Prostate cancer (PCa) is the most commonly diagnosed cancer and the second-leading cause of cancer-related mortality in U.S. men with a projected 248,530 new cases and an estimated 34,130 deaths in 2021. Androgen targeted therapy (ATT) remains a cornerstone of treatment in almost all stages of PCa given the near universal dependence on androgen receptor (AR) signaling for tumor growth and proliferation. For example, androgen deprivation therapy (ADT) is used in the neoadjuvant and/or adjuvant treatment of localized PCa, while ADT is incorporated into salvage therapies for local relapse. In systemic disease, ADT is often combined with chemotherapy or novel hormonal therapies (NHT) that inhibit the androgen signaling axis. ADT can also be combined with NHT in those with PCa who have developed castration resistance but are non-metastatic (M0). Metastatic castrate-resistant PCa (mCRPC) is incurable and often represents the eventual development of resistance to therapies against the androgen pathway.
The historical mechanisms of androgen signaling pathway resistance in PCa have been well-described. The eventual development of therapeutic resistance in castrate-resistant PCa is compounded by the potential for PCa patients to develop neuroendocrine PCa. Although de novo neuroendocrine disease is very rare, >25% developing resistance to ATT have therapy-induced neuroendocrine (NE) differentiation, characterized by an aggressive course with a universally poor prognosis. Further understanding of the mechanisms contributing to therapeutic resistance and progression to lethal states remains a major challenge in improving outcomes for PCa patients.
Research has focused on lineage plasticity as a viable mechanism of progression to mCRPC rather than result of emergence of resistance mutations. Here, prostate tumors may adopt a phenotype no longer dependent on AR signaling and may display NE features, stem cell-like or basal cell-like phenotypes, altered kinase signaling, and epigenetic alterations. Key alterations in SOX2, TP53, and RB1 have been shown to promote lineage plasticity and antiandrogen resistance. Emergence of noncanonical pathways that induce PCa metastasis such as RIPK2 have also led to identification of potentially new therapeutic targets in PCa. Increasing evidence has shown that the tumor microenvironment (TME) plays a critical role in facilitating PCa progression through signaling cascades such as TGF-ß or VEGF, epithelial-to-mesenchymal transition, cancer stem cells, and inflammatory/immune responses. Cancer-associated fibroblasts (CAF) have shown to contribute to progression of PCa to metastatic and therapeutically resistant states. One example, CAF have been shown to support glutamine signaling used by PCa epithelia for proliferation and evolution to advanced states. As researchers expand their efforts to understand the molecular mechanisms of PCa progression, others have developed novel biomarkers such as circulating tumor cells and therapeutics to target advanced PCa states.
This Research Topic will focus on molecular mechanisms involved in the progression of PCa to more advanced and lethal stages of disease. We welcome Original Research Articles, Review Articles and Systematic Reviews that cover the breadth of the multidisciplinary efforts to improve PCa outcomes.
We welcome manuscripts that cover the multitude of evolving molecular mechanisms of PCa to advanced and lethal stages inclusive of castration resistance, NE PCa, metastatic progression, and resistance to systemic therapies.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
Prostate cancer (PCa) is the most commonly diagnosed cancer and the second-leading cause of cancer-related mortality in U.S. men with a projected 248,530 new cases and an estimated 34,130 deaths in 2021. Androgen targeted therapy (ATT) remains a cornerstone of treatment in almost all stages of PCa given the near universal dependence on androgen receptor (AR) signaling for tumor growth and proliferation. For example, androgen deprivation therapy (ADT) is used in the neoadjuvant and/or adjuvant treatment of localized PCa, while ADT is incorporated into salvage therapies for local relapse. In systemic disease, ADT is often combined with chemotherapy or novel hormonal therapies (NHT) that inhibit the androgen signaling axis. ADT can also be combined with NHT in those with PCa who have developed castration resistance but are non-metastatic (M0). Metastatic castrate-resistant PCa (mCRPC) is incurable and often represents the eventual development of resistance to therapies against the androgen pathway.
The historical mechanisms of androgen signaling pathway resistance in PCa have been well-described. The eventual development of therapeutic resistance in castrate-resistant PCa is compounded by the potential for PCa patients to develop neuroendocrine PCa. Although de novo neuroendocrine disease is very rare, >25% developing resistance to ATT have therapy-induced neuroendocrine (NE) differentiation, characterized by an aggressive course with a universally poor prognosis. Further understanding of the mechanisms contributing to therapeutic resistance and progression to lethal states remains a major challenge in improving outcomes for PCa patients.
Research has focused on lineage plasticity as a viable mechanism of progression to mCRPC rather than result of emergence of resistance mutations. Here, prostate tumors may adopt a phenotype no longer dependent on AR signaling and may display NE features, stem cell-like or basal cell-like phenotypes, altered kinase signaling, and epigenetic alterations. Key alterations in SOX2, TP53, and RB1 have been shown to promote lineage plasticity and antiandrogen resistance. Emergence of noncanonical pathways that induce PCa metastasis such as RIPK2 have also led to identification of potentially new therapeutic targets in PCa. Increasing evidence has shown that the tumor microenvironment (TME) plays a critical role in facilitating PCa progression through signaling cascades such as TGF-ß or VEGF, epithelial-to-mesenchymal transition, cancer stem cells, and inflammatory/immune responses. Cancer-associated fibroblasts (CAF) have shown to contribute to progression of PCa to metastatic and therapeutically resistant states. One example, CAF have been shown to support glutamine signaling used by PCa epithelia for proliferation and evolution to advanced states. As researchers expand their efforts to understand the molecular mechanisms of PCa progression, others have developed novel biomarkers such as circulating tumor cells and therapeutics to target advanced PCa states.
This Research Topic will focus on molecular mechanisms involved in the progression of PCa to more advanced and lethal stages of disease. We welcome Original Research Articles, Review Articles and Systematic Reviews that cover the breadth of the multidisciplinary efforts to improve PCa outcomes.
We welcome manuscripts that cover the multitude of evolving molecular mechanisms of PCa to advanced and lethal stages inclusive of castration resistance, NE PCa, metastatic progression, and resistance to systemic therapies.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
