They develop a new drug against cancer that is more effective and has fewer side effects

by time news

A team of researchers at the University of Michigan is developing a new cancer drug that is absorbed through the lymphatic system of the gut rather than the blood vessels, potentially lowering drug resistance while increasing tumor-fighting ability and reduces side effects.

In a study published in “Nature Communications,” researchers report a new kinase inhibitor that significantly reduced disease, limited toxicity, and prolonged survival in mice with myelofibrosis, a precursor to acute leukemia.

They designed the oral drug LP-182 to simultaneously target phosphoinositide 3-kinase, also known as PI3K, and mitogen-activated protein kinase, known as MAPK, molecular signaling pathways that drive a high percentage of cancers.

Treatment of the disease often involves combination therapy to target different vulnerabilities of the cancer cells. But because these drugs circulate and are absorbed and eliminated by the body at different rates, it can be challenging to maintain the correct therapeutic balance of each individual drug at a concentration needed to be effective while limiting toxicity and side effects. side effects of the drug, explains Dr. Brian D. Ross, the Roger A. Berg Research Professor of Radiology at the University of Michigan Medical School and lead author of the paper.

Failure to achieve this balance reduces the effectiveness of anticancer drug combinations and can lead to drug resistance, as PI3K and MAPK crosstalk can activate downstream pathways to resist therapy. Even if one drug blocks one pathway, another may provide an escape survival pathway to compensate and continue to grow.

Unlike traditional oral medications, which are often designed to be rapidly absorbed into the bloodstream, researchers who treated mice with myelofibrosis found that gut lymphatic system absorb the LP-182 first. The lymphatic system serves as a storage reservoir, separating the drug from the rest of the body and gradually releasing the therapy into the general circulation over time to maintain drug concentrations at an optimal therapeutic level.

“Within the therapeutic window, we can maintain target inhibition of two distinct pathways that talk to each other,” says Ross, who is also director of the Center for Molecular Imaging at Michigan Medicine. “This demonstrates the feasibility of managing anticancer agents directly into the lymphatic systemwhich opens up a tremendous new opportunity to improve cancer therapeutic outcomes and reduce the side effects of the agents themselves,” he concludes.

In myelofibrosis, excessive scar tissue forms in the bone marrow, disrupting the normal production of blood cells. Overactive molecular signaling leads to proliferation of malignant stem cells, extensive fibrosis, spleen enlargement, 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 cancer spread. Also, according to the author, because the gut’s lymphatic system is home to more than half of the body’s immune cells, the study results could provide approaches for treating autoimmune disorders and other conditions.

The team will continue to expand its 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.

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