AR SIGNALING 

INHIBITOR RESISTANCE

There are multiple mechanisms driving resistance to FDA approved AR Signaling Inhibitors, such as Zytiga® (Abiraterone) and Xtandi® (Enzalutamide).  Novel therapies are being developed for metastatic castration resistance prostate cancer (mCRPC) to target these specific mechanisms of resistance which may be exploited for the development of therapy selection devices or utilized to demonstrate therapeutic pharmacodynamics and efficacy during the drug development process.

At Epic Sciences, we work with leading academic and government investigators to develop strategies for identifying resistance mechanisms and creating non-invasive tests that aid in the selection and monitoring of patients during clinical trials.  These include tests to measure:

 

 

Constitutively active AR Signaling

Valuable in the clinical development of 3rd gen. AR inhibitor/degraders

 Learn more (below)

1. AR-V7

 

 

 

 

Tumor heterogeneity

Valuable in the clinical development of targeted therapy and combination therapy

Learn more (below)

1. CTC Phenotypic Heterogeneity

 

AR/PI3K reciprocal feedback

Valuable in the development of PI3K/AKT inhibitors

Learn more (below)

1. AR/PTEN Loss

 

AR independence

Valuable in design of clinical trials and measures of resistance 

Learn more (below)

1. NEPC Classifier

2. PSMA

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AR-V7: Measure of nuclear localized AR-V7 derived truncated protein in CTCs

The measure of nuclear AR-V7 protein is a treatment specific biomarker in mCRPC that demonstrates therapy interaction and supports clinical utility.  Fig.1 highlights the poor overall survival rate (HR=11.62) of patients who are biomarker positive for the Epic Sciences AR-V7 test and the 76% reduction of risk of death the use of taxane chemotherapy. 

Click to see Poster

Figure 1. KM Curve of pre-therapy AR-V7 status: AR-V7 positive patients show resistance to AR Signaling Inhibitors and thus exhibit shorter overall survival. 


 

AR/PTEN CTC Analysis

AR resistance can occur through reciprocal feedback between PI3K and AR signaling.  To measure cooperative AR/PI3K signaling we have developed single CTC phenotype and genotypic tools to assess AR protein expression, AR amplification and PTEN deletions within single CTCs.  

Figure 3. Copy Number Variation plot of a single CTC from a mCRPC patient expressing homozygous PTEN loss in conjunction with AR gain. 

Figure 4. NextGen sequencing results of mCRPC patients indicate variety of single CTCs that exhibit coinciding AR amplification and PTEN deletion


 

CTC Phenotypic Heterogeneity

A subset of mCRPC patients harbor high tumor heterogeneity at any line of therapy, in which multiple drivers of disease are present. This could potentially thwart a narrow, targeted therapeutic approach. To assess this phenomenon, high resolution digital pathology was used to identify patients with a high degree of phenotypic heterogeneity in their circulating tumor cells. In a 221 sample cohort presented at ASCO GU 2016, patients with high phenotypic CTC phenotypic heterogeneity demonstrated worse overall survival rates on AR signaling inhibitors than patients with low phenotypic heterogeneity (HR = 5.5, p < 0.00001). Multivariate analyses revealed a 68% reduction of risk of death after taxane therapy for patients with high phenotypic heterogeneity. 

 

Figure 5. KM curve demonstrates how patients with high heterogeneity show poorer overall survival on AR signaling inhibitors and achieve better outcomes when treated with taxane chemotherapy. 


 

Neuroendocrine Prostate Cancer (NEPC) CTC Classifier

CTCs from patients with NEPC determined through metastatic biopsy that confirmes Small Cell Prostate Cancer Pathology or NE expressing tumor cells have a unique morphologic phenotype.  While analysis of this cell type is specific to NEPC patients,  ~10% of mCRPC patients have sub-clonal populations of NEPC CTCs.  These patients demonstrate a worse response to AR inhibitors and are more likely to harbor visceral metastases.

Figure 6. Cell image of a “Small CTC” exhibiting small morphology and positive for Cytokeratin expression. Prevalence of these cells are indicative of neuroendocrine disease. 


 

PSMA

Heterogeneity of prostate-specific membrane antigen (PSMA) expression in traditional and apoptotic circulating tumor cells (CTC) in metastatic castration-resistant prostate cancer (mCRPC). ASCO 2014

Androgen Receptor (AR) Expression in Circulating Tumor Cells (CTCs) and Response to Prostate-Specific Membrane Antigen Antibody Drug Conjugate (PSMA ADC) in Castration-Resistant Prostate Cancer: A Correlative Analysis from a Phase 2 Trial. ESMO 2015

 


 

Our mission is to improve patient lives by enabling precision medicine with non-invasive tests that profile rare cells in cancer.