Credit: Institute of Immunology La Jolla
University of Michigan scientists have developed a cancer drug that is absorbed through the gut’s lymphatic system that can overcome molecular signaling pathways that lead to drug resistance, while increasing the ability to fight cancer and reduce side effects. Their findings show that the kinase inhibitor significantly reduced disease, limited toxicity and prolonged survival in mice with myelofibrosis, a precursor to acute leukemia.
The findings are published in Nature Communications and are led by Brian D. Ross, PhD, the Roger A. Berg Research Professor of Radiology at the University of Michigan Medical School.
The authors explained: “PI3K and MAPK are among the most disrupted oncogenic signaling pathways in solid malignancies, and clinical efficacy with single pathway inhibitors has been poor due to inappropriate target suppression, activation of compensatory signaling and converging downstream targets … kinase treatments Inhibitor combinations remain clinically challenging as trials have struggled to strike a positive balance between gains in survival, therapeutic efficacy and dose-limiting toxicity.”
The orally administered compound LP-182, which has been designed by Ross and colleagues, can simultaneously target the PI3K and MAPK signaling pathways. “Using synthetic medicinal chemistry coupled with computational docking studies, we report the development of a potent and selective, orally bioavailable, single-molecule multifunctional kinase inhibitor (LP-182) against the PI3K and MAPK signaling pathways “, the researchers noted.
In myelofibrosis, excessive scar tissue forms in the bone marrow, which disrupts the normal production of blood cells. Hyperactive molecular signaling leads to proliferation of malignant stem cells, extensive fibrosis, enlarged spleen, and progressive bone marrow failure. The disease spreads through lymphatic tissue, which is also a common route for cancer metastasis, so Ross and his team’s findings may offer new strategies to prevent the spread of cancer.
Unlike traditional oral drugs, which are often designed to be quickly absorbed into the bloodstream, researchers treating mouse models of myelofibrosis using LP-182 confirmed that the new compound is first absorbed by the lymphatic system of the gut. The lymphatic system serves as a storage reservoir, separating the compound from the rest of the body and gradually releasing it into the general circulation over time to maintain drug concentrations at an optimal therapeutic level. “LP-182 achieved selective and potent inhibition of the PI3K and MAPK signaling pathways both in vitro and in vivo,” the authors noted. “… We demonstrate therapeutic selectivity and efficacy by reducing downstream kinase activation, ameliorating disease phenotypes, and improving survival in animal models of myelofibrosis.”
Also, Ross says, because the gut’s lymphatic system houses more than half of the body’s immune cells, “more than 90 percent of the lymphocyte pool resides within the lymphatic system, about 50 percent of which are located in the intestinal lymph and lymphoid tissues”. The team said: The results could point to new approaches to treating autoimmune disorders and other conditions. “The ability to modulate targets using lymphatic-directed small molecules creates the possibility of forming an inhospitable environment to disrupt aberrant signal transduction, cell trafficking, and immune cell networks, thereby reducing viability within the lymphoid niche.” protective,'” the researchers suggested. “Thus, lymphatic targeting of lymphoid or cancer cells represents promising clinical applications for the development of lymphotropic therapy to address the challenges of autoimmunity and metastasis.”
Commenting further on the newly reported study, Ross said: “Within the therapeutic window, we are able to maintain on-target inhibition of two different pathways that talk to each other. This demonstrates the feasibility of delivering anticancer agents directly to the lymphatic system, which opens up a huge new opportunity to improve cancer therapeutic outcomes and reduce the side effects of the agents themselves.” Ross is also director of the Michigan Medicine Molecular Imaging Center and director of the Preclinical Molecular Imaging Shared Resource at the UM Rogel Cancer Center.
The authors acknowledged that further research is required on the transport and properties of lymphatically absorbed compounds. However, they noted, “the presented synthetic medicinal chemistry strategy provides a flexible foundation along with the motivation to stimulate further design of lymphotropic compounds to target single or multiple signaling pathways… The archetypal design of LP-182 sets a benchmark for the development of lymphotropic compounds that include drug repurposing in which existing drugs could be adapted for lymphatic delivery to provide innovative therapeutic opportunities.”
The researchers intend to continue expanding their preclinical studies of LP-182, with the goal of establishing a Phase I clinical trial in human patients with myelofibrosis. They are also developing additional lymphotropic-targeted kinase inhibitors to treat solid tumors, including breast, brain, gastrointestinal and pancreatic cancers, along with autoimmune diseases such as lupus and multiple sclerosis. The team concluded, “Our further characterization of the synthetic and physiochemical properties for lymphatic uptake of small molecules will support continued advances in lymphotropic therapy to alter disease trajectories for a myriad of disease indications human”.