image: Research from WashU Medicine found a possible new treatment strategy for certain types of blood cancers. The bone marrow of a mouse with a myeloproliferative neoplasm (left) shows fibrosis, or scar tissue (horizontal lines). A mouse with the same disease treated with an RSK1 inhibitor shows bone marrow resembling normal tissue (right).
Credit: TIM KONG AND ANGELO B. A. LARANJEIRA
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.”
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Kong T, Laranjeira ABA, Letson CT, Yu L, Lin S, Fowles JS, Fisher DAC, Ng S, Yang W, He F, Youn M, Mark K, San Jose A, Liu J, Kim AB, Cox MJ, Fulbright MC, Jayanthan A, Los G, Rentschler SL, Ding L, Sakamoto KM, Dunn SE, Challen GA, Oh ST. RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia. Nature Communications. Jan. 16, 2025.
This work was supported by the National Institutes of Health (NIH), grant numbers R01HL134952, T32HL007088, R01HL147978, R01HL163274 and T32HL134635; a Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award; and the MPN Research Foundation. Additional support was provided by the Leukemia and Lymphoma Society Translational Research Program; When Everyone Survives Foundation; the Edward P. Evans Foundation; Gabrielle’s Angel Foundation; Stanford Maternal Child Health Research Institute; the Department of Defense, grant number HT94252311008; Hyundai Hope on Wheels; and a Leukemia and Lymphoma Society Scholarship. Additional support was provided by the NCATS Clinical and Translational Sciences Award, grant number UL1 TR002345; the NCI Cancer Center Support Grant, number P30CA91842; and by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs.
Kong T, Laranjeira ABA, Letson CT, Yu L, He F, Jayanthan A, Los G, Dunn SE, Challen GA, Oh ST. RSK1 dependency in FLT3-ITD acute myeloid leukemia. Blood Cancer Journal. Nov. 26, 2024.
This work was supported by the National Institutes of Health (NIH), grant numbers R01HL134952 and R01HL147978; a Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award; and the MPN Research Foundation. Additional support was provided by the Leukemia and Lymphoma Society Translational Research Program; When Everyone Survives Foundation; the Edward P. Evans Foundation; Gabrielle’s Angel Foundation; and a Leukemia and Lymphoma Society Scholarship.
On both papers, three co-authors are employees of Phoenix Molecular Designs, which provided PMD-026. Co-author Sandra E. Dunn, PhD, founder and CEO of Phoenix Molecular Designs, holds patents on using RSK inhibitors for treatment of cancer.
This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
About Washington University School of Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 56% in the last seven years. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
Journal
Nature Communications
Article Title
RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia
Article Publication Date
16-Jan-2025
COI Statement
On both papers, three co-authors are employees of Phoenix Molecular Designs, which provided PMD-026. Co-author Sandra E. Dunn, PhD, founder and CEO of Phoenix Molecular Designs, holds patents on using RSK inhibitors for treatment of cancer. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.