Researchers discovered that by exploiting the lymphatic system as a reservoir, they could tailor drug concentrations to target two molecular signaling pathways crucial for cancer growth at the same time.
Researchers at the University of Michigan are working on a new anti-cancer drug that is absorbed through the lymphatic system in the gut instead of the blood vessels. This could help avoid the molecular signaling pathways that cause cancer cells to become resistant to drugs while also making the drug more effective and reducing side effects.
Published today in Nature Communications, the team describes a new kinase inhibitor that significantly improved disease outcomes, decreased toxicity, and increased survival in mice with myelofibrosis, a pre-leukemia state.
They created the oral medicine LP-182 to concurrently target the molecular signaling pathways known as mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K), which are responsible for a significant portion of malignancies.
Combination therapies are often used to treat cancer because they can attack different weaknesses in cancer cells. But because the body absorbs and gets rid of these drugs at different rates, it can be hard to keep the right therapeutic balance of each drug at a concentration needed to be effective while limiting drug toxicity and side effects, according to lead author Brian D. Ross.
By activating downstream pathways to resist therapy, PI3K and MAPK crosstalk can impair the efficiency of medication combinations against cancer if this balance is not achieved. Even if one pathway is blocked by medicines, there may be an alternative escape or survival pathway that allows the cell to react and continue growing.
When treating mice with myelofibrosis, researchers discovered that LP-182 is first absorbed by the gut’s lymphatic system, in contrast to conventional oral medications, which are frequently created to be quickly absorbed into the bloodstream. To keep drug concentrations at an ideal therapeutic level, the lymphatic system acts as a storage reservoir, separating the therapy from the rest of the body and releasing it gradually into the general circulation over time.
The director of the Preclinical Molecular Imaging Shared Resource at the U-M Rogel Cancer Center and the Center for Molecular Imaging at Michigan Medicine, 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 shows that it is possible to administer anti-cancer drugs directly into the lymphatic system, which creates a vastly improved possibility for treating cancer while minimizing adverse effects.
In myelofibrosis, the bone marrow produces too much scar tissue, which interferes with the normal development of blood cells. An excessively active molecular signaling pathway causes a proliferation of cancerous stem cells, as well as severe fibrosis, an enlarged spleen, and progressive failure of the bone marrow.
Lymphatic tissue is a typical site for cancer metastasis, thus Ross’s and his team’s discoveries may point to novel ways to stop cancer from spreading. Ross also says that because more than half of the body’s immune cells live in the gut’s lymphatic system, the study’s results could help find ways to treat autoimmune diseases and other conditions.
To prepare for a phase I clinical study in people with myelofibrosis, Ross and his team will continue to broaden their pre-clinical research of LP-182. They are also making more lymphatropic targeted kinase inhibitors to treat solid tumors like breast, brain, gastrointestinal, and pancreatic cancers, as well as autoimmune diseases like lupus and multiple sclerosis.
Image Credit: Getty
You were reading: Your Gut Could Make Cancer Therapy Work Better – New Study Shows How