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Influence of EMT on CTCs and Disease Progression in Prostate Cancer

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ClinicalTrials.gov Identifier: NCT04021394
Recruitment Status : Recruiting
First Posted : July 16, 2019
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Alison Allan, Lawson Health Research Institute

Brief 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.


Condition or disease Intervention/treatment
Prostate Cancer Diagnostic Test: CellSearch CTC platform Diagnostic Test: Parsortix CTC platform

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Dynamic Influence of the Epithelial-to-mesenchymal Transition (EMT) on Circulating Tumor Cell (CTC) Generation, Phenotype, and Disease Progression in Prostate Cancer
Actual Study Start Date : June 5, 2019
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Group/Cohort Intervention/treatment
Non-metastatic, high-risk hormone sensitive prostate cancer
Phlebotomy collection of 2 tubes of blood then annual follow up for 5 years
Diagnostic Test: CellSearch CTC platform
epithelial-based marker approach for immunomagnetic enrichment, isolation, and quantitative immunofluorescence of CTCs

Diagnostic Test: Parsortix CTC platform
EMT-independent platform

Low-volume metastatic hormone-sensitive prostate cancer
Phlebotomy collection of 2 tubes of blood then annual follow up for 5 years
Diagnostic Test: CellSearch CTC platform
epithelial-based marker approach for immunomagnetic enrichment, isolation, and quantitative immunofluorescence of CTCs

Diagnostic Test: Parsortix CTC platform
EMT-independent platform

High-volume metastatic hormone-sensitive prostate cancer
Phlebotomy collection of 2 tubes of blood then annual follow up for 5 years
Diagnostic Test: CellSearch CTC platform
epithelial-based marker approach for immunomagnetic enrichment, isolation, and quantitative immunofluorescence of CTCs

Diagnostic Test: Parsortix CTC platform
EMT-independent platform

Metastatic castrate-resistant prostate cancer
Phlebotomy collection of 2 tubes of blood then annual follow up for 5 years
Diagnostic Test: CellSearch CTC platform
epithelial-based marker approach for immunomagnetic enrichment, isolation, and quantitative immunofluorescence of CTCs

Diagnostic Test: Parsortix CTC platform
EMT-independent platform




Primary Outcome Measures :
  1. CTC enumeration capacity [ Time Frame: 1-2 years ]
    Number of CTCs as assessed by the Parsortix system versus the clinical gold standard CellSearch platform

  2. CTC recovery capacity [ Time Frame: 1-2 years ]
    Number of CTCs that can be isolated from the Parsortix system

  3. Comparison of AR and EMT characteristics [ Time Frame: 1-2 years ]
    Level of RNA expression of AR and EMT markers (EpCAM, E-Cadherin, N-Cadherin, Zeb-1) as assessed by multiplex qRT-PCR of CTCs isolated from the Parsortix system


Secondary Outcome Measures :
  1. Relationship of CTC count to disease features [ Time Frame: 1-2 years ]
    Differences in the number of CTCs between each of the 4 patient cohorts, and differences in the level of RNA expression of AR and EMT markers between each of the 4 patient cohorts

  2. CTC counts and prognosis of OS and PFS [ Time Frame: 5 years ]
    Correlation between number of CTCs and progression free survival and overall survival, and correlation between the level of RNA expression of AR/EMT markers and PFS and OS



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Prostate cancer
Criteria

Inclusion Criteria (all patients):

  • histologically diagnosed prostate cancer
  • signed informed consent

HR-HSPC cohort

  • previous prostatectomy
  • previous treatment with androgen deprivation therapy for <90 days and/or recommended but not yet started new line of androgen deprivation therapy
  • adverse pathological findings (>=1 of extracapsular extension, positive margins, and/or seminal vesicle invasion)
  • documented evidence of biochemical failure following adjuvant/salvage radiation therapy
  • PSA of >1 ng/ml

LV-mHSPC cohort

  • previous treatment with androgen deprivation therapy for <90 days and/or recommended but not yet started new line of androgen deprivation therapy
  • documented evidence of metastatic disease (bone only; less than 4 lesions contained within the vertebral column or pelvis)

HV-mHSPC cohort

  • previous treatment with androgen deprivation therapy for <90 days and/or recommended but not yet started new line of androgen deprivation therapy
  • documented evidence of "high volume" metastatic disease (visceral metastases [extranodal] and/or bone metastases [>=4 bone lesions with >=1 lesion outside the vertebral column or pelvis])

mCRPC cohort

  • documented evidence of progression while receiving androgen ablation therapy (medical or surgical castration) according to PCWG2 criteria
  • documented evidence of metastatic disease (bone or visceral)

Exclusion Criteria:

  • patients with a history of other malignancies, except for adequately treated non-melanoma skin cancer (all cohorts)
  • documented evidence of metastatic disease (HR-HSPC cohort)
  • documented evidence of castrate-resistance (all HSPC cohorts)
  • currently on active androgen deprivation therapy (all HSPC cohorts)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04021394


Contacts
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Contact: Alison Allan, PhD 519-685-8500 ext 55134 alison.allan@lhsc.on.ca
Contact: Laura Bailey 519-685-8618 laurad.bailey@lhsc.on.ca

Locations
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Canada, Ontario
London Regional Cancer Program Recruiting
London, Ontario, Canada, N6A 5W9
Contact: Alison Allan, PhD    519-685-8500 ext 55134    alison.allan@lhsc.on.ca   
Contact: Laura Bailey    519-685-8618    laurad.bailey@lhsc.on.ca   
Sponsors and Collaborators
Lawson Health Research Institute
Investigators
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Principal Investigator: Alison Allan, PhD Lawson Health Research Institute

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Responsible Party: Alison Allan, Principal Investigator, Lawson Health Research Institute
ClinicalTrials.gov Identifier: NCT04021394     History of Changes
Other Study ID Numbers: EMT Prostate
First Posted: July 16, 2019    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alison Allan, Lawson Health Research Institute:
circulating tumor cell
epithelial-to-mesenchymal transition
treatment response
phenotype
Additional relevant MeSH terms:
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Prostatic Neoplasms
Disease Progression
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Disease Attributes
Pathologic Processes
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs