Through the lymph nodes it goes — researchers develop a cancer drug that avoids toxicities by skirting the liver
PI3K is a protein that is part of a pathway that regulates cell growth, survival and metabolism — earning it the inscription of master regulator for cancer. However, while a number of PI3K inhibitor drugs have been approved since 2014, the class as a whole has dwindled, as it has been plagued by toxicity issues in various blood cancers.
For example, the FDA hit Secura Bio’s PI3K inhibitor Copiktra, which earned accelerated approval in 2018, with an increased death warning in June following the results of its confirmatory Phase III trial. That warning came after a number of companies, including Secura, Gilead and Incyte, withdrew their accelerated approvals for their PI3K inhibitors after failing to complete confirmatory trials. The FDA now requires randomized trials to be conducted for PI3K inhibitors in blood cancers.
But what if a PI3K inhibitor somehow avoided those toxicities? In a paper published in Nature Communications Wednesday, researchers from the University of Michigan describe a dual PI3K and MAPK inhibitor that limited toxicities and extended survival time in mice through what lead investigator Brian Ross called an “unanticipated” mechanism — going through the lymph nodes.
Six years ago, when Ross — a radiology professor at Michigan — started this project, he was not looking for a cancer drug that was absorbed through the lymph nodes. Instead, his proposal to the NCI was for a multi-targeted kinase inhibitor, for which he was given a special seven-year grant to, in his own words, do anything he wanted, “but make it high risk, high reward.”
Over those six years, Ross’ lab has been looking at unconventional structures for and publishing about multifunctional inhibitors. But when it came to this drug, a PI3K and MAPK inhibitor dubbed LP-182, they noticed it was behaving differently and that it was being absorbed at a different rate. “After talking to colleagues, we thought perhaps this is a lymphatically absorbed drug. So we retooled the group, retooled the lab … and we found it, in fact, was lymphatically absorbed,” Ross said. “It was quite astonishing, actually.”
“To my mind, it’s the world’s first kinase inhibitor that’s lymphatically absorbed,” he said.
Most oral drugs are absorbed through the blood, meaning they first pass through the liver, where some drugs are metabolized. The broken-down parts of those drugs can contribute to liver damage, but their drug avoided that by going through the lymph system, according to Ross. Instead, the lymph nodes were “sort of like a gas can that you fill up in your car,” Ross said. “The drug is filling up this big reservoir — it’s being sequestered away from the entire body by the [lymphatic] absorption, and then slowly draining over a day into a neck vein.”
And that slow drip from the lymphatic system means that the drug doesn’t cause an initial spike like traditional oral drugs.
When the researchers put the drug into mice with myelofibrosis, a form of blood cancer where scar tissue builds up in the bone marrow, they saw that all the mice treated with their drug survived to 28 days after treatment — the planned cutoff for the study — while control group mice had progressive disease, “reaching humane endpoints” before 21 days.
The catch, however, is that Ross and his team are still figuring out how exactly their drug works. They are currently testing potential hypothesis, Ross said, noting that it’s a process that takes time.
Ross has spun his lab’s finding off into a new biotech, named Lympharma, where he is both co-founder and CEO. Other biotechs and researchers are also toying with the concept of a lymphatically absorbed cancer drug, albeit with different approaches. In a paper published earlier this week in PNAS, researchers from Tufts University describe an mRNA cancer vaccine targeted to the lymph nodes that boosts T cell response in skin cancer.
And Elicio Therapeutics, founded based on work done in Darrell Irvine’s lab at MIT, is working on “amph-ligands,” in which some drug or protein is bound to a lymph node-targeting lipid. The biotech has a Phase I/II study ongoing for an amph-ligand cancer vaccine for KRAS-mutated cancers. More similar to Ross’ approach, PureTech has a platform searching for an oral prodrug that can evade the liver by going through the lymph nodes.
When asked when he thought his drug for blood cancer could be in the clinic, Ross noted that there was still a ways to go, responding, “optimistically, within two years.”