A team of University of Michigan researchers has developed a new anti-cancer drug that is absorbed through the gut’s lymphatic system rather than blood vessels, potentially outmaneuvering the molecular signaling pathways that lead to drug resistance, while increasing cancer-fighting ability and reducing side effects. In their reported study the scientists showed that the kinase inhibitor significantly reduced disease, limited toxicity, and prolonged survival in mice with myelofibrosis, a precursor to acute leukemia.
Brian D. Ross, PhD, the Roger A. Berg Research Professor of Radiology at the University of Michigan Medical School, is lead author of the team’s published paper in Nature Communications, which is titled, “A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy.”
Cancer treatment often involves combination therapy to target different cancer cell vulnerabilities. But because these drugs circulate through and are absorbed and removed by the body at different rates, it can be challenging to sustain the right therapeutic balance of each individual drug at a concentration necessary to be effective while limiting drug toxicity and side effects, explained Ross.
Failure to strike this balance reduces the effectiveness of the drug combinations against cancer and can lead to drug resistance, as phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) crosstalk can activate downstream pathways to resist therapy. (PI3K and MAPK are key molecular signaling pathways that drive a high percentage of cancers.) Even if a drug blocks one pathway, another can provide an escape survival pathway to compensate and continue growing.
The authors explained, “PI3K and MAPK are amongst the most altered oncogenic signaling pathways in solid malignancies, and clinical efficiency using single-pathway inhibitors has been poor due to inadequate target suppression, activation of compensatory signaling, and convergent downstream targets … treatments using kinase inhibitor combinations remain a challenge clinically as trials have struggled to create 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 both the PI3K and MAPK signaling pathways. “Using synthetic medicinal chemistry along with computational docking studies, we report the development of a potent and selective, orally bioavailable, single-molecule multi-functional kinase inhibitor (LP-182) against PI3K and MAPK signaling pathways,” the investigators noted.
In myelofibrosis, excessive scar tissue forms in the bone marrow, disrupting normal blood cell production. Overactive molecular signaling leads to a 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 the findings from Ross and his team may offer new strategies to prevent cancer spread.
Unlike traditional oral drugs, which are often designed to be rapidly absorbed into the bloodstream, researchers treating mouse models of myelofibrosis using LP-182 confirmed that the new compound is absorbed by the gut’s lymphatic system first. 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 PI3K and MAPK signaling pathways both in vitro and in vivo,” the authors noted. ” … We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis.”
Furthermore, Ross says, because the gut’s lymphatic system harbors over half the body’s immune cells—“greater than 90% of the lymphocyte pool resides within the lymphatic system, approximately 50% of which are localized in the intestinal lymph and lymphoid tissues,” the team stated—the results could point to new approaches for the treatment of autoimmune disorders and other conditions. “The ability to modulate targets using lymphatically-directed small molecules creates the prospect of forming an inhospitable environment to disrupt aberrant signal transduction, cellular trafficking, and immune cell networks, thereby reducing viability within the ‘protective’ lymphoid niche,” the investigators suggested. “Thus, lymphatic targeting of lymphoid or cancer cells represent promising clinical applications for development of lymphatropic therapy to address challenges in autoimmunity and metastasis.”
Further commenting on the newly reported study, Ross said, “Within the therapeutic window, we are able to maintain the on-target inhibition of two distinct pathways that are talking to one another. This demonstrates the feasibility of delivering anti-cancer agents directly into the lymphatic system, which opens tremendous new opportunity for improving cancer therapeutic outcomes and reducing the side effects of the agents themselves.” Ross is also the director of the Center for Molecular Imaging at Michigan Medicine and director of the Preclinical Molecular Imaging Shared Resource at the U-M Rogel Cancer Center.
The authors acknowledged that more research on the transport and properties of lymphatically absorbed compounds is required. Nevertheless, they noted, “the presented synthetic medicinal chemistry strategy provides a flexible foundation along with motivation to stimulate further design of lymphatropic compounds for targeting single or multiple signaling pathways … The archetypal design of LP-182 establishes a benchmark for development of lymphatropic compounds including drug repurposing in which existing drugs could be adapted for lymphatic delivery to provide innovative therapeutic opportunities.”
The researchers aim to continue to expand their preclinical studies of LP-182, with the goal of setting up a Phase I clinical trial in human patients with myelofibrosis. They are also developing additional lymphatropic 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 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.”