Nature Sub-Journal: New use of old medicine! Classic chemotherapy drug amycin overcomes tumor resistance! Is it just fantastic?

!-- webeditor: page title -- May 4, 2020 / -- Drug resistance is a major barrier to cancer treatment, causing many patients to relapse.
In a new study published in Nature Cell Biology, researchers at the Stolls Institute of Medicine, Kansas City Children's Charity Hospital and the University of Kansas Cancer Center reported a promising new strategy to overcome leukemia resistance by using only the target dose of the widely used chemotherapy drug amycin.
researchers found that low-dose cyclic antibiotic amycin inhibited the interaction between two molecular pathways that worked closely together to promote tumor growth and resistance to treatment.
the study's authors say the targeted approach also clears the way for cancer-targeted immune cells to function, a surprising new discovery.
Photo Source: Dr. John M. Perry, a researcher at the Kansas City Children's Charity Hospital at the Stowers Institute, said, "Low doses of amycin actually stimulate the immune system, whereus the typical clinical dose is immunosuppression, which selectively kills healthy immune cells."
" he completed his postdoctoral work at Stolls and was the first author of the report.
findings are the result of a decade-long collaboration between researchers at the Stolls Institute, Children's Charity Hospital, the University of Kansas Cancer Center and others on how normal, healthy stem cells can self-renew.
in their earlier study, Dr. Linheng Li, a researcher at the Stolls Institute, and Dr. Xi He, a research specialist, showed that the protein kinase Akt enhances the Wnt signal by phosphorylated beta-serial proteins, thereby promoting tumors in the gut.
Perry further studied the Wnt/beta-serial protein and PI3K/Akt path pathrains in the hemastation system.
Perry found in mouse models that genetically modified the Wnt/beta-link protein and PI3K/Akt path path paths, which together drive stem cell renewal, leading to excessive hematopoietic stem cell production.
, but not just stem cell expansion, but the permanent activation of these path paths also led to leukemia in mice.
, the researchers shifted their focus to inhibiting interactions between these pathways and targeting leukemia stem cells.
many drugs that directly target the Wnt/beta-link protein or PI3K/Akt pathfly will eventually fail because cancer cells are resistant to them, and widely used chemotherapy drugs can have serious side effects and systemic toxicity.
researchers worked with Dr. Scott Weir and Dr. Anuradha Roy of the University of Kansas Cancer Center to find different compounds in the center's small molecular database.
We're looking for a drug whose goal is to block the interaction between Wnt/beta-serial proteins and PI3K/Akt and reduce toxicity," said Li, who is a liaison between Stolls and KU Cancer Center and co-director of the center's cancer biology research program.
the team conducted high-volume drug screening, which showed that amycin worked best at suppressing the interaction between the two pathways.
they found that the drug also works at low doses, which is better than using high doses of chemotherapy drugs, which can cause lasting heart damage in some patients.
samples from childhood leukemia patients were also at the center of the study.
samples from each patient before and after chemotherapy to compare the effectiveness of treating drug-resistant leukemia stem cells with treating sensitive leukemia stem cells.
the samples were then transplanted into mice to test them for leukemia and whether low-dose amycin therapy improved their survival and reduced the development of leukemia.
Perry said: "We found that mice transplanted from patients with drug-resistant leukemia stem cells developed rapidly into leukemia, but low-dose amycin therapy improved survival by reducing leukemia stem cells.
, however, mice transplanted from patients without drug-resistant leukemia stem cells did not respond to low-dose amycin therapy.
results suggest that chemotherapy-resistant leukemia stem cells from patients can be reduced through low-dose amoelin therapy, at least in animal model trials.
" Following the success of the mouse model trial, the researchers conducted a small clinical trial with Dr. Tara Lin of Northeastern University Cancer Center to test the effectiveness of low-dose cyclococytic drugs on adults with therapeutic acute myeloid leukemia (AML).
the trial used erythromycin, a chemotherapy drug of the same class as amycin, widely used in the treatment of AML.
bone marrow samples before and immediately after treatment.
half of the study participants responded to treatment and the number of leukemia stem cells, which showed Akt-activated beta-serial protein biomarkers.
addition to these encouraging results, this comprehensive study also reveals startling insights into immune escape -- a sign of the development of cancer, in which cancer cells evade the immune system and multiply.
they found that leukemia stem cells express a variety of proteins called immune checkpoints that shut down the immune response or could identify and eliminate leukemia stem cells.
, another team member, found that beta-serial proteins bind to gene bits at multiple immune checkpoints.
low-dose amycin therapy reduces the expression of these immune checkpoints, including PD-L1, TIM3, and CD24, which causes drug-resistant leukemia stem cells to be killed by immuno-mediated cells.
, Perry is conducting further research on how to screen other drugs, kill drug-resistant cells with low doses of atomycin, and reactivate cancer immunity in children.
team recently conducted a clinical trial of low-dose amycin in pediatric patients.
Li Labs is working on similar strategies to overcome resistance to solid tumors, including breast, glioblastoma and colon cancer.
!--/ewebeditor:page--!--webeditor:page title"--Li said, "This study promises to be a more effective strategy for overcoming drug resistance and immune escape in cancer treatment, which can be used in combination with other cancer treatments, including immunotherapy in patients with chemotherapy, radiotherapy, leukemia, and other types of cancer."
" low-dose amycin also avoids serious side effects of high-dose amycin and may provide a better quality of life for patients.
high doses of amycin can damage the heart muscle.
even if patients survive in the long term, highly toxic anti-cancer treatments often lead to long-term health problems and shorten life expectancy.
pediatric patients should live half a century or more, so we need to work better not only to ensure long-term survival, but also to ensure a healthy and productive life," Perry said.
" () Reference: What's old is new again: Researchers repurpose classic processy drug to overcome cancer therapy resistance John M. Perry et al, Overcoming Wnt-beta-catenin dependent anticancer therapy resistance in leuka stememia cell, Nature Cell Biology (2020). DOI: 10.1038/s41556-020-0507-y/!--/ewebeditor:page--.