ARV7 splice variant in CRPC

Editor's Notes

• #2: ARV7 in CRPC…focus of discussion
• #4: Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment Castration resistant prostate cancer(CPRC) : Majority of patients initially respond to ADT, most eventually develop castrate Resistance ADT is known to provide remission of the disease, best evidenced by a decline of prostate-specific antigen (PSA) in about 90% of patients.2 After a mean time of 2–3 years, however, the disease progresses despite continuous hormonal manipulation. This type of cancer is known as castrate-resistant prostate cancer (CRPC).2 Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis and mean survival time of only 16–18 months.3 Docetaxel and cabazitaxel are the only United States Food and Drug Administration (FDA)-approved chemotherapies for the treatment of mCRPC (Table 1). These tubulin-binding taxanes have been proven to decrease PSA levels and palliate symptoms but survival benefits are modest Disease progression despite serum testosterone levels of <50 ng/dl Rising PSA from nadir(baseline) on ADT Radiographic progression Clinical Progression Docetaxel and cabazitaxel are the only United States Food and Drug Administration (FDA)-approved chemotherapies for the treatment of mCRPC (Table 1). These tubulin-binding taxanes have been proven to decrease PSA levels and palliate symptoms but survival benefits are modest Enzalutamide exerts its antitumor activity through its interaction with the ligand-binding domain of the androgen receptor and is ligand-independent and Abiraterone inhibits P-450 CYP17A1 which blocks androgen synthesis Patients who initially have a response to enzalutamide or abiraterone, virtually all eventually acquire secondary resistance Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research One explanation for the resistance to both agents may involve the presence of androgen receptor splice variants Patients who initially have a response to enzalutamide or abiraterone, virtually all eventually acquire secondary resistance
• #6: Moreover, the characterization of splicing deregulation in cancer will lead to a better comprehension of malignant transformation. Cancer-associated alternative splicing variants may be new tools for the diagnosis and classification of cancers and could be the targets for innovative therapeutical interventions based on highly selective splicing correction approaches.
• #8: The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, 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. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer R
• #9: Even though AR-V7 results in continuous activation of the androgen receptor in animal models and human prostate cancer cell lines, it was not previously clear whether AR-V7 would confer resistance to enzalutamide. Enzalutamide was given at a dose of 160 mg daily; abiraterone was given at a dose of 1000 mg daily, with prednisone at a dose of 5 mg twice daily Hypothesized that detection of AR-V7 in circulating tumor cells may be associated with resistance to enzalutamide and abiraterone In CRPC Prospectively enrolled men with metastatic CRPC treatment with enzalutamide or abiraterone Progressive disease despite “castration levels” of serum testosterone (<50 ng per deciliter), with continued ADT, and documented metastases, as confirmed on computed tomography (CT) Patients were excluded if they planned to receive additional concurrent anticancer therapies Analysis of circulating tumor cells (Kit Method- AlereTM CTC AdnaTest) Detection and quantification of AR-V7 by quantitative real-time PCR using custom primers specific for AR-V7 and also in tissue based samples
• #10: Analysis of circulating tumor cells (Kit Method- AlereTM CTC AdnaTest) Prostate Cancer Detect (Product No. T-1-521) kit was used to make cDNA for detection of prostate cancer-associated RNA transcripts using polymerase chain reaction (PCR) Detection and quantification of AR-V7 by quantitative real-time PCR using custom primers specific for AR-V7 Detection and quantification of AR-V7 by quantitative real-time PCR using custom primers specific for AR-V7 and also in tissue based samples
• #12: 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
• #13: Overall proportion of patients who had a PSA response while receiving enzalutamide was 32% In enzalutamide cohort, PSA response rate among AR-V7–positive patients was 0% and the rate among AR-V7–negative patients was 53% (P = 0.004) Panel A shows the 31 enzalutamide-treated patients, and Panel B the 31 abiraterone-treated patients. The dotted line shows the threshold for defining a PSA response (=50% reduction in PSA level from baseline). Asterisk indicate an increase of more than 100% in best PSA response. Daggers indicate patients in the enzalutamide cohort who had previously received abir aterone and patients in the abiraterone cohort who had previously received enzalutamide. Overall proportion of patients who had a PSA response while receiving abiraterone was 55% In the abiraterone cohort, the PSA response rate among AR-V7–positive patients was 0%, and the rate among AR-V7–negative patients was 68%((P = 0.004) AR-V7 status remained predictive of PSA response after adjustment for the expression of full-length androgen receptor mRNA
• #14: Among enzalutamide-treated patients, PSA progression–free survival was shorter among men with detectable AR-V7 at baseline than among those with undetectable AR-V7 (P<0.001) Among abiraterone-treated patients, PSA progression– free survival was shorter among men with detectable AR-V7 at baseline than among those with undetectable AR-V7 (P<0.001 The median PSA progression–free survival in enzalutamide-treated patients (Panel A) was 1.4 months (95% CI, 0.9 to not reached) in AR-V7–positive patients and 6.0 months (95% CI, 3.8 to not reached) in AR-V7–negative patients (hazard ratio for PSA progression with AR-V7 positivity, 7.4; 95% CI, 2.7 to 20.6; P<0.001 by the log-rank test). The median PSA progression–free survival in abiraterone-treated patients (Panel B) was 1.3 months (95% CI, 0.9 to not reached) in AR-V7–positive patients and more than 5.3 months (95% CI, 5.3 to not reached) in AR-V7–negative patients (hazard ratio for PSA progression with AR-V7 positivity, 16.1; 95% CI, 3.9 to 66.0; P<0.001 by the log-rank test). The median clinical or radiographic progression–free survival in enzalutamide-treated patients (Panel C) was 2.1 months (95% CI, 2.0 to not reached) in AR-V7–positive patients and 6.1 months (95% CI, 4.7 to not reached) in AR-V7–negative patients (hazard ratio for clinical or radiographic progression with AR-V7 positivity, 8.5; 95% CI, 2.8 to 25.5; P<0.001 by the log-rank test). The median clinical or radiographic progression–free survival in abiraterone-treated patients (Panel D) was 2.3 months (95% CI, 1.4 to not reached) in AR-V7–positive patients and more than 6.3 months (95% CI, 6.3 to not reached) in AR-V7–negative patients (hazard ratio for clinical or radiographic progression with AR-V7 positivity, 16.5; 95% CI, 3.3 to 82.9; P<0.001 by the log-rank test).
• #15: Clinical outcomes (PSA responses, PSA-PFS and PFS) for the entire patient population according to their AR-V7 ‘conversion’ rates.
• #17: Recent study shows a strong association between the presence of AR-V7 and resistance to enzalutamide and abiraterone
• #19: AR-V7/AR3 is important most studied and constitutive splice variant in prostate cancer and detected in circulating tumor cells from patients with castration-resistant prostate cancer CRPC - Development of new drugs targeting these AR isoforms(ARV7) may potentially be effective for treatment of ablation-resistant CRPC
• #21: Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research Pharmacokinetic (PK) factors such as drug absorption, distribution, metabolism and elimination (ADME) limit the amount of a systemically administered drug that reaches the tumour. In the tumour, the effects of the drug on the cancer cell are collectively termed its pharmacodynamic (PD) properties. The anticancer activity of a drug can be limited by poor drug influx or excessive efflux; drug inactivation or lack of activation; alterations such as changes in expression levels of the drug target; activation of adaptive prosurvival responses; and a lack of cell death induction due to dysfunctional apoptosis, which is a hallmark of cancer.