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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Double-negative prostate cancer: Evolutionary mechanisms, microenvironmental remodeling, and clinical translation
Lei Fan1, Jiawei Li1, Chunhao Mo1
1Department of Urology, Gansu Province Clinical Research Center for urinary system disease, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
Abstract:
The management of metastatic castration-resistant prostate cancer (mCRPC) is continuously challenged by the emergence of therapeutic resistance. Under the selective pressure of profound androgen inhibition, a significant proportion of tumors undergo lineage plasticity, evolving into double-negative prostate cancer (DNPC). Defined by the concomitant loss of androgen receptor (AR) dependence and the absence of classic neuroendocrine markers, DNPC represents a highly aggressive, independent evolutionary steady state. The fundamental drivers of this phenotypic transition include the concurrent functional loss of TP53 and RB1, coupled with pervasive epigenetic reprogramming. These genetic and epigenetic events profoundly rewire core transcriptional networks, activate alternative kinase pathways, and establish an immunosuppressive microenvironment. Because the downregulation of conventional targets renders standard diagnostic and therapeutic interventions ineffective, a paradigm shift in clinical strategy is imperative. This review delineates the molecular ontogeny of DNPC. We further explore mechanistically grounded therapeutic modalities, including epigenetic modulation, synthetic lethality, and precision delivery systems. Ultimately, we advocate for the concept of "evolutionary interception," providing a strategic roadmap to dismantle the survival networks of advanced DNPC.
Insights
Metastatic castration-resistant prostate cancer (mCRPC) can evolve into aggressive double-negative prostate cancer (DNPC) due to genetic changes like TP53 and RB1 loss. This review explores DNPC
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) management faces challenges from therapeutic resistance.
- Tumor evolution under androgen inhibition can lead to double-negative prostate cancer (DNPC), a highly aggressive phenotype.
- DNPC is characterized by androgen receptor (AR) independence and lack of neuroendocrine markers.
Purpose of the Study:
- To delineate the molecular origins and drivers of DNPC.
- To explore novel therapeutic strategies for DNPC.
- To propose a framework for "evolutionary interception" in advanced prostate cancer treatment.
Main Methods:
- Review of molecular mechanisms driving lineage plasticity in mCRPC.
- Analysis of genetic alterations (TP53, RB1 loss) and epigenetic reprogramming in DNPC.
- Exploration of emerging therapeutic modalities targeting DNPC.
Main Results:
- Functional loss of TP53 and RB1, alongside epigenetic reprogramming, drives DNPC phenotype.
- DNPC exhibits rewiring of transcriptional networks, activation of alternative kinase pathways, and an immunosuppressive microenvironment.
- Conventional therapies are ineffective against DNPC due to altered molecular targets.
Conclusions:
- DNPC represents a distinct, aggressive evolutionary state in prostate cancer progression.
- A paradigm shift in clinical strategy is necessary for effective DNPC management.
- Mechanistically grounded approaches like epigenetic modulation and synthetic lethality offer promising therapeutic avenues.
