scholarly journals Overcoming mutation-based resistance to antiandrogens with rational drug design

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Minna D Balbas ◽  
Michael J Evans ◽  
David J Hosfield ◽  
John Wongvipat ◽  
Vivek K Arora ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Novel Mutation ◽  
Ectopic Expression ◽  
Rational Drug Design ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Rational Drug ◽  
Duration Of Response ◽  
Helix 12 ◽  
Dynamics Simulations

The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen–AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide.

scholarly journals Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer

2019 ◽  
Vol 11 (498) ◽  
pp. eaaw4636 ◽  
Author(s):  
Ning Zhao ◽  
Stephanie O. Peacock ◽  
Chen Hao Lo ◽  
Laine M. Heidman ◽  
Meghan A. Rice ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Arginine Vasopressin ◽  
Ectopic Expression ◽  
Vasopressin Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Castration Resistant ◽  
Promising Therapeutic Approach

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein–coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed thatAVPR1Ahas a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectableAVPR1AmRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

Chemotherapy in hormone-refractory prostate cancer: Docetaxel with and without VT122.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16062-e16062
Author(s):  
Gouri Shankar Bhattacharyya ◽  
Newell Bascomb ◽  
Hemant Malhotra ◽  
Ghanashyam Biswas ◽  
Shailesh Arjun Bondarde
Keyword(s):  
Prostate Cancer ◽  
Randomized Study ◽  
Castration Resistant Prostate Cancer ◽  
Protein Levels ◽  
Reactive Protein ◽  
End Point ◽  
Castration Resistant ◽  
Number Of Patients ◽  
Duration Of Response ◽  
Hormone Refractory

e16062 Background: Randomized study in metastatic castration resistant prostate cancer treated with docetaxel and the benefit of adding VT122. Methods: Castration resistant prostate cancer with bone metastasis, symptomatic were treated with docetaxel 75 mg/m2 every 3 week and prednisolone with continued androgen suppression, LHRH analogue and zoledronic acid, every 28 days with or without VT122. VT122 is a drug combination of etodolac, a COX-2 inhibitor and propranolol, a beta blocker with anti angiogenic properties; this combination has previously been shown to be anti cachectic, anti neoplastic.The dose of etodolac was titrated by C-reactive protein levels to a maximum of 800 mg/day. The dose of propranolol was titrated to keep heart rate at around 60 b/min to 70 b/min. GCSF was allowed, all patients were given Calcium and VitaminD. The primary end point was time to progression, a composite end point of objective progression by RECIST criteria, PSA progression or pain progression, whichever occurred first was applied.The McGill questionnaire was applied to patients. Number of patients 69; 34 in docetaxel arm; 35 in VT122 arm. Age between 50-65 years. Taken from 3 centers with PS ECOG <2 controlled comorbidity with stable analgesic regime. All patients were planned for 6 cycles of docetaxel. Follow-up was for a period of two years. Results: Median age of 62 years with ECOG status 1 was seen in 88%. The median PSA value was seen as 138 ng/ml (10 - 600). 66% in both arms had measurable disease. Conclusions: Addition of VT122 improves response rates, duration of response and symptom scales along with 1-year survival which are statistically significant; toxicities are also significantly decreased and indicating increased efficacy and safety profile of docetaxel. The efficacy and control of toxicity and easy to administer makes this an attractive combination. [Table: see text]

scholarly journals Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study

2020 ◽  
Vol 38 (5) ◽  
pp. 395-405 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey Goh ◽  
Kristiina Ojamaa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Disease Control ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Duration Of Response

PURPOSE Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)–positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1–positive and PD-L1–negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

scholarly journals The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

2015 ◽  
Vol 35 (8) ◽  
pp. 1350-1362 ◽  
Author(s):  
Lin Zhang ◽  
Shuping Yang ◽  
Xingcheng Chen ◽  
Seth Stauffer ◽  
Fang Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Prostate Tumors ◽  
Castration Resistant

Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive statein vitro, and YAP conferred castration resistancein vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase–ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC).

scholarly journals Impact of Time to Castration Resistance on Cytoreductive Radiotherapy in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Lixin Mai ◽  
Zitong Zhang ◽  
Yonghong Li ◽  
Ruiqi Liu ◽  
Jibin Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Factors ◽  
Eastern Cooperative Oncology Group ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Castration Resistant ◽  
Duration Of Response ◽  
Psa Response ◽  
Grade 3

BackgroundThe role of local radiotherapy in metastatic castration-resistant prostate cancer (mCRPC) remains undefined. This study aimed to identify the value of local radiotherapy and potential candidates for mCRPC.MethodsA total of 215 patients with mCRPC treated with or without cytoreductive radiotherapy (CRT) between June 2011 and February 2019 were analyzed. Overall survival (OS) was calculated from the onset of mCRPC. The receiver-operating characteristic (ROC) curve was used to find the cutoff point for time to castration resistance (TCR).ResultsOne-hundred and fifty-five (72.1%) patients received abiraterone after mCRPC, and 54 (25.1%) patients received CRT. The median TCR was 14.9 months. After a median follow-up of 31.7 months, the median OS was 33.3 months. The Eastern Cooperative Oncology Group (ECOG) performance scores 0–1, oligometastases, abiraterone after mCRPC, CRT, and TCR ≥9 months were independent prognostic factors for better OS. Stratified analyses showed improved survival when CRT was applied to patients treated with abiraterone (HR 0.44; 95% CI 0.23–0.83; P = 0.012) and TCR ≥9 months (HR 0.39; 95% CI 0.21–0.74; P = 0.004). The percentage of PSA response after radiotherapy was higher in patients with TCR ≥9 months compared to those with TCR &lt;9 months. No grade 3 or worse adverse events after radiotherapy were reported.ConclusionsECOG performance score, oligometastases, abiraterone application, TCR and CRT were independent prognostic factors for OS in patients with mCRPC. Patients with a short duration of response to primary androgen deprivation therapy were less likely to benefit from CRT.

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