Researchers have identified 116 genes as key molecular vulnerabilities for multiple myeloma, according to a novel study published by de Matos Simoes et al in Nature Cancer. The findings demonstrated the potential for these genes to act as leads and help researchers discover new therapeutic options for patients with the disease.
For nearly 20 years, the predominant approach to finding candidate therapeutic targets in multiple myeloma and other cancers has started with a search for mutated or overexpressed genes associated with the cancer type compared with its respective normal cells. These techniques have led to targeted cancer therapies that have benefited many patients.
Study Methods and Results
In the new study, the researchers sought to identify the distinct functional vulnerabilities that distinguish multiple myeloma from other cancer types without the need for mutations or alterations. The researchers analyzed cell lines from multiple myeloma and a large collection of non–multiple myeloma tumor types to identify the new leads. Using clustered regularly interspaced short palindromic repeats (CRISPR) to disable genes one by one in each cell line, they identified genes that may be essential for the survival of the multiple myeloma cells but much less important for cancer cells from other lineages.
The researchers then relied on several analytical tools to narrow down the list of the genes that are preferentially essential for multiple myeloma cells. The list included genes responsible for producing molecules that control which genes are activated or how proteins are secreted in plasma cells, and many other genes not previously considered important for the biology of multiple myeloma or most other cancers. The researchers also validated the large majority of these genes in animal models.
Therapeutics that target molecules that are preferentially essential for multiple myeloma but not for most other cancer types might have another advantage. They could also be less likely to harm the normal tissues that correspond with other cancer types. The researchers stressed that this could mean patients may have a lower risk of experiencing serious side effects. Further, they may be effective at treating many patients with multiple myeloma because their tumor cells do not need have to have a certain mutation in order to respond to such treatments.
“This study emphasizes how selectively critical a gene is for myeloma cells,” explained senior study author Constantine Mitsiades, MD, PhD, Associate Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute. “If turning off a gene causes important damage in multiple myeloma cells, but not all or most other cell types, we’ve found something important,” he added.
This approach to discovery of new therapeutic targets identified an almost completely new and unique set of potential multiple myeloma cell vulnerabilities compared with those discovered in previous studies. For instance, of the 116 genes identified, only a few of them had been found in earlier studies looking for mutations or alterations that contribute to multiple myeloma.
“It’s a shift in thinking about targeted therapies for a given cancer. Instead of targeting the genes that are mutated more frequently or expressed at higher levels, we’re thinking about molecular targets that are more functionally important for this specific cancer type,” Dr. Mitsiades emphasized.
Conclusions
A few of the genes that the researchers identified were already known therapeutic targets for multiple myeloma. For example, the multiple myeloma drug thalidomide—as well as drugs derived from it—is capable of degrading proteins made by the genes IKZF3 and IKZF1, a discovery made 10 years ago. These two genes showed up on the researchers’ list.
“It was reassuring that molecules that are already known as important therapeutic targets for multiple myeloma and not for most other cancers came up as preferential targets for [multiple] myeloma in our studies,” Dr. Mitsiades highlighted. “It strongly supports the value of the other leads we identified,” he underscored.
While the researchers pointed to a range of potential targets for multiple myeloma therapies, they also suggested a different approach to targeted therapy in general—one in which treatment takes aim at the unique functional vulnerabilities that distinguish an individual type of cancer from all others, regardless of whether these vulnerabilities are caused by genetic mutations.
“It’s very exciting to find so many new and underappreciated candidate targets. We are actively working to determine which of these can be targeted by new therapeutic interventions for multiple myeloma,” Dr. Mitsiades concluded.
Disclosure: The research in this study was supported by the National Institutes of Health, the de Gunzburg Myeloma Research Fund, the Leukemia and Lymphoma Society, the Multiple Myeloma Research Foundation, the Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research, the Cobb Family Myeloma Research Fund, the International Waldenstrom’s Macroglobulinemia Foundation, the U.S. Department of Defense, the International Myeloma Foundation, the American-Australian Association, the Associazione Italiana per la Ricerca sul Cancro, and the Claudia Adams Barr Program in Innovative Basic Cancer Research at the Dana-Farber Cancer Institute. For full disclosures of the study authors, visit nature.com.
