August 18, 2022 -- A novel kinase inhibitor, absorbed through the gut’s lymphatic system rather than blood vessels, significantly reduced disease, limited toxicity, and prolonged survival in mice with myelofibrosis, according to a University of Michigan study published August 17 in Nature Communications.
Researchers designed an oral medication LP-182 to simultaneously target phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), molecular signaling pathways that drive a high percentage of cancers.
While problems can arise when cancer drug combinations lead to drug resistance, as PI3K and MAPK crosstalk activate downstream pathways to resist therapy, researchers demonstrate how this type of novel drug is absorbed through the lymphatic system, potentially outmaneuvering the molecular signaling pathways that lead to drug resistance while increasing cancer-fighting ability and reducing side effects.
Treating mice with myelofibrosis, a type of bone marrow cancer that disrupts normal production of blood cells, researchers discovered that LP-182 is absorbed by the gut's lymphatic system first in which the drug is separated from the rest of the body and gradually released into the general circulation over time maintaining concentrations at an optimal therapeutic level. Traditional oral drugs are often designed to be rapidly absorbed into the bloodstream.
"We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications," the study's authors wrote.
Lead author Brian Ross, PhD, the Roger A. Berg Research Professor of Radiology at the University of Michigan Medical School, in a statement noted that myelofibrosis spreads through lymphatic tissue and his team's findings may offer new strategies to prevent cancer spread. Ross contends that because the gut's lymphatic system harbors over half the body's immune cells, results of the study could also provide approaches for the treatment of autoimmune disorders and other conditions.
Going forward, researchers plan to expand their preclinical studies of LP-182 with the goal of setting up a phase I clinical trial in human patients with myelofibrosis. In addition, they are developing lymphatropic-targeted kinase inhibitors to treat solid tumors, including breast, brain, gastrointestinal and pancreatic cancers, as well as autoimmune diseases such as lupus and multiple sclerosis.