Oct. 30, 2024
Prostate cancer, one of the most common malignant tumors in men, has increased significantly in recent years. Prostate cancer is the fifth-leading cause of cancer-related deaths among men worldwide. Despite progress in treatments such as surgery, radiotherapy and chemotherapy, metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSIs), is often lethal. Approximately one-third of patients with mCRPC develop lethal resistant disease.
Seeking answers on how to treat patients with the lethal form of the disease led researchers at Mayo Clinic Comprehensive Cancer Center, in Rochester, Minnesota, to a cutting-edge discovery: A new blood analysis biomarker for lethality in patients with mCRPC.
The novel mCRPC work of using liquid biopsy to identify stemness as a lethal factor in patients with mCRPC could explain why patients with AR/enhancer alterations have worse survival outcomes. The findings were part of a multi-institutional study published in Clinical Cancer Research.
This discovery has the potential to:
- Identify new causes of treatment resistance.
- Individualize treatment.
- Improve survival.
Tracking stemness signatures
Earlier studies in prostate cancer as well as other cancer types have primarily relied on analyzing tumor tissue. "We asked if we could get some of these major tumor genomic insights via liquid biopsy from blood plasma and tried to understand the reason behind treatment resistance in patients with lethal prostate cancer. We performed whole genome methylation sequencing of plasma cell-free DNA and developed advanced liquid biopsy analytical technology to infer which transcription factors were more active in these lethal prostate cancer patients," says Pradeep S. Chauhan, Ph.D., a research associate in Radiation Oncology at Mayo Clinic in Rochester, Minnesota, and lead first author of the study.
"Using single-cell RNA sequencing data, we developed a transcription factor signature associated with cancer stemness and worse patient survival. We then validated this signature for increased lethality using new technology that we developed for plasma cell-free DNA in mCRPC patients. We also applied this same lethality signature to a completely held out cohort of patients with mCRPC tumors that were profiled by bulk RNA sequencing and observed that the underlying biology spans well beyond cell-free DNA," says Aadel A. Chaudhuri, M.D, Ph.D., vice chair of Translational Research in Radiation Oncology, enterprise co-director of the Center for Individualized Medicine at Mayo Clinic in Rochester, Minnesota, and senior corresponding author of the study. Dr. Chaudhuri leads the Liquid Biopsy and Translational Immunogenomics Laboratory at Mayo Clinic.
In addition to this validation, the study showed that the underlying mechanism for lethality in prostate cancer involves reprogramming cancer developmental states toward increased stemness. "We found that the stemness program was associated with much worse survival outcomes. This suggests that we could identify this highest risk, most deadly form of the disease, and potentially improve these patients' outcomes by trying to turn down this stemness program, which is likely driving lethal prostate cancer," says Dr. Chaudhuri.
Study highlights
Researchers analyzed 220 patients with mCRPC. Targeted cell-free DNA sequencing detected AR/enhancer alterations prior to first line ARSIs, which correlated with significantly worse PFS (p = 0.01; HR = 2.12) and OS (p = 0.02; HR = 2.48).
Plasma methylome analysis revealed that patients with AR/enhancer lethal mCRPC have significantly higher promoter-level hypomethylation than patients with AR/enhancer wild-type mCRPC (p < 0.0001).
In patients with lethal mCRPC, gene ontology and single-cell RNA sequencing-informed CytoTRACE analysis of nucleosomally more accessible transcription factors in cell-free DNA revealed enrichment of a stemness program.
This stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing.
Transforming the practice
The study findings have the potential to help increase survival with quick and precise intervention. "Prostate cancer in many forms is highly treatable with long survival outcomes, but this lethal subset of the disease is challenging for our prostate cancer doctors. We want to improve outcomes for this deadly form of cancer in men," says Dr. Chaudhuri. "Now that we can identify these patients more precisely using liquid biopsy, we could potentially target their aggressive tumor cells and improve these patients' outcomes."
Next steps
With the ability to detect lethal cancer early in patients with mCRPC, experts at Mayo Clinic Comprehensive Cancer Center could save more lives in the future.
"We're already working on the next study," says Dr. Chaudhuri. "There are other groups working on prostate cancer liquid biopsy, but in terms of this line of research and the impact we're trying to create here at Mayo Clinic, I think we're right at the cutting edge," says Dr. Chaudhuri. "Mayo Clinic is the perfect place to do this highly collaborative, highly translational research with the potential to significantly improve patient outcomes."
For more information
Chauhan PS, et al. Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival in lethal prostate cancer. Clinical Cancer Research. 2024; 10.1158.
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