An investigational drug currently in clinical trials for breast cancer, PMD-026, has shown promise in treating certain blood cancers, according to new research from Washington University School of Medicine in St. Louis. The studies, published in Nature Communications and Blood Cancer Journal, found that inhibiting the protein RSK1 can halt the progression of myeloproliferative neoplasms (MPNs) and an aggressive form of acute myeloid leukemia (AML). This suggests a potential new treatment strategy for these challenging blood cancers, especially in patients who are not candidates for stem cell transplantation.
Targeting RSK1 to Block Cancer Progression
MPNs are slow-growing blood cancers that can persist for years, but they carry a high risk of transforming into secondary AML, a particularly aggressive disease with limited effective treatment options. Current therapies for MPNs primarily focus on managing symptoms such as fatigue and enlarged spleen, without effectively slowing disease progression or preventing transformation to AML.
"Patients with chronic MPNs can live with the disease sometimes for decades, but they’re at increased risk of developing secondary AML, which has a poor prognosis," said Stephen T. Oh, MD, PhD, associate professor of medicine and co-director of the Division of Hematology at WashU Medicine. "These patients have no effective medical therapies, so we hope this new drug will help fill that gap in clinical care. At minimum, we’re hopeful this drug can stop the chronic disease from progressing to AML. But the goal is to eliminate the disease and get patients into remission."
Preclinical Efficacy of PMD-026
The studies utilized PMD-026, an investigational RSK inhibitor currently in clinical trials for breast cancer. In mouse models of MPN, inhibiting RSK1 with PMD-026 reversed disease progression, reducing fibrosis (scar tissue formation) in the bone marrow. After four weeks of treatment, PMD-026 eliminated up to 96% of cancer cells in mice and showed evidence of preventing the chronic disease from transforming into secondary AML.
In a separate study published in Blood Cancer Journal, PMD-026 demonstrated efficacy against FLT3-ITD AML, a specific type of AML that often develops resistance to existing FLT3 inhibitors. Because PMD-026 blocks a different pathway, it could potentially overcome this resistance.
Mechanism of Action and Clinical Implications
An earlier study by Oh’s group identified DUSP6 as a key signaling molecule driving MPN progression. Further investigation revealed that RSK1 is a downstream signal triggered by DUSP6, making it a viable target for intervention. PMD-026 is a pan-RSK inhibitor, blocking all four versions of the protein: RSK1, RSK2, RSK3, and RSK4. In breast cancer, evidence suggests that PMD-026 may work by blocking RSK2.
According to Oh, inhibiting RSK1 may improve patients’ health to the point where they become eligible for stem cell transplants, which are often the preferred therapy for achieving long-term remission in blood cancers. The research team is now exploring the design of clinical trials for patients with advanced MPNs who are not eligible for stem cell transplantation due to age or overall health.
Collaboration and Future Directions
Oh and his team collaborated with Phoenix Molecular Designs, the biotech company that developed PMD-026, which provided the drug for these studies. "We are excited about these studies because they highlight RSK1 as a novel therapeutic target for MPNs and AML with a viable strategy for moving an investigational drug into clinical trials in the near future," Oh said.
