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Third Rock’s Tango Aims For Drugs That Turn Cancer Against Itself

Xconomy Boston — 

As the understanding of cancer advances, scientists are discovering built-in features of the disease’s own biology that can be tapped to halt its growth. Biotech startup Tango Therapeutics believes it can build on this concept to develop new cancer drugs, and it is now unveiling its approach, backed by $55 million in financing.

The Series A investment comes from Third Rock Ventures, the Cambridge, MA-based venture capital firm where Tango has been incubating for the past two years. With the funding, Tango plans to continue its research as it works to build a pipeline of cancer drug candidates.

Underlying Tango’s approach is an understanding of the genetics of cancer. Cancer cells have genes that speed up their growth, like stepping on a car’s accelerator, says Barbara Weber, a venture partner at Third Rock and Tango’s interim CEO. But genes whose role is to suppress tumor growth can become inactive, which is like cutting the brakes on a car, she says. The result is a faster-growing cancer.

Biology has redundant processes that offer more than one way to stymie a cancer’s mechanisms for growth, Weber says. The challenge is finding them. Tango is basing its search on a concept called “synthetic lethality.” For example, two genes that are dependent on each other can remain harmless to the body as long as only one of them has a mutation. The mutation makes that gene inactive. But if both genes have mutations and are inactive, their interaction is lethal to the cell. Tango aims to find genes that, in the presence of another mutated gene, will trigger a cancer cell’s death. A Tango drug would target the gene corresponding to the mutated one in order to spark the lethal combination.

Synthetic lethality has already been demonstrated in cancer drugs. A new class of ovarian cancer drugs work by targeting poly (ADP-ribose) polymerase, or PARP, an enzyme that helps cancer cells repair the damage caused by chemotherapy and other drugs. This enzyme works in the presence of a mutated BRCA gene and the first PARP inhibitor drugs were approved only for patients who have that genetic mutation.

Waltham, MA-based Tesaro (NASDAQ: TSRO) received FDA approval for its PARP inhibitor, niraparib (Zejula), this week—the first such drug that doesn’t require a test for the genetic mutation. AstraZeneca (NYSE: AZN) secured the first FDA approval on a PARP inhibitor in 2014 for its drug olaparib (Lynparza). That drug was based on research from Alan Ashworth, former chief executive of the Institute of Cancer Research in London, who discovered that blocking PARP in the presence of the mutated BRCA gene is lethal to ovarian cancer cells. Weber says that this feature makes targeting PARP selective—it doesn’t harm healthy cells. Ashworth, now a professor of medicine at the University of California San Francisco and the president of the university’s Helen Diller Family Comprehensive Cancer Center, is one of Tango’s scientific founders.

Rather than a blanket attack that harms cancer cells and normal cells alike, the synthetic lethality approach offers the potential for a selective strike that only hits cancerous cells, Weber says. Those results have been observed with PARP inhibitors. But Weber says that Tango will take a more sophisticated approach to drug discovery, due largely to advances in technology. Tango is using DNA sequencing technology to analyze tumor samples, as well as the CRISPR gene-editing system as a research tool to find gene combinations that are synthetically lethal. Finding and validating those targets would be more difficult without those tools, Weber says.

Other biotech startups are pursuing this approach to cancer drug discovery—and they’re attracting support from big pharma companies (and potential partners) in the process. Nearly a year ago, Israel-based Metabomed raised $18 million to support its efforts to find targets associated with inactivated metabolic genes in cancer cells. That Series A investment round brought on new investors Pfizer (NYSE: PFE) and Arkin Holdings.

Shortly after Metabomed’s announcement, South San Francisco-based Ideaya Biosciences unveiled its approach to finding new drugs based on the concept of synthetic lethality. Ideaya raised $46 million in a Series A round backed by 5AM Ventures, Canaan Partners, Celgene (NASDAQ: CELG), WuXi Healthcare Ventures, Novartis Institutes for Biomedical Research, and Alexandria Real Estate (NYSE: ARE). Ideaya CEO Yujiro Hata told FierceBiotech at the time that his company is searching for synthetic lethal pairs using editing tools such as CRISPR.

Tango is still in the early stages and clinical trials are years away. Cary Pfeffer, Tango’s interim chief business officer, says that the Series A funding is enough to build out the company’s drug target and drug discovery software engines. The company could also validate the targets that it finds. By then, Pfeffer says, Tango will have reached a point where it can raise more money or strike a deal with a partner. For now, Tango isn’t disclosing which cancers it will target other than saying that it aims to develop drugs for cancers that lack effective treatment options.

Image of lung cancer metastasis by the National Cancer Institute.