Acute myeloid leukemia (AML), an aggressive and often fatal blood cancer, has long been resistant to a class of drugs called proteasome inhibitors that are effective against multiple myeloma.
A new study by researchers at the University of California, San Diego shows why. When proteasome inhibitors are blocked, AML cells activate backup stress response systems to maintain survival.
By combining a proteasome inhibitor with a second drug that disables one of two backup survival pathways, the research team was able to more effectively kill AML cells in preclinical models, reducing disease burden and extending survival.
Why are proteasome inhibitors alone ineffective in treating AML?
AML, the most common adult leukemia, is notoriously difficult to treat. Approximately 70% of patients die within 5 years of diagnosis.
Current treatments are either broadly toxic, such as chemotherapy, or narrowly focused on rare genetic mutations.
A new study by Dr. Robert Signer, senior author and associate professor in the Department of Regenerative Medicine at the University of California, San Diego School of Medicine, and his team demonstrated why proteasome inhibitors alone are ineffective against AML.
Unlike multiple myeloma cells, AML cells can use a backup system controlled by the HSF1 gene, autophagy, to stay healthy when such drugs are used. These emergency salvage and recycling pathways prevent protein “garbage” from accumulating, allowing AML cells to maintain health and resist death, even when the proteasome is disabled.
“Imagine you’re driving down the freeway and you hit a construction site. All you have to do is choose a different route. When AML cells hit a proteasome inhibitor ‘construction site,’ they do the same thing, rewiring their networks to take the exit ramp and stay on the road.”
“Multiple myeloma, on the other hand, remains a sitting duck in traffic.”
Combining proteasome inhibitors slows cell growth
By combining a proteasome inhibitor with the drug Lys05, which inhibits autophagy, the researchers were able to block the AML bypass pathway.
Tests on AML patient cells showed that the combination slowed the growth and establishment of cancer cells.
“There are so many potential genetic mutations involved in AML, which makes developing treatments extremely difficult,” said lead author Kentson Lamb, MD, PhD, assistant professor of medicine at the University of California, San Diego School of Medicine.
“Even if a therapy that targets a particular genetic mutation is successful, it only benefits a small percentage of patients whose cancers carry that particular mutation. We wanted to help more patients by making this attack more mutation-agnostic.”
“We tested this approach on a variety of AML cell lines and patient samples, and it worked on nearly all cell lines, regardless of mutation.”
Improving treatment options for more patients
The researchers used their expertise in stem cells, from which AML cells are formed, as opposed to multiple myeloma cells, to develop an alternative treatment pathway.
They are currently working to identify additional drugs that may disable back-up survival strategies in AML, with the goal of advancing the combination therapy into clinical trials.
“Targeting these protein pathways is a new approach to cancer treatment. Our hope is that this new research will improve treatment options for a wide range of AML patients.”
“As scientists, that is our ultimate goal: to find new ways to treat diseases to improve lives.”
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