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KRAS in lung cancer. Purple microscopy image.

Across the world, conferencing software flicked open on computer screens. It was 8 a.m. in San Francisco, 11 a.m. in Frederick, 5 p.m. in Madrid, 11 p.m. in Hong Kong. The first day of the Third National Cancer Institute RAS Initiative Symposium was about to begin. Time zones notwithstanding, scientists and onlookers were tuning in from offices, studies, and living rooms to watch the livestream of the virtual event.

The interest in and support for both the field of RAS research and the host—the NCI RAS Initiative—was a good sign. Clearly, the science is substantial and can draw attention.

Just how far has the effort come?

Goal to enable, equip, and discover

The eight-year-old Initiative is NCI’s wide-ranging network to study and find treatments for cancers driven by mutations in the three RAS genes: KRAS, HRAS, and NRAS. These mutations cause more than 30 percent of all human cancers and are exceptionally hard targets for treatment. There were no approved targeted treatments until just this year.

The Initiative’s answer to the challenge has been a hub-and-spoke partnership model to unite scientists around the effort. The aim is to consolidate their strengths and perform research that invigorates and equips the larger scientific community to tackle the problem too.

“We’re enabling and nucleating. A lot of the efforts here nucleated efforts elsewhere that have contributed to advancements in the field. That was the goal from the beginning,” said Dwight Nissley, Ph.D., the Frederick National Laboratory’s senior scientist in the Initiative. He also directs the national laboratory’s Cancer Research Technology Program.

Frederick National Laboratory is the Initiative’s hub. It conducts its own RAS research and is the focal point that binds the spokes: RAS researchers at NCI laboratories, external NCI-funded institutions, and biotechnology and pharmaceutical companies.

Of course, the model requires the scientific community to get on board with more communal science. The center can’t hold without support from the spokes and other interested groups.

Camaraderie and commitment

The recent symposium suggests many groups are committed to the effort. Not only did participants around the globe tune into the three-day event at all hours of the day and night, 1,700 registered to do so. It was the largest meeting (albeit virtual) on RAS the world has seen to date—and it was well received.

“It’s important to have the [symposia]. It would be great to have them every year. I think that’s been difficult, so every two years, at least, to really bring the field together,” said Marie Evangelista, Ph.D., principal scientist in Discovery Oncology at Genentech, who presented research at the event but is not affiliated with the RAS Initiative. Other viewers echoed similar sentiments.

Some of the attendance can be attributed to the virtual format. Not having to attend in person made the event more accessible.

However, there was a second indicator that the scientific community is committed to collaboration and not simply tuning in due to interest: several presenters shared as-yet unpublished data from their studies, so much so that even veteran scientists were surprised. Collaborators have regularly and readily shared published data in the past, but voluntary disclosure of unpublished data has been less common.

“That’s quite unusual, especially in a large meeting,” Nissley said. “That’s part of the spirit that we’re trying to engender, … an interactive RAS community.”

Frank McCormick, Ph.D., RAS national program advisor at the Initiative and a professor at University of California, San Francisco, (UCSF) Hellen Diller Family Comprehensive Cancer Center, said it indicated “comfort” and the “camaraderie of the RAS community.”

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Man stands in front of a podium in an auditorium
Frank McCormick at the RAS Initiative Symposium in 2017.

Adding to the breakthroughs

Comfort, camaraderie, and good intentions only go so far without scientific progress. The Initiative is delivering here too, answering important questions about RAS biology and structure and creating tools for other RAS researchers to use. These aren’t discoveries that solve the problem outright (those are rare in biomedical research), but they advance the field, nevertheless.

“Sometimes in a field, you really need to just say, ‘These are the things we need to solve. We just need to get to it and not exactly worry that solving that will break everything open. It will add to the breakthroughs.’ That’s what’s great about the RAS Initiative,” said Kevan Shokat, Ph.D., a professor at UCSF and University of California, Berkeley, whose laboratory has received NCI grants through the Initiative. Shokat and his team were also the first researchers to demonstrate—apart from the Initiative—that it’s possible to target mutant KRAS proteins, which was the first discovery in the research path to drugging a subset of RAS-driven cancers.

“A lot of the tools that have come out of the Initiative have enabled researchers to perform experiments that are consistent across other labs. The reagents that Initiative has been willing to share … allow people to be confident in the data and really be consistent in how we think about RAS and targeting KRAS and the biology of that,” Evangelista said.

The confidence and discoveries have flowed into an international dialogue held across conferences, forums, and editorials. Initiative scientists have published a lengthy list of studies and spoken at several high-profile conferences. The Initiative’s network has grown, and its collaborations span industry, government, and academia. Groups, such as Evangelista’s team at Genentech, continue to seek to become more involved.

“Having the RAS Initiative continually adding opportunities keeps, I think, many more resources going at RAS, even beyond what’s in the RAS Initiative,” Shokat said.

The dam burst

The scientific progress is paying off. The iterative and intertwined discoveries from the Initiative, its collaborators, and the scientific community have burst the dam on RAS research.

Amgen’s KRAS drug Lumakras recently received FDA approval, becoming the first treatment approved for a RAS-driven cancer. The Initiative was not directly involved in this, but it’s working on its own treatments. Genentech, Mirati Therapeutics, Johnson & Johnson, Boehringer Ingelheim, Eli Lilly, Revolution Medicines, and Kezar Life Sciences are among the industry groups working on compounds as well.

“There’s a lot going on right now behind the company walls, and they were willing to say it [at the symposium],” Shokat said. “[When] we actually see the pieces, … that’s going to be a real breakthrough, I think, because everybody will have everybody’s LEGO pieces to play with and make new drugs.”

The community is lively, equipped, and collaborative. The hub-and-spoke is thriving: the center has held. The exceptionally hard target is now vulnerable.

“Generally speaking, I think the model has worked brilliantly,” McCormick said. “The structure of the whole thing was brilliant and has worked really well.”