Potential Genetic Target Found for Treating Pediatric Leukemia

Mesothelin (MSLN), a known therapeutic target in solid tumors, has been shown to be expressed in children and young adult patients with acute myeloid leukemia (AML) and shows promise as a diagnostic and therapeutic target, according to a study published in the American Society of Hematology.

“What prompted us to look at different options was that the current treatment these children are receiving is chemotherapy, which kills both normal cells and cancer cells,” said Sonali Barwe, Ph.D., a researcher at Alfred I DuPont. Hospital for Children and a lead author of the study, in an interview with CURE®. “And often it’s a battle between killing the cancer and killing the patient.”

Other treatments such as stem cell and bone marrow transplants have long-term toxicities and side effects in children, Barwe added. “So it was therefore necessary to find a therapy that specifically kills only the leukemia cells and does not damage the normal cells in the bone marrow, as well as the other normal cells in a growing child.”

Targeted and immunotherapy strategies hold promise as potential treatment strategies to improve survival and reduce toxicity in patients with AML, according to the study. Expression of MSLN (which is absent from normal hematopoietic cells) in a patient with AML can help identify therapies to attack the cancer cells.

“Having mesothelin doesn’t mean you have a worse prognosis or a bad outcome,” Barwe said. “So it’s just a good thing, it’s only good news, you can benefit from these specific therapies.”

For their analysis, the researchers collected diagnostic samples from 2,051 pediatric patients (aged 1 week to 25.59 years) with de novo AML, which means this diagnosis is the first time AML appears in the body. They identified MSLN as highly overexpressed in 36% of AML patients, regardless of age, using next-generation large-scale sequencing efforts.

“MSLN is an ideal therapeutic target in AML because leukemic cells can be targeted with virtually no hematopoietic toxicity,” the authors wrote.

The researchers also demonstrated the target-dependent killing of MSLN + leukemia in vitro and in vivo (outside a living organism and inside, respectively). They also showed that MSLN targeting with antibody-drug conjugates, or highly targeted biopharmaceutical drugs, can be enhanced in AML using a DNA-damaging payload of small molecules or cellular toxins, protein toxins, proteins, enzymes and radionuclides.

“This is just a small opening of the door that we have identified one target, but more studies are certainly underway to identify other specific targets,” Barwe said.

The knowledge of MSLN expression in pediatric AML may lead to the availability of immunotherapy options, Barwe said.

“There are, in my mind, five or six different ways that you can activate the patient’s immune system so that it specifically recognizes the tumor cells and kills those cells,” Barwe said. So you’re trying different methodologies to activate this immune system. And it’s really exciting in the sense that it works. My strongest point is preclinical models, so it works very well in the preclinical model. We’re excited to take it further into clinical trials and see how it works in children. “

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