AR-V7 Splice Variant in Prostate Cancer : Taking Centre Stage

Presented by:Mohsin MaqboolPh.D Student, MO, IRCH

15-11-2014

Department of Medical Oncology

Outline

Introduction

Splicing- AR Splice variants , ARV7

Clinical role of ARV7 in CRPC

Discussion and Conclusion

Prostate cancer : present therapies and Resistance

Androgen-deprivation therapy (ADT) remains the principal treatment, most patients eventually develop castrate resistance - Castration resistant prostate cancer(CRPC)

Enzalutamide and Abiraterone represent breakthroughs in CRPC treatment

20 to 40% of patients have no response (i.e., they have primary resistance) Ryan CJ et al , JCO 2011

C. B HugginsNobel Prize -1961

C V. Hodges

Splicing and splice variants

mRNA(Coding for final gene and protein)

Splice variant 1 Splice variant 3Splice variant 2

Splice variants in drug resistance

Alternative splicing (Splice variants)- key molecular mechanism for protein diversity, but has implications in drug resistance too

Splicing profile of several cancer associated genes is altered- role in tumor progression

Cancer-associated alternative splicing variants- as new biomarkers in cancers ( Breast cancer, Pancreatic cancer)

Normal Variants

Sharmistha Pal et al Pharm & therp 2012C Holohan et al Nat Rev, 2013

AR Splice variants in Androgen receptor

and ARV7

Splice variants : Role of ARV7 in resistance

ARV7(AR3) is most studied AR, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens

ARV7 is significantly up-regulated during PCA progression and ARV7 expression level is correlated with the risk of tumor recurrence

 Zhiyong Guo, Feng Sun, et al Can Res 2009

Clinical relevance of ARV-7 in CRPC

Clinical relevance of androgen- receptor variants in castration-resistant prostate cancer receiving enzalutamide or abiraterone not known

Prospectively evaluated androgen receptor splice variant-7 messenger RNA (AR-V7) in circulating tumor cells from patients receiving enzalutamide or abiraterone

Patient Characteristics

62 patients with detectable circulating tumor cells, of whom 31 received enzalutamide and 31 received abiraterone

Median follow-up time was 5.4 months (range, 1.4 to 9.9) among enzalutamide- treated patients and 4.6 months (range, 0.9 to 8.2) among abiraterone-treated patients

Emmanuel S. Antonarakis et al, NEJM 2014

Emmanuel S. Antonarakis et al, NEJM 2014

Progression–free Survival

Kaplan –Meier Analysis of PSA Progression free survivalKaplan –Meier Analysis of Clinical/ Radiographic Progression free survival

Overall Survival

Preliminary survival analysis was conducted at 32% maturity in the enzalutamide-treated cohort (i.e., after 32% of the patients [10 patients] had died) (median follow-up, 8.4 months) and at 16% maturity in the abiraterone-treated cohort (i.e.,after 16% of the patients [5 patients] had died)(median follow-up. 9.3 months)

Overall survival was shorter in men with detectable AR-V7 at baseline than among those with undetectableAR-V7 both in the enzalutamide and abiraterone cohort (median,5.5 months vs. not reached; hazard ratio fordeath, 6.9; 95% CI, 1.7 to 28.1; P = 0.002 by the log-rank test)PSA- PFS

R- PFS

Discussion

• Treatment options for patients with castration-resistant prostate cancer (CRPC) has changed with FDA(US) approved agents have shown survival benefit for patients with CRPC

• Enzalutamide and abiraterone- two new therapies directed at the androgen receptor, represent important advances in the management of castration- resistant prostate cancer

20 to 40% of patients have no response to these agents with respect to prostate-specific antigen (PSA) levels and that detection of ARV7 in tumor cells appears to be associated with resistance to both enzalutamide and abiraterone

DiscussionEfforts directed towards ablating androgen-receptor activity, particularly

by interfering with the functions of the N-terminal domain of the androgen receptor, are likely to be fruitful

ConclusionARV7/AR3 is important most studied and constitutive splice

variant in prostate cancer appears to be upregulated during prostate cancer progression during hormone therapy, and is associated with androgen-resistant growth

AR-V7 could be used as a biomarker to predict resistance to enzalutamide and abiraterone and to facilitate treatment selection-of more advanced disease or a higher disease burden

Thankyou ..!!

Cause of Resistance ??

Studies in castration-resistant prostate cancer have shown that androgen receptor variants are often expressed in metastases, with faster disease Progression and shorter cancer-specific survival

Protein isoforms of AR function may be dependent on the activity of full- length androgen receptor??

One explanation for the resistance to both agents (Enzalutamide and Abiraterone) may involve the presence of androgen receptor splice variants Attard G et al JCO,2008

Scher HI et al NEJM, 2012