Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04021394 |
| Other study ID # |
EMT Prostate |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 5, 2019 |
| Est. completion date |
December 1, 2022 |
Study information
| Verified date |
April 2023 |
| Source |
Lawson Health Research Institute |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The presence of circulating tumor 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.
Description:
The presence of circulating tumor 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. Although these cells are very rare (~1 CTC per 105-107 leukocytes), recent
technological advances have now facilitated sensitive enumeration and characterization of
CTCs. Techniques to enrich and analyze CTCs include size- and/or density-based separation and
antibody-based techniques with/without the aid of microfluidics, while detection techniques
rely almost exclusively on protein- (immunofluorescence/flow cytometry) or nucleic acid-based
(RT-PCR/qRT-PCR) assays. 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.
CellSearch® uses an epithelial-based marker approach for immunomagnetic enrichment,
isolation, and quantitative immunofluorescence of CTCs. Using this assay, it has been
demonstrated that CTCs are readily detectable in ~65% of castrate-resistant prostate cancer
(CRPC) patients and that the presence of ≥5 CTCs in 7.5ml of blood is indicative of
progressive metastatic disease and reduced overall survival. 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
(EpCAM+/Cytokeratin 8/18/19 [CK]+/DAPI+/CD45-). 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. Activation of EMT leads to profound phenotypic changes
resulting in loss of cell polarity, loss of cell-cell adhesion, resistance to apoptosis, and
acquisition of migratory/invasive properties. It has also been proposed that tumor cells (via
the mesenchymal-to-epithelial transition [MET]) may revert back to an epithelial phenotype in
order to facilitate metastatic growth in secondary sites, suggesting a role for phenotypic
plasticity during metastatic progression. At the molecular level, EMT is mediated by
decreased expression of epithelial proteins (E-cadherin, CK, EpCAM); as well as corresponding
increases in mesenchymal factors (N-cadherin, Vimentin, Twist, Zeb), with MET mediated by the
opposite changes.
Clinically, Gleason grading can arguably be viewed as morphological evidence of EMT, since
increasing Gleason score is associated with progressive loss of epithelial architecture, loss
of defined basement membrane/cell polarity, and increased invasion. In support of this,
studies have demonstrated that decreased expression of E-Cadherin or increased expression of
mesenchymal markers (Vimentin, N-Cadherin, SNAIL) in primary prostate tumors is associated
with advanced Gleason score, metastasis, and/or poor prognosis. 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 the 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.
