New ideas for targeted therapy of drug-resistant leukemia

This preclinical study, published in the September issue of " Blood Cancer Discovery ", is expected to clear pharmacological obstacles for the development of AML molecular targeted therapies
.

About one-third of AML patients have FLT3 gene mutations
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The normal FLT3 gene produces an enzyme that signals bone marrow stem cells to grow and replenish

FLT3 mutant AML is particularly sensitive to a class of drugs called e-family tyrosine kinase inhibitors (TKIs), making them the first choice for drug development, said first author David Young, MD, who was in Johns Hopkins The University Kimmel Cancer Center conducted this research
.
Dr.

However, these TKIs and other drugs often fail and patients relapse
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In a series of experiments on human leukemia cell lines and mice, the Kimmel Cancer Center team proved that the combination of human α(1)-acid glycoprotein (AGP) with the drug effectively prevents the drug from reaching the expected FLT3 mutation target and killing Dead cancer cells

Johns Hopkins University Kimmel Cancer Center Pediatric Oncology Department Director and Kyle Haydock Professor of Oncology Dr.
Donald Small, and colleagues used letatinib, TTT-3002 or midostaurin (midostaurin) It is a drug approved by the Food and Drug Administration (FDA) that targets different concentrations of FLT3 to treat mutant FLT3 cell lines grown from healthy donors or human plasma under standard laboratory conditions
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Plasma is the transparent part of the blood that contains proteins and other non-cytokines

In order to prove the clinical significance of these findings, the researchers collected blood samples from adults newly diagnosed with AML and observed the effect of their plasma on midostauline
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In the case of high inflammation, such as in newly diagnosed leukemia patients, AGP levels are elevated

Young said: "Midotuolin is very specific and effective.
Since the FDA approved it for adult AML patients in 2017, we have seen an improvement in patient prognosis by about 10%, but we have never got the'duty we want'.
'Because it is combined with AGP
.
"

In another set of experiments, the team showed that by adding an agent that also binds to AGP, this plasma protein inhibition can be reversed
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The affinity of midostauline to AGP is equal to or greater than that of the three drugs in the study

Young explained: "We want to release enough midostauline for the drug to work
.
If we give people AGP and then midostauline and mifepristone, it will kill the leukemia cells

Although more testing and verification are needed, the researchers said that mifepristone or other drugs with similar AGP binding properties can be tested in future clinical trials of combined TKI therapy, or developed as protein plasma "bait".

"Maybe there is a way to influence the pharmacology of the human body and give these old drugs a new life," Young said
.

David J.
Young, Bao Nguyen, Li Li, Tomoyasu Higashimoto, Mark J.
Levis, Jun O.
Liu, Donald Small.
A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors .
Blood Cancer Discovery , 2021; 2 (5): 532 DOI: 10.
1158/2643-3230.
BCD-20-0119