Recent research from the Washington University School of Medicine in St. Louis has uncovered a promising approach to halt the advancement of various types of blood cancers by using a medication that is currently being tested for breast cancer.
These studies, which involved both patient samples and animal models, showed that blocking a protein called RSK1 can reduce inflammation and inhibit the progression of myeloproliferative neoplasms (MPNs) and a severe form of acute myeloid leukemia (AML). Since the RSK1 inhibitor is already undergoing clinical trials, it could potentially be fast-tracked for treating blood cancers.
One of the studies is published on January 16 in Nature Communications, while another is available online in Blood Cancer Journal.
MPNs in humans can develop slowly, lasting for years without a definitive cure to slow their progression. Physicians can only manage symptoms, but the disease can eventually lead to a more aggressive form of AML for which there are limited treatment options.
“Individuals with chronic MPNs may live with the illness for decades, but they face a heightened risk of developing secondary AML, which has poor outcomes,” explained senior author Stephen T. Oh, MD, PhD, an associate professor of medicine and co-director of the Division of Hematology at WashU Medicine. “At this point, there are no effective treatments, so we are optimistic that this new drug will help bridge that gap. Ideally, we want to stop the chronic disease from advancing to AML and work towards completely eliminating it to allow patients to achieve remission.”
Oh noted that researchers have long sought ways to inhibit MPN progression, as existing therapies only alleviate symptoms such as fatigue, night sweats, loss of appetite, weight reduction, and spleen enlargement without effectively slowing the disease or preventing its transition to acute leukemia.
Theoretically, treating patients with chronic MPNs with RSK1 inhibitors might enhance their health to a level where they could qualify for a stem cell transplant — considered the preferred treatment for many blood cancers and potentially leading to long-term remission. Oh provides care for patients with MPNs and related blood disorders at the Siteman Cancer Center associated with Barnes-Jewish Hospital and WashU Medicine.
In the study published in Nature Communications, RSK1 inhibition reversed MPN progression in mice, reducing bone marrow fibrosis. After four weeks, the inhibitor eliminated up to 96% of cancerous cells in these mice, and it also displayed potential in preventing the chronic disease from evolving into secondary AML.
The Blood Cancer Journal study highlighted that blocking RSK1 can be effective against a specific type of AML known as FLT3-ITD AML that arises directly without prior MPN development. Although this AML can initially be treated with FLT3 inhibitors, many patients eventually develop resistance. Because RSK1 inhibitors target a different biological pathway, Oh and his colleagues proposed that they could help counteract this resistance.
The RSK1 inhibitor studied in both experiments, PMD-026, is administered orally and is under clinical trials for breast cancer treatment. The trials aim to assess its effectiveness, and initial findings suggest that participants with metastatic breast cancer have tolerated it well, experiencing minimal side effects.
Understanding and halting MPN development
Previous research from Oh’s group identified a signaling molecule named DUSP6 as a critical protein contributing to MPN progression. They then discovered downstream signals activated by DUSP6, with RSK1 emerging as a target that might be inhibited by the RSK1 blocker already in breast cancer trials.
The investigational drug PMD-026 acts as a pan-RSK inhibitor, which means it inhibits all four variants of the RSK protein family: RSK1, RSK2, RSK3, and RSK4. In the context of breast cancer, evidence indicates that PMD-026 may function by inhibiting RSK2. If the FDA approves it for breast cancer treatment, it would become the first medication available that targets the RSK protein family.
Oh and his team, including Tim Kong, who is the lead author of both studies and an MD-PhD student, expressed interest in collaborating with the drug’s manufacturer, Phoenix Molecular Designs, after pinpointing RSK1 as a significant contributor to various blood cancers. They speculated that this drug could be effective in suppressing RSK1’s activity as well. The company supplied the drug for these research projects.
“We are thrilled about these findings because they underscore RSK1 as a new target for treating MPNs and AML, suggesting a feasible path to move this investigational drug into clinical trials soon,” Oh remarked. “We are considering several approaches for designing future clinical trials, likely focusing on patients who have exhausted standard therapies for chronic phases of the disease and are ineligible for stem cell transplantation due to age or health issues.”
