Tango Therapeutics Inc. expects clinical proof of concept "within a five-year time frame," interim CEO Barbara Weber told BioWorld Today, as the company takes to the floor with a $55 million series A round from Third Rock Ventures LLC, where she is a venture partner.

Cambridge, Mass.-based Tango leverages DNA sequencing and CRISPR-based target discovery and goes beyond cancer therapies as they exist today. "For the most part, those are single-agent therapies that induce partial, non-sustained responses," Weber noted. "A lot of our thinking around that, in general in the field, is that there are multiple lesions in each cancer that are important in making it a cancer cell, and therefore [these] will need to be targeted" in order to gain sustained, complete responses and cures. "One of those big areas is the loss of tumor-suppressor genes," she said. "The problem with trying to target tumor suppressors is that they're inactivated or they're gone."

But that itself can be exploited, Weber said. "If a cancer had lost a particular tumor suppressor gene, that loss has created a vulnerability unique to cells that have lost that cancer gene," she said, and made an analogy that compares regular cars to race cars. The latter "have lost some of the things that protect from driving our cars like maniacs and this lets them go faster, but it also puts them in a more vulnerable position to getting in a crash or throwing a piston or whatever. There are often drug targets you can find that, when you pair them with that tumor suppressor gene loss, [they] uniquely kill those cells but not normal cells," she said, a concept known as synthetic lethality. "The best, first – and only, so far – clinical example of this is the PARP inhibitors in BRCA1 and BRCA2-mutant tumors," she added. "The data are really spectacular."

Tango's effort is "a little complicated to explain, but it's actually a relatively straightforward path when you assemble the right tools and team to do it," Weber said. "Even though people have known about this approach for 15 or 20 years, it's only been in the last year or two that we've had the technology available to do it in a productive way." That technology includes extensive deep sequencing of tumors and CRISPR. "Some companies are using CRISPR directly to treat patients," she said. "We are using [it] as a research tool to find the targets." The cycle time for target discovery screening is in the "less than one-year range," hence "relatively fast. I don't think you'd want to build a CRISPR platform in your garage, but it's not a super-complicated thing to do."

Tango has garnered "some target nominations from informatics approaches we've taken on public datasets," she said. Regarding the series A cash, Tango is "not going into specific details about how that's going to be spent," but the funds should enable reaching key value-creation points so that the company can make a deal and/or raise money.

OF COMBOS AND T CELLS

The firm will "go after those tumor types for which there's not good therapy – that's a pretty broad swath of cancer patients," and of particular interest will be cases in which a specific tumor suppressor gene is lost. "The good part of that, if there is a good part, is that essentially every solid tumor has specific tumor suppressor gene loss patterns, with usually not more than one or two tumor suppressor genes lost, and that they occur in very specific genetic subtypes." P53 is a "famous" tumor suppressor gene, she noted. "This is just an example but we could pick, say, p53-mutant gastric cancer, do target discovery, and move straight into p53-mutant gastric cancer patients."

It's been woefully common for a developer to conduct a trial, have it fail and then ransack the data for subsets where the drug seemed to have activity. "That's a back-door approach into exactly [Tango's approach]," Weber said. "We're starting with that very specific patient-selection approach and doing target discovery in that space. We didn't have a way to do it before." The work done so far was presented to "multiple potential pharma partners" to pleasing effect at the J.P. Morgan Healthcare Conference in January in San Francisco, she said.

The other two legs of Tango's tripartite platform involve identifying the right combinations of drugs for the agents that the company hopes to discover, since the combo attack is necessary for solid tumors, and finding a way to make T-cell-targeting therapies do their job better. "Most cancers have developed mechanisms to evade T-cell killing and make themselves invisible to T cells," and Tango methodology can make tumors easier for the immune system to spot, Weber said.

Third Rock has been plenty busy lately. In December, the company put $55 million into the series A round for Goldfinch Bio Inc., a Cambridge, Mass.-based company founded to discover and develop precision kidney disease therapies for conditions including focal segmental glomerulosclerosis and polycystic kidney disease. Using a patient registry to collect and integrate genomic and phenotypic data, it will focus on helping molecularly defined patient groups. The goal of the investment is to move Goldfinch to the point of taking its first molecule into the clinic in early 2019. (See BioWorld Today, Dec. 15, 2016.)

It was $55 million of series A cash from Third Rock that also went into Fulcrum Therapeutics Inc., of Cambridge, Mass., in July 2016. Fulcrum said it would combine findings in the biology of gene regulation to develop small-molecule therapies. The first efforts are focused on fragile X syndrome and a form of muscular dystrophy called facioscapulohumeral muscular dystrophy, both of which arise from a single mutated gene. Fulcrum models gene regulation in disease tissue using patient cells that are either donated through tissue biopsy or derived from skin using induced pluripotent stem cells. (See BioWorld Today, July 20, 2016.)