Two new studies led by researchers at Washington University School of Medicine in St. Louis have identified a possible way to block the progression of several forms of blood cancer using a drug already in clinical trials against breast cancer.
The studies — both conducted in patient samples and animal models — found that inhibiting a protein called RSK1 reduces inflammation and stops the progression of blood cancers called myeloproliferative neoplasms (MPNs) as well as an aggressive form of acute myeloid leukemia (AML). With the RSK1 inhibitor already in clinical testing, the path to expanded use as a treatment for blood cancers likely is accelerated.
One study appears Jan. 16 in Nature Communications. The second is available online in Blood Cancer Journal.
In humans, MPNs can be slow-growing blood cancers that simmer for years. Doctors can monitor the disease and treat symptoms, but there is no reliable way to cure it or slow progression. Patients with MPNs are at high risk of developing a secondary AML that is very aggressive with no effective treatment options.
"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 senior author Stephen T. Oh, MD, PhD , an 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."
According to Oh, researchers have long been seeking an inhibitor to block MPN progression because current therapies only reduce symptoms caused by the disease, including severe fatigue, night sweats, poor appetite, weight loss, and an enlarged spleen, but do not slow progression of the disease or reduce the risk of it evolving into acute leukemia.
In theory, using RSK1 inhibitors to treat patients with chronic MPNs may improve their health to a point where they could become eligible for a stem cell transplant, which is the preferred therapy for many blood cancers because it can potentially lead to long-term remission. Oh treats patients with MPNs and related blood cancers at Siteman Cancer Center , based at Barnes-Jewish Hospital and WashU Medicine.
In the Nature Communications study, inhibiting RSK1 helped reverse the progression of MPNs in mice, reducing fibrosis, or scar formation, in the bone marrow. Inhibiting RSK1 eliminated up to 96% of cancer in mice after four weeks. It also showed evidence of preventing the chronic disease from transforming into secondary AML.
In the Blood Cancer Journal study, blocking this protein treats a specific form of AML called FLT3-ITD AML that develops directly — without an MPN developing first. This type of AML can be treated with established drugs called FLT3 inhibitors, but the cancer often develops resistance to this treatment over time. Because the RSK1 inhibitor blocks a different pathway, Oh and his co-authors suggested, it could help address this resistance.
The specific RSK1 inhibitor used in both studies, called PMD-026, is given as a pill and is currently in clinical trials as a treatment for breast cancer. Those ongoing studies seek to determine efficacy, and early testing showed trial subjects with metastatic breast cancer have tolerated the drug well with low-grade side effects.
Tracking the path to MPN development – and stopping it
An earlier study by Oh's group identified a signaling molecule called DUSP6 as an important protein driving the progression of MPNs. Further work identified the downstream signals triggered by DUSP6, and RSK1 stood out as the one they could potentially block with the RSK1 inhibitor already in clinical trials for breast cancer.
The investigational drug PMD-026 is a pan-RSK inhibitor in that it blocks all four versions of the protein — RSK1, RSK2, RSK3 and RSK4. In breast cancer, the evidence suggests that PMD-026 may work by blocking RSK2. If approved by the Food and Drug Administration to treat breast cancer, it would be the first drug on the market to inhibit the RSK family of proteins.
Oh and his team, including Tim Kong, first author of both studies and an MD-PhD student in Oh's lab, became interested in working with the company that makes the drug — a biotech firm called Phoenix Molecular Designs — when they identified RSK1 as a key driver of several blood cancers and hypothesized that this drug potentially could block its activity as well. The company 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. "There are a few scenarios that we're considering in designing a future clinical trial. It will most likely be for patients who are beyond the standard therapies that we use for the chronic phase of this disease but are not eligible for stem cell transplantation due to age or overall health."