Penn State researchers have identified a promising new therapeutic approach for acute myeloid leukemia (AML) using two FDA-approved prostate cancer drugs, potentially offering hope for patients with this challenging blood cancer where treatment options have remained largely unchanged for years.
The study, published in Blood Advances, demonstrated that apalutamide and finasteride effectively suppressed AML progression in experimental models using both mice and patient-derived AML cells. This discovery emerged from an unexpected observation during routine laboratory work that led to the identification of androgen signaling as a previously unexplored pathway in leukemia treatment.
Novel Mechanism of Action
The drugs work by inhibiting pathways activated by dihydrotestosterone, an androgen hormone more potent than testosterone. K. Sandeep Prabhu, head of the department of veterinary and biomedical sciences at Penn State and lead author, explained that while androgen signaling is well-established in prostate cancer treatment, "its role in AML has been under-explored."
The research revealed that finasteride slows AML progression by inhibiting dihydrotestosterone production, while apalutamide targets androgen receptor activity through a slightly different pathway. Both drugs demonstrated effectiveness in treating AML in both male and female mice, highlighting their broad therapeutic potential.
Serendipitous Discovery
The breakthrough came when Fenghua Qian, now a senior scientist at Regeneron who led the study as a graduate student at Penn State, noticed unusual patterns while developing an AML mouse model. Some female mice failed to develop AML, while the disease appeared unusually aggressive in certain male mice.
"This was when I switched gears to analyzing the potential role of androgen," Qian said. His investigation revealed that androgen receptors are highly expressed in female donor leukemic cells, and the interaction between androgens and androgen receptors could serve as a therapeutic target.
The team found that in male mice, high dihydrotestosterone promoted AML development despite low androgen receptors in leukemia cells. Conversely, female mice with low dihydrotestosterone levels showed high androgen receptor expression in their leukemia cells, creating a different but equally significant pathway for disease progression.
Clinical Implications
Robert Paulson, professor of veterinary and biomedical sciences at Penn State and co-author, emphasized the clinical significance of these findings. "AML is a tough disease. Many patients relapse and the treatments haven't really changed. It is exciting to identify a new target, the androgen receptor, where there are already FDA approved drugs."
Current AML treatments include chemotherapy, radiotherapy, stem cell transplantation, and emerging immunotherapies. However, androgen receptors have never been considered as therapeutic targets. This study provides what Qian describes as "a novel targetable pathway for leukemia patients" that could potentially benefit those resistant to traditional treatments.
Path to Clinical Translation
The researchers have registered a patent for using androgen receptor inhibitors to treat AML and are preparing for clinical trials. Qian expects to test both drugs in leukemia patients with strict inclusion criteria, particularly those with increased androgen receptor expression in leukemic cells.
The study represents a significant advancement in AML research, as the connection between leukemia and androgen receptors was previously unknown. The discovery demonstrates how careful observation of unexpected experimental results can lead to major therapeutic breakthroughs.
Research Support and Future Directions
The research was supported by the American Institute for Cancer Research, National Institutes of Health, and U.S. Department of Agriculture's National Institute of Food and Agriculture. Additional testing, including human clinical trials, will be necessary to validate the therapeutic potential of these repurposed drugs in AML treatment.
This work exemplifies the potential of drug repurposing strategies, where existing FDA-approved medications are investigated for new therapeutic applications, potentially accelerating the development of treatments for diseases with limited options.
