The concept of synthetic lethality has been around for decades, but only recently has it been exploited for cancer therapy. The idea is to hit cancer cells in at least two places at once; the trick is to find the right combination of genetic mutations that make the cells vulnerable.
The newest company aiming to fight cancer with synthetic lethality is Repare Therapeutics, which today announced a $68 M Series A funding after more than 18 months in stealth. Repare can thank the early success of a class of drug called PARP inhibitors, which block an enzyme that cancer cells with specific mutations such as BRCA use to repair themselves. These drugs are an example of synthetic lethality in action. They induce a weakness in tumors that, together with the tumors’ own mutations, render them defenseless. Two of these compounds have already been approved for ovarian cancer— AstraZeneca’s olaparib (Lynparza) and Clovis Oncology’s rucaparib (Rubraca)—with others under review or in late-stage trials.
Repare, based in Boston and Montreal, is looking beyond PARP for other targets that would prevent cells from repairing their own DNA. “We’re grateful to PARPs for having proved the case,” says Repare CEO Lloyd Segal. “But we think this is just the tip of the iceberg.”
Backed by lead investors Versant Ventures and MPM Capital, Repare isn’t the only company to think this. Banking off the success of PARP inhibitors, other startups such as Cambridge, MA-based Tango Therapeutics and Ideaya Biosciences in California are also pursuing synthetic lethality for cancer drug discovery.
While PARP inhibitors hit one type of DNA polymerase, Repare is going after a different one known as POLQ (for DNA polymerase theta). In 2015, one of Repare’s scientific founders, Agnel Sfeir at the Skirball Institute of Biomolecular Medicine at NYU Langone Medical Center in New York, and her co-authors showed in a Nature paper that the POLQ gene is a crucial part of a self-repair mechanism in cells and that blocking POLQ in cells missing BRCA genes kills them. BRCA mutations are at the heart of many breast and ovarian cancers.
The approval of PARP inhibitors has set off a scramble. Repare officials hope to move faster than the competition by recreating cancer mutations in collections of cells using the CRISPR-Cas9 gene-editing system to look for lethal mutation pairs. Using patient databases and informatics tools, the team hopes to figure out how common these mutation combinations are in patient populations, to assess potential market size for the compounds that they plan to develop.
Instead of pursuing tissue-specific cancers, such as lung, breast, and colon, Segal says Repare will target tumors according to their genetic signatures. For the first time, the FDA recently approved a cancer drug, pembrolizumab (Keytruda), based on the genetic profile of the targeted cancer, and data that Loxo Oncology (NASDAQ: LOXO) released earlier this month drew attention to its drug’s ability to shrink tumors in several cancer types with shared genetic profiles. New FDA commissioner Scott Gottlieb said this week the agency would soon release new guidelines for the approval of “tumor-agnostic” cancer drugs.
Jerel Davis, a managing director at Versant who sits on Repare’s board, says the large
Series A round reflects the progress the company has made in stealth. “This is a deceptively mature company,” says Davis. Two years ago, Versant’s academic science scouters came across the work of Sfeir and the other scientific founders, Daniel Durocher and Frank Sicheri at Toronto’s Lunenfeld‐Tanenbaum Research Institute. Versant began talking to them about starting a company.
Segal says the funding will allow Repare to take two compounds into clinical trials with a goal of starting by 2019.
Other synthetic lethality companies have gotten a head start. Tango Therapeutics launched in March with $55 million after a two-year incubation period with Third Rock Ventures. Tango is also using CRISPR-based screening to find synthetically lethal cancer targets. Its founders include Alan Ashworth at the University of California, San Francisco, who discovered that inhibiting PARP could kill cancer cells with the BRCA mutation. (He was at the Institute of Cancer Research in London at the time.)
Ideaya Biosciences, split between San Francisco and San Diego, raised a $46 million Series A round last year, and one of its scientific founders is Alan D’Andrea at the Dana-Farber Cancer Institute in Boston. He published a Nature paper at the same time as Sfeir that also showed that blocking POLQ killed tumors deficient in BRCA.
Image of cancer cells by Kevin Janes of the the National Cancer Institute.