“By the end of 2017, we identified eight novel targets and have selected three for drug discovery. We now have three full drug discovery programs centering on these new targets.”
Tango Therapeutics was launched by Third Rock Ventures in March 2017. What were the influencing factors surrounding the company’s conception?
The basis of Tango Therapeutics is to identify novel genetic drug targets for specific cancer subtypes. First generation genetically-targeted drugs are used against known mutated and amplified oncogenes. However, there were two problems: firstly, we quickly ran out of mutated oncogenes; secondly, solid tumors have multiple genetic alterations, of which likely two to six must be targeted in combination to kill the cells. For example, BRAF was identified as a target because it is mutated in a majority of melanomas and BRAF inhibitors are effective drugs, but they result in only partial responses in most patients, and those patients all eventually relapse. The primary issue is that many genes that need to be targeted in various subtypes of cancer are not marked by mutation. The question then becomes how to figure out what they are.
Alan Ashworth and I began to talk about starting a company based on shRNA screening technology to identify synthetic lethal targets and develop new drugs more than 10 years ago when he discovered the BRAC1/2 -PARP interaction. However, it became apparent that the technical aspects of shRNA screening, including multiple false positives prevented that approach from being used at scale for cancer target discovery. When CRISPR was discovered, it became clear that it was now an option. The success and ease of CRISPR technology was the foundation for Tango and why we can now do what we do.
Could you walk us through Tango’s three main areas of focus for drug targets and their significance?
Our first platform focuses on tumor suppressor gene loss and classic synthetic lethal pairings to drug those tumors. Oncogenes, when mutated or amplified, can be found by sequencing and targeted. Tumor suppressor genes can only be targeted by finding the synthetic lethal pairs for those genes. There are at least 30 to 40 important known tumor suppressor genes. Our first consideration is the most straightforward approach of finding the tumors with suppressor gene loss and identifying the druggable synthetic lethal pair that go with them.
The second area of focus is what we call context-dependant oncogenes, which also can be found with CRISPR screening. We do the screens in contexts where available therapies are not as good as they should be based on the tumor genetics, and we do these screens not just with the cell line and our druggable genome CRISPR Library but with the existing drug as well. For example, in RAS mutant lung cancer, RAS is a common mutated oncogene but not druggable. MEK inhibitors should theoretically work because MEK is downstream of RAS in the MAPK pathway, so if RAS is activating a cell and hits a downstream target it should inhibit the pathway. However, this is not the case, although the reason is as yet not fully explained. We did a screen with a RAS mutant lung cancer line, a MEK inhibitor and a druggable genome CRISPR library and have identified an excellent candidate gene for a novel drug target in the top five hits.
The third platform is more complicated, and we have just collected our first dataset. The last five years of immuno-oncology clinical data have shown that tumors themselves can keep T-cells from killing them. One of our founders, Toni Ribas, was the first to show that one of the ways this happens is through tumor suppressor gene loss. This target discovery approach is a two-step process. The first step is to develop in vivo systems to define which tumor suppressor genes are mediating immune evasion. In our first context discovery screen, we have discovered very several interesting tumor suppressor genes that are commonly lost in human cancers and are clearly playing an important role in driving immune evasion in those models. Now that we know the context, our second step is to look for drug targets that will drive a cold tumor to become hot. That will have a fundamentally important outcome – the ability to enhance activity of immune checkpoint inhibitors. The effects should be limited to just the tumor cells and not normal cells, and for the first-time all us to use genetics to select patients for those clinical trials.
How does this research tie into the development of potentially new drugs and possible collaborations?
We have just finished our first year, which has been mostly focused on target discovery. By the end of 2017, we identified eight novel targets and have selected three for drug discovery. We now have three full drug discovery programs centering on these new targets. Due to our small size, we are looking for a pharma partner who shares our vision and wants to help us build our company while we help them build their pipeline.
How does Tango Therapeutics endeavour to keep the patient at the center of the story?
We start by thinking about patient subgroups and areas of high unmet need. This forms the basis of all that we do. From there, we identify targets and move those drugs forward in a way that facilities us moving those drugs to the patients most likely to respond to them in a very efficient way. The likelihood of success with a known genetic target, a good molecule and the right patient population is very high. I do not know of a situation in which a drug failed with this combination in place. In addition, we can get a good sense of the strength of the clinical signal to expect with pre-clinical models that closely match patient tumors. This approach also makes sense financially because by knowing which patients to address with drugs that have a large therapeutic index, we can expect clinical proof-of-concept in our in Phase 1 studies.
What are Tango Therapeutics key objectives over the coming years?
We will continue to fine-tune our target discovery platform to a steady, productive level of target discovery. We will also progress our drug discovery programs and hope to get our first new drugs into patients in 2020. Externally, our goal is to form a partnership within the next two years or to carry out a series B equity financing round. We are also on the lookout for a Chinese pharma partner that might want Chinese drug rights, in exchange for a non-dilutive R & D collaboration.