<< Back to MOTIFvations Blog Home Page

Can We Manage Cancer with NEMO Analysis of cfDNA in Liquid Biopsies

By Stuart P. Atkinson, Ph.D.

February 19, 2025

Tweet

Introduction: Epigenetic Alterations Accompany Aggressive Prostate Cancer Development

The diagnosis of castration-resistant neuroendocrine prostate cancer (CRPC-NE) - reported in up to 15-20% of patients with late-stage castration-resistant prostate cancer (CRPC) (Bluemn et al. and Abida et al.) - remains a challenging and invasive process beset by intrapatient tumor heterogeneity. This situation represents a significant problem for patients with this aggressive subtype of treatment-resistant cancer, who lack safe and effective therapeutic recourses; however, the delineation of CRPC-NE-specific molecular biomarkers could support early detection and the development of intervention strategies to significantly improve patient management. Can epigenetic analyses play a role?

The evaluation of the epigenetic alterations (such as DNA methylation) that accompany prostate cancer development – which passes from CRPC through castration-resistant adenocarcinoma (CRPC-Adeno) to CRPC-NE (Beltran et al., 2016) – may offer a robust means of disease monitoring/management. Several studies - including those headed by Francesca Demichelis (University of Trento) and Himisha Beltran (Dana Farber Cancer Institute) – revealed the detection of the extensive alterations to DNA methylation profiles observed in CRPC-NE tumor samples (Beltran et al. 2016 and Zhao et al.) in cell-free DNA (cell-free DNA) isolated from patient blood plasma (Berchuk et al. and Beltran et al. 2020). Therefore, the epigenetic analysis of plasma cell-free DNA could represent a non-invasive and accurate means of managing prostate cancer patients, which could improve outcomes of patients with aggressive prostate cancer subtypes.

In a recent study published in Cancer Discovery, Franceschini et al. describe the development and validation of a cell-free DNA-based targeted DNA methylation sequencing panel to non-invasively detect cases of CRPC-NE that they call the NEuroendocrine detection and MOnitoring (NEMO) assay (Franceschini et al.). They hope epigenetic analyses in non-invasive "liquid biopsies" (Heitzer et al.) will support improved and non-invasive prostate cancer management and aid the enhanced detection of the CRPC-NE subtype.

 Back to Table of Contents

DNA Methylation Analysis of Plasma Cell-free DNA: A Non-invasive Means of Managing Prostate Cancer Patients?

As part of their efforts to create a targeted DNA methylation sequencing panel, Franceschini et al. prioritized informative regions of the human genome that reflect CRPC phenotypic states during the extensive investigation of publicly available datasets from pathologically confirmed CRPC-Adeno and CRPC-NE tumor samples, white blood cells, and plasma cell-free DNA from healthy individuals; furthermore, they also integrated the selection of knowledge-driven biomarkers. Interestingly, the analysis of DNA methylation profiles revealed that a very small proportion of CpGs possessed highly informative differential DNA methylation sites that may inform disease progression; therefore, the team designed a relatively small custom DNA methylation sequencing panel to capture only regions of interest in cell-free DNA samples. Overall, a small-sized sequencing panel supports higher coverage sequencing with a lower read throughput, which suits the analysis of cell-free DNA isolated from cancer patients.

Encouragingly, results of the targeted DNA methylation sequencing panel, when applied to cell-free DNA samples (the NEMO assay), sufficed to consistently demonstrate tumor burden, which remains vital for disease management, and distinguish between most cases of CRPC-NE and CRPC-Adeno. Furthermore, the team revealed that the NEMO assay could detect cases of CRPC-NE from independent datasets that previously studied prostate cancer cell lines, organoids, patient-derived xenografts, and patient samples, demonstrating this sequencing panel's overall utility. The team also demonstrated the clinical utility of the NEMO assay through its application to clinical cohorts (demonstrating highly efficient detection of pathology-confirmed CRPC-NE) and clinical trials for aggressive variant CRPC (phase II trials of the aurora kinase A inhibitor alisertib (Beltran et al., 2019) or carboplatin plus docetaxel (Aparicio et al.)), where results provided evidence that methylation-defined cell-free DNA tumor content associated with clinical outcomes. These results suggest that the NEMO assay could aid patient selection for future trials that test the efficacy of novel CRPC–NE–specific therapeutic strategies.

 Back to Table of Contents

Epigenetic Analyses and Liquid Biopsies: The Future of Cancer Management?

Overall, these data support the application of targeted DNA methylation sequencing panels in patient management - including cancer diagnosis and prognosis and the choice of therapeutic strategies - and further support the implementation of both liquid biopsies and epigenetic analyses in routine clinical practice. Additionally, the successful application of a targeted instead of a non-targeted genome-wide approach provides the impetus for implementing "informative" strategies, which may prompt the development of cheaper, faster, and more robust cancer detection strategies.

For more on how the epigenetic analysis of cell-free DNA in liquid biopsies may represent the future of cancer management, see Cancer Discovery, March 2024.

 Back to Table of Contents

About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on X with any questions

Related Articles

<< Back to MOTIFvations Blog Home Page