Scientists at the Sanford Burnham Prebys Medical Discovery Institute have shown that two existing drug candidates – JAK inhibitors and Mepron – have potential as treatments for a deadly acute myeloid leukemia (AML) subtype that is more common in children. The foundational study, published in the journal Blood, is a first step toward finding effective treatments for the difficult-to-treat blood cancer.
“While highly successful therapies have been found for other blood cancers, most children diagnosed with AML subtype are still treated with aggressive, toxic chemotherapies,” said Ani Deshpande, Ph.D., assistant professor at Sanford Burnham Prebys. National Cancer Institute (NCI) designated cancer center and senior author of the study. “We are excited about this study because we have uncovered two promising therapeutic targets for which drugs already exist, paving the way for potential clinical trials.”
AML is often caused by a chromosomal fusion – when part of one chromosome attaches to another chromosome – resulting in a fused protein that stimulates the uncontrolled growth of immature blood cells. There are dozens of different fusion proteins that can cause the cancer, and survival rates can vary depending on the fusion type. This study focused on a subtype of AML with fusions with a protein called AF10, which is common in pediatric AML and is more deadly. Many children with these subtypes do not survive very long; and when a child responds to treatment, they often have debilitating, lifelong side effects that come from undergoing chemotherapy at a young age.
“After Luke battled AML, we found that there are few to no treatment options for his fusion type and that this type of cancer research is really underfunded,” said Rena Johnson, co-founder of the Luke Tatsu Johnson Foundation, which partially funded the research. . . “These findings give me hope for a future where kids like Luke can grow up and thrive.”
Focused on cancer-specific mergers
When chromosomal fusions were first identified as a cause of AML, cancer researchers hoped that treatments could be found with relative ease. The protein produced by the fusion is unique to cancer cells and provides a target that can selectively kill tumors and spare healthy cells.
“One of the most successful cancer drugs ever developed, Gleevec, actually targets a fusion protein. This drug melts away tumors in people with a different type of blood cancer, chronic myeloid leukemia or CML,” explains Deshpande. “We were lucky, however, because the fusion protein that Gleevec targets is a kinase, a type of protein that is relatively easy to drug against. Now we know that most fusions involve other types of proteins, such as transcription factors or chromatin modifiers, which are not so readily drugable. “
To overcome this hurdle, Deshpande and his team got creative. The scientists decided to map out which proteins interact with – or are “friends” with – the abnormal AF10 fusion proteins, using mouse models that can turn on and off production of the protein. This work revealed that AF10 fusion proteins activate the inflammatory signaling proteins JAK1 and STAT3 – both drugable targets for which inhibitors already exist. The scientists showed that both JAK1 and STAT3 inhibitors slowed the growth of human AML cells; and that Mepron, a STAT3 inhibitor, melted AML tumors and extended survival in mice with the CALM-AF10 mutation.
“Interestingly, many people with AML are already receiving Mepron to protect against infection after a bone marrow transplant, and analysis suggests this is related to better outcomes. Our studies show that AF10 fusion positive patients may benefit from this drug”, says Bo-Rui. Chen, Ph.D., who completed the study as a postdoctoral fellow in the Deshpande lab, and is the study’s co-lead author. “We are also very excited about our findings because one JAK inhibitor has already been approved by the FDA and many others are being developed for autoimmune diseases, meaning they can be brought to the clinic relatively quickly.”
The scientists warn that while the results are exciting, more data is needed before children or adults with these AML subtypes can start receiving the drug candidates.
“Before we can proceed with clinical trials to test these drugs in humans with these AML subtypes, we need to test both drugs in larger cohorts of mouse models,” said Anagha Deshpande, Ph.D., senior research associate in the Deshpande lab and co. -first author of the study. “However, if those studies are favorable, clinical development will be accelerated as these drugs are known to be safe for humans already.”
Reference: Chen BR, Deshpande A, Barbosa KO, et al. A JAK / STAT-mediated inflammatory signaling cascade stimulates oncogenesis in af10-rearranged AML. Blood. 2021; (blood.2020009023). doi: 10.1182 / blood.2020009023
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