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DON

DON

One of the other new drugs in the pipeline is built around depriving cancers cells of the nutrients they need to outgrow and overpower normal cells. Cancer cells are really just normal cells in hyperdrive. “To grow, cancer cells need fuel—lots of fuel—so they suck up all available nutrients,” says Jonathan Powell, an associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. The process is called tumor metabolism, and it has become a promising new cancer target. In essence, cancer cells devour all of the nutrients in their vicinity. They steal glucose and another nutrient called glutamine away from other cells to sustain their growth, creating a position of power for the cancer and, at the same time, weakening normal, healthy cells, including immune cells. While cancer cells are feasting, immune cells are starving and unable to fight the cancer. “An immunotherapy like anti-PD-1 might do a great job in activating T cells, but when they show up to an environment like this, they can’t do their job. They need the nutrients that the cancer is taking,” says Powell.

Powell’s idea was to create a drug that cuts cancer cells off from the nutrients that feed them so that when immunotherapy is given, T cells show up to a different environment, one that has nutrients available to them so they can energize and go to work against the cancer. “We’re not actually targeting the immune system, but rather creating a friendlier environment for the immune system,” says Powell. Coincidentally, Powell and drug development expert Barbara Slusher were working together on a student thesis committee. It turned out that the Slusher lab had already been designing drugs for the same target. He shared his idea, and she offered up some compounds for the Powell lab to try. Slusher was Johns Hopkins trained but had been working for a pharmaceutical company for the last 18 years, where she was senior vice president of research and translational development.

When another pharmaceutical company acquired the business in 2009, Slusher returned to Johns Hopkins with a seasoned team of medicinal chemists, assay developers, and pharmacology/toxicology and pharmacokinetics experts. She is also founder and president of a world consortium of academic drug discovery centers. Started just three years ago, it has already grown to 150 universities and 2,000 members, reflecting the growing role of the academic researcher in drug discovery. As the pharmaceutical industry has largely withdrawn from drug discovery research, the university researcher has tried to pick up the slack. “There are so many good ideas and therapeutic target discoveries in academia, but the ability to synthesize drugs against the newly identified targets has not typically existed within universities,” says Slusher.

“We will never be set up to commercialize drugs. That remains pharma’s role, but now we are required to move our basic science discoveries farther along the translational path than we did in the past. As a translational leader, Hopkins is set up to do this—we can synthesize new drugs, show their benefit and take them to a point where a pharmaceutical company becomes interested in picking them up for clinical development.” Among the compounds Slusher and Powell began working on was one called DON, a glutamine-blocking drug originally extracted from soil in Peru. In the early assaults against cancer, it was common to use bacteria and other toxins found in soil around the world to make drugs to kill cancer cells. The goal is to give patients the highest dose possible to kill as many cancer cells as possible without harming too many normal cells. It was a delicate balancing act that led to the dose-escalating paradigm that has dominated cancer drug discovery for decades. In the era of precision medicine and targeted therapies, however, that paradigm is slowly but surely shifting.

Earlier versions of glutamine blocking drugs showed they had cancer-fighting potential but were too toxic to normal cells. Although Powell and Slusher’s DON was not new, what Slusher did to make it work was. She changed the drug’s chemistry, sticking something to the active drug that makes it inactive as it circulates throughout the body. The drug only becomes active when it gets inside cancer cells. Once in cancer cells, that extra thing she stuck on the drug gets clipped off, and the benevolent passenger traveling through the bloodstream is transformed into a cancer cell killer. The approach is called a prodrug strategy, and the selective activation decreases toxicity to normal cells. Since the active drug is only released in cancer cells, it requires very low doses to work.

“I consider this our real contribution,” says Slusher. “We’ve been able to change the distribution of DON so that they hit more of the target and less normal cells.” Slusher plans to use the concept for other drugs. She is already working on a modification to 5-azacytidine, an epigenetic-targeted cancer drug that corrects chemical alterations that support cancer growth. “Using existing drugs as starting points is one way to expedite drug discovery,” says Slusher. “It doesn’t mean it’s easy. As in this case, we still have to do medicinal chemistry and pharmacokinetics to get it just right, but it is a faster start with higher probability of success.” Powell first envisioned the drug as a way to extend the benefits of immunotherapy to more patients. “I thought it would help in tumors that currently don’t respond to immunotherapy,” says Powell. It could be given before immunotherapy to create a better environment for T cells to thrive.

Targeting tumor metabolism increases the numbers of cancer-fighting T cells, and anti-PD-1 drugs remove a shield cancers use to hide from T cells, creating the perfect one-two punch for an immune assault against cancer. When he studied the drug in animal models, he found it was a potent cancer fighter by itself. “We seemed to unleash the normal immune response just by targeting the nutrients in the microenvironment of the tumor,” says Powell. “It makes us think that patients will develop antitumor immune responses when treated with our prodrug alone, but when we add anti-PD-1 to it, we really finish off the job.” Since all cancers are dependent on glucose and glutamine, tumor-targeted DON prodrugs should work across all cancer types. Slusher and Powell were particularly excited to see some of their prodrugs pass the often-impenetrable blood-brain barrier, making it a potential new option for brain cancers, which are among the most treatment-resistant cancers.

Powell is optimistic that their new drug will work in many cancers that have been resistant to chemotherapy and immunotherapy. In animal studies of cancers given time to grow very large, anti-PD-1 immunotherapy eliminated the cancer in about10 percent of the mice. When our DON prodrugs were added, that number jumped to 90 percent. “We’re very excited about taking this drug to patients with cancers that have not responded to other therapies. We think it has the potential to really help them,” says Powell. Ongoing studies proved that their modified drug is so cancer specific that it only releases its power in cancer cells, virtually remaining nontoxic in all other cells. Their research also shows signs that the drug may also sensitize cancer cells to radiation therapy. Slusher and Powell hope to have the drug in clinical trials in two years.

To get there, they will need to complete additional studies to get the FDA approval needed to take their investigational new drug to patients. Deerfield Management recently announced plans to invest $40.5 million in Dracen Pharmaceuticals, Inc., a start up company founded by Powell and Slusher to develop DON and other cell metabolism-tartgeting drugs. Powell echoes Berger’s and Liu’s emphasis on more resources to help investigators bridge the funding gaps that limit drug discovery. “Until we got dedicated funding from the Bloomberg~ Kimmel Institute, we were funding this research with bake sales, cobbling together small amounts from different places to keep it going,” says Powell. “If we had a fully supported program for drug discovery, it would make a huge difference in speeding progress.” The collaborative environment at Johns Hopkins makes it a fertile ground for scientific progress.

“The value of discovery is underrated. It’s messy and risky, but it’s essential,” says Powell. He points to a time early on in the research when one of the compounds wasn’t working at all in the laboratory studies. Powell was disappointed until he received a call from Slusher who, unaware of his laboratory outcomes, advised him not to use the compound. She spotted a problem with her compound’s stability and knew it wasn't going to work. “Her team on the drug discovery side and our team on the cancer research laboratory side came to the same conclusion independent of one another and provided extra confirmation for what we were seeing. Her observation of the drug confirmed what I was seeing in the laboratory, and my observation in the laboratory confirmed that she was right about the problem she spotted with the compound,” he says. “That’s the beauty of science. You put people together with diverse skills, and they find something unexpected,” says Powell. “There is no formula for it. You just put people together and let them work. This kind of collaboration thrives in the Kimmel Cancer Center.”

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