Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Abstract

Prostate cancer is a hormone-driven disease and its tumor cell growth highly relies on increased androgen receptor (AR) signaling. Therefore, targeted therapy directed against androgen synthesis or AR activation is broadly used and continually improved. However, a subset of patients eventually progresses to castration-resistant disease. To date, various mechanisms of resistance have been identified including the development of AR-independent aggressive variant prostate cancer based on neuroendocrine transdifferentiation (NED). Here, we review the highly complex processes contributing to NED. Genetic, epigenetic, transcriptional aberrations and posttranscriptional modifications are highlighted and the potential interplay of the different factors is discussed.BackgroundAggressive variant prostate cancer (AVPC) with traits of neuroendocrine differentiation emerges in a rising number of patients in recent years. Among others, advanced therapies targeting the androgen receptor axis have been considered causative for this development. Cell growth of AVPC often occurs completely independent of the androgen receptor signal transduction pathway and cells have mostly lost the typical cellular features of prostate adenocarcinoma. This complicates both diagnosis and treatment of this very aggressive disease. We believe that a deeper understanding of the complex molecular pathological mechanisms contributing to transdifferentiation will help to improve diagnostic procedures and develop effective treatment strategies. Indeed, in recent years, many scientists have made important contributions to unravel possible causes and mechanisms in the context of neuroendocrine transdifferentiation. However, the complexity of the diverse molecular pathways has not been captured completely, yet. This narrative review comprehensively highlights the individual steps of neuroendocrine transdifferentiation and makes an important contribution in bringing together the results found so far.

Treatment-related neuroendocrine prostate cancer managed with partial stereotactic ablative radiotherapy (P-SABR) for long-term survival: a case series

“…The characteristics of t-NEPC are as follows: (I) the morphological manifestations congruent with the characteristics of small cell carcinoma and (II) the molecular markers characterized by low or no expression of AR (21) and positive NE markers such as CgA, Syn, and CD56; (III) the clinical manifestations are prone to extensive visceral metastases, osteolytic metastases, large masses, low PSA levels relative to the tumor burden, a effective time for hormonal therapy, and extremely poor prognosis (22,23). In one study, the time from diagnosis of prostate cancer to t-NEPC in 123 patients was 20 months, and the median survival after t-NEPC was only 7 months (24).…”

Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer

“…In addition, treatment alternatives are lacking after the failure of the platinum-etoposide combination in NEPC. Moreover, the optimal therapeutic strategy in “double-negative” patients with a loss of typical adenocarcinoma differentiation but without concurrent neuroendocrine markers remains elusive [ 23 ]. Thus, there is a high medical need for novel treatment approaches.…”

Systemtherapie des metastasierten Prostatakarzinoms

“…Es kommt außerdem vermehrt zur Resistenzentwicklung durch Alterationen des AR (Amplifikationen, Mutationen, Splice-Varianten). Mit zunehmender Aggressivität der Erkrankung geht die Expression des AR verloren [4].…”

“…Verglichen wurde jeweils die Prüfsubstanz plus Standard of Care (SOC) im Vergleich zum alleinigen SOC beim metastasierten hormonsensitiven Prostatakarzinom (mHSPC). HR = Hazard Ratio; KI = Konfidenzintervall; mOS = medianes Gesamtüberleben; NSA = nichtsteroidales Antiandrogen; 1 M1-Patienten; 2 high risk nach LATITUDE-Kriterien siehe Tabelle 1; 3 Docetaxel-Vorbehandlung möglich; 4 Gabe nur im Kontrollarm; 5 [29]. In der Phase-II-Studie TheraP wurde 177 Lu-PSMA-617 mit Cabazitaxel nach Docetaxel-Vorbehandlung prospektiv verglichen und zeigte ein signifikant besseres PSA-Ansprechen (66 % vs. 37 % in der Intent-to-treat-Population; p < 0,0001) bei gleichzeitig besserer Verträglichkeit und Lebensqualität [35].…”