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New Study Removes Pharmacological Barrier in Development of Molecularly Targeted Therapies for AML

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New research from researchers at the Johns Hopkins Kimmel Cancer Center shows why some drugs in clinical trials to treat a form of acute myeloid leukemia (AML) often fail and demonstrate a way to restore their effectiveness.

The preclinical study, published in September in Discovery of blood cancer, potentially eliminates a pharmacological barrier in the development of molecularly targeted therapies for AML.

About a third of patients with AML have a mutation in the FLT3 gene. Normal FLT3 genes produce an enzyme that signals stem cells in the bone marrow to grow and rebuild. Once mutated, FLT3 causes rapid growth of leukemia cells, resulting in higher relapse rates after treatment and lower overall survival.

FLT3-mutated AML is particularly sensitive to a class of drugs called electronic family tyrosine kinase (TKI) inhibitors, making them prime candidates for drug development, says lead author David Young, MD, Ph.D., who conducted the study while at the Johns Hopkins Kimmel Cancer Center. Dr Young is now at the National Heart, Lung and Blood Institute of the National Institutes of Health.

However, these and other TKIs often fail and patients relapse. In a series of experiments with human leukemia cell lines and mice, the Kimmel Cancer Center team demonstrated that human alpha (1) -acid glycoprotein (AGP) binds to the drug, effectively preventing it from being released. ‘hit its FLT3 mutation target and kill cancer. cells.

Donald Small, MD, Ph.D., director of the division of pediatric oncology and Kyle Haydock professor of oncology at the Johns Hopkins Kimmel Cancer Center, and colleagues processed FLT3 mutant cell lines grown in human plasma from donors or under standard laboratory conditions with lestaurtinib, TTT-3002 or midostaurin, a drug approved by the Food and Drug Administration (FDA) that targets FLT3 – at various concentrations. Plasma is the clear part of the blood that contains proteins and other non-cellular factors. They found that adding human plasma reduced the ability of TKI to inhibit FLT3, unlike blood components from other sources. Further tests identified human AGP as binding the three drugs and inhibiting their ability to kill leukemia cells.

To demonstrate the clinical relevance of the results, the researchers collected blood samples from adults newly diagnosed with AML and examined the effect of their plasma on midostaurin. In the presence of high inflammation, such as in newly diagnosed leukemia patients, AGP levels are high. As expected, the drug lost its effectiveness in measuring human plasma in these cases.

Midostaurin is very specific and potent, and we’ve seen about a 10% improvement in patient outcomes since the FDA approved it for use in adults with AML in 2017, but we never got the ” home run “which we were looking for because it is bound by AGP.”

David Young, MD, Ph.D., first author

In another set of experiments, the team showed that this inhibition of plasma proteins could be reversed by adding an agent that also binds to AGP. Mifepristone is known to bind AGP with comparable or greater affinity than the three drugs in the study. The researchers performed the FLT3 test with plasma of human proteins, midostaurin, and mifepristone. They found that mifepristone displaced AGP-bound midostaurin, restoring its anti-FLT3 activity. By testing the concept on mice, they obtained similar results.

“We wanted to release enough midostaurin to allow the drug to do its job,” Young explains. “If we give human AGP and midostaurin plus mifepristone, it kills leukemia cells. Mifepristone acts as a decoy that prevents midostaurin from binding to glycoprotein.”

Although more testing and validation is needed, the researchers say mifepristone or other agents with similar AGP-binding properties could be tested in future clinical trials of TKI combination therapy, or developed as ” decoys “of plasma proteins to increase the effectiveness of molecularly targeted therapies. Johns Hopkins Drug Library Screening – a collection of nearly 3,000 FDA-approved drugs and compounds, curated by study co-author Jun Liu, Ph.D., co-director of the chemical biology program and structural cancer at the Johns Hopkins Kimmel Cancer Center – offered tantalizing promises of more drugs that might work like mifepristone to restore anti-FLT3 activity and might synergize with TKI therapies in other ways .

“There may be ways to affect the pharmacology of the human body to breathe new life into these old drugs,” Young said.

Source:

Journal reference:

Young DJ et al. (2021) A method to overcome plasma protein inhibition of tyrosine kinase inhibitors. Discovery of blood cancer. doi.org/10.1158/2643-3230.BCD-20-0119.


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