Synthetic Lethality: A whole new way to develop drugs
A personalized therapy targets the molecular mechanism behind a specific kind of tumor.
MIT Technology Review, June 29, 2009, by Jocelyn Rice — A drug tailor-made to strike at a tumor cell’s Achilles heel shrinks or stabilizes tumors in patients with certain treatment-resistant hereditary cancers while causing few side effects. The results of the early-stage trial were published online today in the New England Journal of Medicine.
The drug, called olaparib, is the first success story from a new and highly personalized approach to anticancer drug development. This strategy harnesses a concept known as synthetic lethality, in which a drug is designed to work in tandem with the molecular glitch underlying a specific kind of cancer.
“It’s a whole new way to develop drugs,” says J. Dirk Iglehart, a professor of women’s cancers and surgery at Brigham and Women’s Hospital, in Boston, and coauthor of an editorial accompanying the paper. Iglehart was not involved in the study.
While existing chemotherapeutic agents may take advantage of synthetic lethality to some degree, they do so by accident rather than by design, says Daniel P. Silver, an assistant professor of cancer biology at the Dana-Farber Cancer Institute and coauthor of the editorial. “It’s a particularly elegant idea,” says Silver. “I do think that this will become an important methodology among many for developing cancer drugs.”
A small percentage of breast, ovarian, and prostate cancers are associated with defects in one copy of the BRCA1 or BRCA2 gene, which encode proteins that help proofread the genome during replication. If a BRCA-mutated cell happens to lose its one functional copy of the gene, proofreading is impaired, and mutations begin to accumulate as the cell divides. These mutations can cause a multitude of other cell processes to go awry, opening the door to tumor development.
Because there are several mechanisms for DNA repair, the loss of BRCA function doesn’t completely incapacitate a cell. But it does create a weakness not present in normal cells, which still carry a working copy of the BRCA gene. Olaparib targets that weakness by inhibiting an enzyme involved in another DNA proofreading pathway, generating a lethal double whammy to the cancer cell’s DNA while sparing healthy cells.
Of 19 patients with BRCA-associated cancer treated by olaparib in the trial, 12 experienced substantial and lasting stabilization or shrinkage of their tumors. “[The drug] was given as a single agent to treatment-resistant advanced cancers–these cancers shouldn’t respond to a piddly little enzyme inhibitor,” says Iglehart. “So the fact that it was so effective was very exciting to people.”
The drug’s specificity means that unlike conventional chemotherapy drugs, which are toxic to normal cells and cancer cells alike, olaparib causes remarkably few side effects. “Compared to chemotherapy, this drug’s a breeze,” says Johann de Bono, a medical oncologist at the Institute of Cancer Research, in Sutton, England, who is co-leading the trial. “It’s like taking Tylenol twice a day.”
But the drug’s highly targeted nature also means that it’s only effective in patients whose cancer results from a BRCA1 or BRCA2 mutation. For now, the trial’s success serves as a proof of concept that synthetic lethality offers a promising strategy for anticancer drug development. By leveraging an understanding of the molecular basis for different kinds of cancers, researchers can begin to design a panoply of personalized therapies. And the researchers believe that olaparib’s benefits may extend to other cancers characterized by defects in DNA repair.
The BRCA genes are classic examples of tumor suppressors–genes that, when absent or dysfunctional, set the stage for tumors to proliferate. Traditionally, researchers have struggled to find treatments that target tumor suppressors because it’s difficult to restore a cellular function that’s gone missing. “That has been a great problem in cancer-drug development,” says Iglehart.
Synthetic lethality offers an alternate therapeutic route to those genes. “This trial is the first time that hypothesis was tested in people,” says Iglehart. “That’s why it’s so interesting–nobody had ever developed a drug based against a tumor-suppressor gene using this concept of synthetic lethality. And they tested it in humans, and lo and behold, it worked just exactly the way you would expect it to work.”