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Lung Cancer Dream Team Makes Progress

More than 2 years ago, the American Cancer Society and Stand Up To Cancer (SU2C) formed a Lung Cancer Dream Team and charged it with the mission of finding a new or more effective treatment for a hard-to-treat type of lung cancer that has a mutation in a gene called KRAS (KAY-rass).

In this interview, Pasi A. Jänne, MD, PhD, a coleader on the team, provides a high-level overview of what they have learned so far, the clinical trials they’re running, and their hope for the future. Jänne is 1 of the 3 coleaders for the Lung Cancer Dream Team. He’s a clinician and researcher at Dana Farber Cancer Institute in Boston.

When the KRAS gene is mutated, the cell loses its ability to stop growing and dividing. As growth continues, cancer develops.

Pasi A. Jänne, MD, PhD, Coleader Lung Cancer Dream Team

Q: Why did the Lung Cancer Dream team decide to focus on KRAS-mutations?

A: “KRAS-mutant lung cancer is the largest genetic subset of non-small cell lung cancers,” Jänne says. “It’s the one we’ve known about for the longest time. Researchers have studied it for decades. Yet, we don’t have any effective treatments for it.”

If about 222,500 people are diagnosed with lung cancer each year, and 20% of them have the KRAS mutation, he explains, that means more than 44,000 people are diagnosed with KRAS-mutant lung cancer each year. That’s more than 44,000 people without a viable treatment option. “That’s a bigger number of patients affected by this one subset of lung cancer than the number of patients diagnosed each year for a lot of our common cancers,” he says.

Another benefit of studying KRAS is because it’s linked with pancreatic and colon cancer too, so the work in lung cancer could ultimately help researchers move forward with treatments for them. 

What Is KRAS?

The KRAS gene is needed for normal cell growth. The gene gives instructions to make the KRAS protein. That protein is like the 2nd runner in a relay race. The finish line is at a cell’s nucleus, the control center.

Normal cell growth. In a healthy, normal cell:

  • Like a runner getting to the starting line, a molecule called a growth factor on the outside of the cell attaches (binds) to a receptor on the cell membrane.
  • That binding sends a signal to the KRAS protein inside the cell. It’s like runner 1 in a relay race passing the baton to runner 2.
  • The KRAS protein (runner 2) sends the signal to the next of 3 more proteins (runners 3, 4, and 5) in the path.
  • When the signal reaches the last protein (runner 5), it signals the nucleus to grow and divide.

Managed cell growth. Sometimes your cells need to grow and divide, and sometimes they don’t. Your body manages this process. A healthy cell controls its growth by starting or not starting down the signaling path. If the growth factor molecule outside the cell doesn’t bind to the receptor on the cell membrane, the KRAS protein doesn’t get a signal. So, the nucleus doesn’t get the signal to grow, and the cell stops growing and dividing.

Uncontrolled, KRAS-mutated, growth. If something happens to change (mutate) the KRAS gene, the cell’s growth is no longer managed – and can get out of control. The mutation causes the KRAS protein to go rogue. It’s like runner 2 starts before it’s his turn:

  • Instead of waiting for a signal from the growth factor, the KRAS protein independently sends a signal down the pathway.
  • Signals continue down the path to the 3rd, 4th, and 5th proteins, until the nucleus gets the signal to make the cell grow and divide.
  • Signals between proteins keep going so the cell keeps growing and dividing. That uncontrolled growth turns the normal cell into a cancer cell.
  • Genes like KRAS that have the potential to turn a healthy cell into a cancerous one are called oncogenes. 

Q. What kinds of research are you doing with targeted therapy?

A. “Our first aim is to do preclinical tests with  cells and mice to look for ways to block the cancer-causing signal from KRAS,” Jänne says. A member of the Lung Cancer Dream Team, Kevan Shokat, PhD, at UCSF Helen Diller Family Comprehensive Cancer Center, previously had found the first kind of a new targeted therapy that can directly block a subset of KRAS-mutant cancers called G12C cancer.

Of course, there’s a lot to be done, and it takes a while to get a laboratory drug ready to use in humans, Jänne says. Though “these drugs are eagerly awaited in clinical trials starting, hopefully, in the spring of 2018. And they promise an amazing degree of hope,” Jänne says.

“Our second aim is to identify the critical signals that KRAS turns on. The question is, if we can block those signals, can we have an effective therapy?” Jänne asks. “Some of these are in various stages of clinical trials or are going to start.”

