Focusing on internal factors that drive genomic instability creates an opportunity to design drugs that can synergize with DNA mismatch repair, and be less harmful to healthy cells, says Degasperi. But this approach can even be used to exploit available treatments with greater precision. Indeed, copy number changes can be used as biomarkers that distinguish the efficacy of treatments in different patients, says Markowetz.
The Nature publication touches on this in the case of platinum-based chemotherapy. There, copy number changes can be used to differentiate between patients who respond to platinum chemotherapy and those who do not, explains Markowetz.
Macintyre says that some of the drug targets identified in the Nature study are novel, and relevant therapies will likely appear in the next decade. But other targets already have treatments in early development, which could potentially make early drug development more efficient, he says.
The use of copy number changes is particularly noteworthy, Macintyre says, as it can be used to identify drug targets that can work across different cancers, which differentiates it from other precision therapies that often rely on gene mutations. Those are limited by their specificity and patient population, whereas copy number changes could benefit broader blocks of patients, he explains.
Both Markowetz and Macintyre are now taking this technology to develop new treatments at the Cambridge spinoff Tailor Bio. Markowetz, who is the technology lead at the company, says it is now raising seed funds.
Given the large number of sequenced samples, the Nik-Zainal study was able to detect new signatures, many of which are rare, states Degasperi. Even if only a few of these rare mutational signatures point to an appropriate therapy for a medical condition, this could benefit some patients, he adds.
Indeed, focusing on mutational burden is very important for cancer and personalized medicine-related research, says Michael Snyder, PhD, professor of genetics at Stanford University. At the moment, high mutational burden can be used to determine response to immunotherapies. In the future, it could be used to design personalized cancer vaccines, some of which are based on very specific sequences, Snyder says. But he also says that the development of drugs utilizing such methods will lag behind use with existing treatments.
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