.”
A significant advance from the study was the discovery that some myeloma patients have very specific mutations in the ‘BRAF’ gene, which had not formerly been associated with myeloma. Individually this mutation is fairly uncommon and might have remained undiscovered had the researchers not looked at such a large collection of patient samples. When the scientists looked at a further 150 patients with myeloma specifically for mutations in the BRAF gene, they found mutations in 4% of cases.
The BRAF mutation was known to be also connected to melanoma and there is an existing drug designed to target it, PLX4032, which is showing huge promise in clinical trials for skin cancer patients. The researchers argue that new trials of this drug in myeloma patients with the relevant mutations should be an urgent priority.
Dr David Grant, Scientific Director at Leukaemia & Lymphoma Research, said: “New treatments are desperately needed to improve the outlook of patients with myeloma. It’s becoming easier to create targeted ‘designer’ drugs to fight cancer, but to design these drugs it’s necessary to understand the mechanisms by which the disease arises. This research gives incredibly valuable and previously unknown insights into the myeloma genome, which will lead to new avenues for the creation of life-saving drugs.”