Q. What kinds of research are you doing with immunotherapy?

A. We know that not every cancer, including KRAS-mutant ones, will respond to immunotherapy. We’re trying to understand why, Jänne says, “and it’s much, more complex than anyone on the team previously appreciated.”

“Right now, if everyone who’s eligible for immunotherapy got it, only a minority – 10% or 15% – of lung cancer patients would have their tumors shrink,” he says. “Our hope is that if we find the determinants – exactly what makes immuno-therapy work – we can change the success rate to at least 50% or 60% of patients.”

The Dream Team’s studying those determinants by taking biopsies from lung cancer patients before they receive a commercially available immunotherapy. “That means the drug’s not tied to any clinical trial or company,” Jänne explains.

“Sometime in the future, when a patient gets diagnosed, we hope a comprehensive analyses of their tumor will predict a person’s response to immunotherapy. Then, we could say, ‘you have a 60% chance of this treatment working,’” Jänne says. “Or, we could say, ‘there’s 0% chance this drug will help you, so we need to find another treatment.’” That’s just as important, Jänne says. “We don’t want to waste treatment and expose patients to toxicities that come with treatment if the likelihood of it working is very, very low.”

"This is where we're really leveraging the power of the Dream Team group,” Jänne explains. “We’re able to pool our resources. So now, we can look at hundreds and hundreds of patients treated with immunotherapy to learn why some patients respond and some don’t.” It’s more than any single institution could study. “By pooling our numbers, we have the power to answer some questions. It’s been a very successful effort as a part of this grant,” he says. “And it’s ongoing.”

Q. What are you learning about putting the 2 types of treatment together?

A. This is the 3rd goal of the study, “to understand if there’s an interaction between immunotherapy and inhibiting the signals of KRAS directly through targeted therapy,” Jänne says. “We hope there’s an intersection between them. But we don’t know. That’s why we’re testing.” They have already started clinical trials combining inhibitors of KRAS signaling and immunotherapy, he says.

“These things take longer than any of us want them to take,” he says. “I think we’ve already strengthened our scientific understanding about KRAS over the course of this grant so far. It remains to be seen whether we’ll have new treatment approaches that merge immunotherapy with targeted therapy ready for clinical trials by the end of the grant, or 1 to 2 years after the grant. Either way, we’ll succeed at our goal of advancing the therapy for this subclass of lung cancer patients,” he says.

Q. How does the team work together?

A. All 8 of the institutions work on all 3 of the project’s goals – improving targeted therapy, better understanding how immunotherapy works, and trying to combine the two treatments. But some groups spend more time on one goal than another, Jänne says. “We have multiple project managers to make sure we’re keeping up with all the schedules,” he says. “The operational aspect has been critical. We have teleconferences or bigger meetings in person to bring ideas together. We also have subgroup meetings that allow us to be more focused.” 

Q. Would you like to see the work of the Dream Team to continue as a group after this grant ends?

A. “There’s a certain activation energy that is needed to start working together and seeing results. We have that momentum going now, so why stop? But we do need to find a way to fund that, so we can, hopefully continue to make discoveries and translate them into new treatments for patients with KRAS-mutant lung cancers.”  

About the Dream Team

The Mission: To be able to offer people with lung tumors that have a KRAS gene mutation targeted therapiesimmunotherapy, or a combination of them. 

Who’s Involved: Led by Jedd Wolchok, MD, PhD, Pasi Jänne, MD, PhD, and Alice Shaw, MD, PhD. Jänne and Shaw replaced co-leader Jeffrey Engleman, MD, PhD, when he took a job in the private sector. The team includes more than 35 specialists from these 8 institutions with the largest lung cancer research programs in the United States:

  • Dana-Farber Cancer Institute in Boston
  • Helen Diller Family Comprehensive Cancer Center at The University of California San Francisco
  •  Massachusetts General Hospital Cancer Center in Boston
  • MD Anderson Cancer Center at The University of Texas in Houston
  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore
  • Taussig Cancer Institute at the Cleveland Clinic in Ohio
  • University of California Davis Comprehensive Cancer Center in Sacramento
  • Yale Cancer Center in New Haven, Connecticut

How’s It Funded: By a 20 million dollar grant co-funded by the American Cancer Society and SU2C, a charitable program of the Entertainment Industry Foundation that raises funds to speed the pace of cancer research.

Their Grant Period: April 2015 to September 2018