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de Kouchkovsky et al. J Transl Genet Genom 2021;5:265-77 https://dx.doi.org/10.20517/jtgg.2021.32 Page 273

remodeling and AR recruitment have thus been implicated in modulating AR signaling in t-SCNC. As
discussed above, repressive histone methylation marks induced by the cooperative action of N-MYC and
EZH-2 downregulate canonical AR transcriptional programs in t-SCNC. The histone modulator LSD1 (also
known as KDM1A) similarly regulates AR signaling via both transcriptional repression (through H3K4 and
H3K9 demethylation) and coactivation (through histone H3 phosphorylation) of AR-target genes .
[70]
[71]
Increased LSD1 expression, which is associated with RB1 loss in prostate cancer cells , has been implicated
in lineage plasticity through upregulation of stemness and EMT transcriptional programs, as well as
[72]
induction of glycolysis‐shifted metabolism . A t-SCNC-specific splice variant of LSD1 (LSD1+8a) induced
by SRRM-4 and associated with activation of neuronal gene expression was recently described .
[73]
CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS
t-SCNC is an aggressive clinical entity with limited treatment options. Establishing a diagnosis of t-SCNC
has important therapeutic implications due to the increased resistance to conventional hormonal therapies.
Unfortunately, reliable diagnostic biomarkers are still lacking . While metastatic biopsies provide
[11]
important information, they remain both technically challenging and subject to intra-patient
heterogeneity . Although circulating tumor DNA-based biomarkers have the potential to provide a non-
[14]
invasive patient-wide assessment of the tumor genome, their utility in this clinical scenario has been limited
by the significant genomic overlap between t-SCNC and mCRPC. More recently, advances in epigenetic
profiling of CRPC and the observation of stark differences in the DNA methylation landscape between the
two histologic subtypes have helped to develop novel epigenetic biomarkers. Bisulfite sequencing of cell-free
DNA has thus been shown to distinguish t-SCNC cases from mCRPC-adenocarcinoma .
[29]

Improved molecular characterization of t-SCNC has also highlighted a spectrum of neuroendocrine
[14]
differentiation across patient metastases (i.e., intra-patient heterogeneity) , underscoring the role of
continued AR-targeted therapy in patients with t-SCNC. Additionally, the gradient of t-SCNC
transcriptional expression observed across t-SCNC samples (i.e., intra-class heterogeneity) suggests a
[14]
gradual and dynamic process of neuroendocrine differentiation ; therapeutic strategies targeting the
[28]
epigenetic mechanisms of lineage plasticity in t-SCNC may offer the potential of reversing neuroendocrine
differentiation and restoring AR-dependence. Finally, the development of t-SCNC transcriptional
signatures has identified a subset of mCRPC-adenocarcinoma patients with transcriptional features of t-
SCNC [14,21,41] , and there is growing evidence to suggest that stemness and t-SCNC transcriptional profiles
may predict de novo resistance to ADT and AR-targeted therapies in PC lacking t-SCNC histology [31,74,75] .
Although the optimal management of such patients has not been established, these findings support the
increasing use of molecularly defined inclusion criteria for clinical trials of t-SCNC directed therapies. In
the future, the diagnosis of t-SCNC may transition from a purely histology-based definition to a composite
of histologic and molecular features.

Beyond its role in the diagnosis of t-SCNC, improved molecular characterization of t-SCNC has also helped
identify novel therapeutic strategies in t-SCNC. These include both attempts to target increased cellular
proliferation and molecular pathways upregulated in t-SCNC, as well as efforts to reverse lineage plasticity
and restore AR-dependence. Aurora kinase A is a cell cycle kinase that stabilizes N-MYC and prevents N-
MYC protein degradation. Early observations of MYCN upregulation in t-SCNC spurred the development
of alisertib, an allosteric inhibitor of Aurora kinase A. Although a phase II trial of single-agent alisertib in
SCNC failed to meet its primary endpoint of six-month radiographic progression-free survival, exceptional
[76]
responses were observed in a subset of patients with N-MYC and Aurora A kinase overactivity . Aurora
kinase inhibitors may thus still play a role in a molecularly selected subset of t-SCNC. Targeting DNA
damage response pathways in MYCN-upregulated tumors has also shown promising activity in pre-clinical