Taking a decades-old treatment concept in cancer and enabling it for the 21st century
CEO: Lloyd Segal
Clinical focus: Oncology
The scoop: Repare Therapeutics has the ambitious aim of putting a very old and tantalizing cancer treatment theory—which has largely eluded any attempt to be harnessed by the drug industry—into practice. The concept of synthetic lethality rests on the premise that there is an interaction between two or more genes that can cause cell death, but only when both are inactivated. That means a cancer cell can survive if it has a mutation in either gene alone, but if the activity of the other is blocked using a drug it will die, leaving normal cells unaffected. It’s a compelling idea and one that has already attracted an investment from cancer heavyweight Celgene.
What makes Repare Fierce: The first big publications that revealed the promise of synthetic lethality as a cancer treatment were published around the turn of the millennium, but the tools to explore the relationship between pairs of genes amongst many thousands in biological samples were lacking, according to President and CEO Lloyd Segal. That all changed with the emergence of gene-editing tool CRISPR, which he notes has been a "game changer" as it has made it possible to increase both the scale and precision of the search for drug targets that can induce synthetic lethality in cancer cells.
The drive to apply CRISPR to synthetic lethality came from Dan Durocher, Ph.D., a molecular geneticist at the University of Toronto and Lunenfeld-Tanenbaum Research Institute who is a co-founder of Repare.
"CRISPR is to us what Moore's Law was to the computing industry," says Segal, referring to the observation made by Intel co-founder Gordon Moore that the number of transistors per square inch on silicon chips doubled every year. "It has allowed us to do things that could not previously be done," and as a result of Durocher's work Repare now has its "secret sauce," a library of around 90,000 CRISPR guide RNAs that are tuned to candidate synthetic lethal drug targets.
It's also encouraging that Repare isn't treading completely new ground with its focus on synthetic lethality, as the concept underpins the mechanism of action of PARP inhibitors for BRCA1-positive ovarian cancer like AstraZeneca's Lynparza, Tesaro's Zejula and Clovis' Rubraca. With BRCA1 mutated, inhibiting its synthetic lethal partner PARP inhibits the tumor's ability to grow.
The PARP story unquestionably provides great proof-of-concept for the approach but is generally considered a "low-hanging fruit" in synthetic lethality circles. Now, the challenge for Repare is to uncover other pairs—for BRCA1 as well as other cancer-related mutations—and to start building a preclinical pipeline.
First off the line is DNA polymerase theta (PolQ), a potential target paired to BRCA1 that emerged from the lab of another Repare co-founder, Agnel Sfeir, Ph.D., a cell biologist at NYU Langone Medical Center. In some cancers, PolQ seems to act just like PARP in its interaction with BRCA1, as it is overexpressed in many tumor types and is associated with poor clinical outcomes in ovarian cancer and breast cancer.
Repare raised a healthy $68 million in its oversubscribed series A financing in June, and that gives it the resources needed to bring at least two small-molecule drugs against synthetic lethal targets into the clinic by 2020, harvested from six to 10 programs that will run simultaneously, according to Segal, who says designating clinical candidates is the primary task for the company right now. It already has the first couple of programs in play to add to PolQ, and is targeting a first small-molecule candidate in the clinic by 2019.
"I think we have the differentiated technology and the capability to deliver a sufficient number of novel compounds to aspire to become a company with a portfolio of products," he says.
It's only been a few months since the company was founded, but Repare already has 24 employees, almost all based in Montreal but with a few people at an office in Cambridge, Massachusetts, just across the Charles River from Massachusetts General Hospital. And there are a few more hires in play, with a headcount of 28 to 30 envisioned for this year.
Investors: Versant; Celgene; MPM Capital; FTQ; BDC Capital