Official Title
Dynamic Influence of the Epithelial-to-mesenchymal Transition (EMT) on Circulating Tumour Cell (CTC) Generation, Phenotype, and Disease Progression in Prostate Cancer
Summary:
The presence of circulating tumour cells (CTCs) in the blood of prostate cancer patients has
been shown to be an important indicator of metastatic disease and poor prognosis.
Additionally, changes in CTC number throughout treatment have been demonstrated to reflect
therapy response. However, the CellSearch® (Menarini-Silicon Biosystems) is the only FDA- and
Health Canada-cleared CTC platform available at the present time, and is thus considered the
current "gold standard" for clinical CTC analysis.
Notably, CTCs are undetectable in ~35% of metastatic CRPC patients. This suggests that either
CTCs are truly not present in >1/3 of patients with advanced metastatic disease; and/or that
CTCs are present but not detectable as they do not meet the standard CellSearch® definition
of CTCs. Given the accumulating evidence that prostate cancer cells can lose epithelial
characteristics as they evolve towards a more metastatic phenotype, the investigators believe
the latter scenario is most likely.
The epithelial-to-mesenchymal transition (EMT) is a critical process during embryonic
development and cancer metastasis.
Although the role of androgen receptor (AR) signaling in EMT is poorly understood, studies
have also demonstrated that EMT may be facilitated by androgen deprivation,
castration-resistance, and/or disruption of androgen signaling.
Importantly, several clinical studies have demonstrated that CTCs with a purely mesenchymal
phenotype are undetectable by CellSearch®, but that the presence of mesenchymal marker
expression on CTCs with a hybrid epithelial-mesenchymal phenotype is indicative of poor
prognosis. In addition, previous pre-clinical data from the Allan laboratory has demonstrated
that in animal models, prostate cancers with a mesenchymal phenotype shed greater numbers of
CTCs more quickly and with greater metastatic capacity than those with an epithelial
phenotype. Notably, the clinically-used CellSearch®-based assay captured the majority of CTCs
shed during early-stage disease in vivo, and only after the establishment of metastases were
a significant number of undetectable CTCs present. This suggests that current clinical assays
may be limiting ability to capitalize on the full potential of CTCs, and that a greater
understanding of CTC biology is necessary in order to guide future technology development and
translation to the clinic.
Trial Description
Primary Outcome:
- CTC enumeration capacity
- CTC recovery capacity
- Comparison of AR and EMT characteristics
Secondary Outcome:
- Relationship of CTC count to disease features
- CTC counts and prognosis of OS and PFS
The presence of circulating tumour cells (CTCs) in the blood
of prostate cancer patients has been shown to be an important indicator of
metastatic disease and poor prognosis. Additionally, changes in CTC number
throughout treatment have been demonstrated to reflect therapy response.
However, the CellSearch® (Menarini-Silicon Biosystems) is the only FDA- and
Health Canada-cleared CTC platform available at the present time, and is thus
considered the current "gold standard" for clinical CTC analysis.
Notably, CTCs are undetectable in ~35% of metastatic CRPC
patients. This suggests that either CTCs are truly not present in >1/3 of
patients with advanced metastatic disease; and/or that CTCs are present but not
detectable as they do not meet the standard CellSearch® definition of CTCs.
Given the accumulating evidence that prostate cancer cells can lose epithelial
characteristics as they evolve towards a more metastatic phenotype, the
investigators believe the latter scenario is most likely.
The epithelial-to-mesenchymal transition (EMT) is a critical
process during embryonic development and cancer metastasis.
Although the role of androgen receptor (AR) signaling in EMT
is poorly understood, studies have also demonstrated that EMT may be
facilitated by androgen deprivation, castration-resistance, and/or disruption
of androgen signaling.
Importantly, several clinical studies have demonstrated that
CTCs with a purely mesenchymal phenotype are undetectable by CellSearch®, but
that the presence of mesenchymal marker expression on CTCs with a hybrid
epithelial-mesenchymal phenotype is indicative of poor prognosis. In addition,
previous pre-clinical data from the Allan laboratory has demonstrated that in
animal models, prostate cancers with a mesenchymal phenotype shed greater
numbers of CTCs more quickly and with greater metastatic capacity than those
with an epithelial phenotype. Notably, the clinically-used CellSearch®-based
assay captured the majority of CTCs shed during early-stage disease in vivo,
and only after the establishment of metastases were a significant number of
undetectable CTCs present. This suggests that current clinical assays may be
limiting ability to capitalize on the full potential of CTCs, and that a
greater understanding of CTC biology is necessary in order to guide future
technology development and translation to the clinic.
View this trial on ClinicalTrials.gov
