Researchers Gain Insight into How a Drug Fires Up an Immune Response to Cancer

By Jim Stallard,

Monday, December 19, 2016

Image of fireball-type explosion on black background.
Summary

A drug called Val-boroPro triggers an immune response against cancer in mice, but until now, researchers didn’t know the mechanism. The laboratory of Daniel Bachovchin at MSK discovered that Val-boroPro blocks two proteins, DPP8 and DPP9, causing a form of inflammatory cell death called pyroptosis, which spurs an immune attack. This is the first time pyroptosis has been known to be caused by a drug, which can be used as a tool to study immune function.

Highlights
  • A drug called Val-boroPro shrinks tumors in mice.
  • It triggers an immune response — but exactly how was unclear.
  • Research shows it causes an inflammatory form of programmed cell death.
  • This cell death, called pyroptosis, spurs the immune attack.

Despite several immunotherapy drugs gaining FDA approval to treat multiple cancers, these therapies do not work in every patient. In light of this, researchers are continuously searching for new ways to activate the immune system and make such treatments more widely effective.

One drug, called Val-boroPro, has intrigued scientists for nearly a decade because it has been shown to shrink tumors in mice and “immunize” them against future cancers. But there was one hitch: For years, nobody could quite figure out how it works.

A team led by Daniel Bachovchin, a chemical biologist in the Sloan Kettering Institute (SKI), has discovered that Val-boroPro activates the immune system to attack through a form of highly inflammatory programmed cell death called pyroptosis. This finding, reported in Nature Chemical Biology, could help researchers unravel how various immune system components interact, using Val-boroPro as a tool.

Pyroptosis occurs in immune cells called monocytes and macrophages. It usually is induced when a pathogen (such as a bacterium or virus) infects these cells, in part to hide from immune detection. In response, the cells swell, burst, and die, releasing pro-inflammatory signaling molecules. This self-destruction also releases the pathogens back into the surrounding environment and attracts other immune cells to fight the infection.

This gives us molecular control over one part of the immune system to start answering important questions.
Daniel  Bachovchin
Daniel Bachovchin Chemical biologist

Although pyroptosis had been studied extensively, researchers had never seen a small molecule drug induce this form of cell suicide. Uncovering this cause and effect opens the door to a range of new research and therapeutic applications.

“Not only does this give us something that could be a therapeutic tool, it reveals an element of the biology that we didn’t know existed,” Dr. Bachovchin says.

“Off-Target” Proteins as the Key

Dr. Bachovchin’s laboratory in SKI’s Chemical Biology Program studies a group of enzymes called serine proteases and the roles they play in cancer and immune system signaling. Serine proteases are involved in a large number of biological processes and are needed for cell growth. They also are easy to block with drugs for potential therapeutic purposes. (One serine protease called DPP4 has been targeted with drugs for the treatment of type 2 diabetes.)

Val-boroPro was originally designed to inhibit DPP4, but it also blocks several additional serine proteases, including DPP8 and DPP9. And it’s that blocking of DPP8 and DPP9 that Dr. Bachovchin and his colleagues discovered ultimately causes pyroptosis through the activation of an enzyme called pro-caspase-1.

“If DPP8 and DPP9 are active, they appear to be constantly preventing pyroptosis from occurring and acting as a check on this type of immune response,” he says. “When you inhibit them, it triggers this type of cell death, inflammation, and immune attack. We’re going to highlight what else these enzymes do — which is clearly of profound biological consequence.”

An important next step will be designing new drugs that selectively inhibit only DPP8 and DPP9 to reduce toxic effects resulting from hitting other targets, Dr. Bachovchin says. Researchers also aren’t sure whether inhibiting DPP8 and DPP9 will itself be sufficient to induce a strong enough anti-cancer immune response.

“Although much of our other research is in an early stage, this finding is going to frame a lot of downstream work,” Dr. Bachovchin says. “This gives us molecular control over one part of the immune system to start answering important questions.”

Comments

I am a prostate cancer patient who has just given initial information to the main office for an appointment. I have aggressive disease that caused elevated PSA (4.0 followed by 8.0 over several weeks) after RP. I have been on androgen therapy for about 18 months with undetectabel PSA thus far. I am interested in immunotherapy and I believe in mind over matter as related to immunity. I have done some self-hypnotic inductions relating to overcoming microscopic disease. I would be interested in pursing this along with other therapies that may be prescribed by Sloan Kettering.
John Wilbur

Dear John, we are sorry to hear about your diagnosis. You will be able to discuss possible treatment options such as immunotherapy at your upcoming appointment with your oncologist. If you are interested in learning more about complementary therapies (such as mind-body therapies) to help manage the symptoms and side effects of cancer and treatment, please visit our Integrative Medicine pages at https://www.mskcc.org/cancer-care/treatments/symptom-management/integra….

You may also be interested in some of our at-home multimedia tools, which include a piece on "self hypnosis for relaxation and stress relief" that you can download from iTunes: https://www.mskcc.org/cancer-care/treatments/symptom-management/integra…

Thank you for reaching out to us.

I'm at stage 4 mesothelioma spread to the lymph nodes and groin. I heard immunotherapy may help.

Dear Milton, we're sorry to hear about your diagnosis. MSK has a number of clinical trials for mesothelioma. You can view a list here: https://www.mskcc.org/cancer-care/clinical-trials/search?keys=mesotheli…

If you are interested making an appointment to find out if any of these trials may be right for you, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Add new comment

We welcome your questions and comments. While we share many of them with our world-class doctors and researchers, we regret that in order to protect your privacy, we are not able to make personal medical recommendations on this forum, nor do we publish comments that contain your personal information. If you would like to consult with an MSK doctor, we encourage you to make an appointment at 800-525-2225 or request an appointment online.

Your email address is kept private and will not be shown publicly.