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Christopher H. Evans - One of the best experts on this subject based on the ideXlab platform.
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cross resistance among next generation antiandrogen drugs through the akr1c3 ar v7 axis in advanced prostate cancer
Molecular Cancer Therapeutics, 2020Co-Authors: Jinge Zhao, Joy C Yang, Wei Lou, Christopher H. Evans, Allen C. Gao, Cameron M Armstrong, Shu Ning, Alan P Lombard, Leandro S Dabronzo, Chengfei LiuAbstract:The next-generation antiandrogen drugs, XTANDI (Enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to Enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that Enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in Enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to Enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with Enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.
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Enzalutamide in men with chemotherapy naive metastatic castration resistant prostate cancer extended analysis of the phase 3 prevail study
European Urology, 2017Co-Authors: Tomasz M Beer, Christopher H. Evans, Andrew J Armstrong, Dana E Rathkopf, Yohann Loriot, Cora N Sternberg, Celestia S Higano, Peter Iversen, Go Kimura, Kurt MillerAbstract:Abstract Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naive metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of Enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28–0.37; p 0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67–0.88; p =0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9–22.1) in the Enzalutamide arm and 5.4 mo (95% CI 4.1–5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2–not yet reached) in the Enzalutamide arm and 31.3 mo (95% CI 28.8–34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive Enzalutamide. The most common adverse events in the Enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of Enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. Patient summary According to data from longer follow-up, Enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer.
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the prevail study primary outcomes by site and extent of baseline disease for Enzalutamide treated men with chemotherapy naive metastatic castration resistant prostate cancer
European Urology, 2016Co-Authors: Christopher H. Evans, Fred Saad, Celestia S Higano, Peter Iversen, Go Kimura, Kurt Miller, Thomas E Keane, Gerald L Andriole, Choung Soo Kim, Andrew J ArmstrongAbstract:Abstract Background Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naive metastatic castration-resistant prostate cancer. Objective To assess the effects of Enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. Design, setting, and participants One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to Enzalutamide ( n =872) or placebo ( n =845). Subgroup analyses included nonvisceral (only bone and/or nodal; n =1513), visceral (lung and/or liver; n =204), low-volume bone disease ( n =867), high-volume bone disease (≥4 bone metastases; n =850), lymph node only disease ( n =195). Intervention Oral Enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy. Outcome measurements and statistical analysis Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc. Results and limitations Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14–0.22), visceral disease (HR, 0.28; 95% CI, 0.16–0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11–0.22; HR, 0.22; 95% CI, 0.16–0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04–0.19). For OS, HRs favored Enzalutamide ( 1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55–1.23). Enzalutamide was well tolerated in patients with or without visceral disease. Conclusions Enzalutamide provided clinically significant benefits in men with chemotherapy-naive metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. Patient summary Patients with metastatic castration-resistant prostate cancer—including those with or without visceral disease or widespread bone disease—benefitted from Enzalutamide, an active well-tolerated therapy.
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Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation
The Prostate, 2015Co-Authors: Ramakumar Tummala, Nagalakshmi Nadiminty, Wei Lou, Christopher H. Evans, Allen C. GaoAbstract:BACKGROUND Prostate cancer (PCa) is androgen-dependent initially and progresses to a castration-resistant state after androgen deprivation therapy. Treatment options for castration-resistant PCa include the potent second-generation anti-androgen Enzalutamide or CYP17A1 inhibitor abiraterone. Recent clinical observations point to the development of resistance to these therapies which may be mediated by constitutively active alternative splice variants of the androgen receptor (AR). METHODS Sensitivity of LNCaP cells overexpressing Lin28 (LN-Lin28) to Enzalutamide, abiraterone, or bicalutamide was compared to that of control LN-neo cells using cell growth assays, proliferation assays using MTT, anchorage-dependent clonogenic ability assays and soft agar assays. Ability of LN-Lin28 cells to maintain AR activation after treatment with Enzalutamide, abiraterone, or bicalutamide was tested using immunofluorescence, Western blotting, ChIP assays, and qRT-PCR. Importance of Lin28 in Enzalutamide resistance was assessed by the downregulation of Lin28 expression in C4-2B and 22Rv1 cells chronically treated with Enzalutamide. Requirement for sustained AR signaling in LN-Lin28 cells was examined by the downregulation of either full length AR or AR-V7 using siRNA. RESULTS We show that Lin28 promotes the development of resistance to currently used targeted therapeutics by enhancing the expression of AR splice variants such as AR-V7. PCa cells overexpressing Lin28 exhibit resistance to treatment with Enzalutamide, abiraterone, or bicalutamide. Downregulation of Lin28 resensitizes Enzalutamide-resistant PCa cells to Enzalutamide treatment. We also show that the upregulation of splicing factors such as hnRNPA1 by Lin28 may mediate the enhanced generation of AR splice variants in Lin28-expressing cells. CONCLUSIONS Our findings suggest that Lin28 plays a key role in the acquisition of resistance to AR-targeted therapies by PCa cells and establish the importance of Lin28 in PCa progression. Prostate 76:445–455, 2016. © 2015 Wiley Periodicals, Inc.
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niclosamide inhibits androgen receptor variants expression and overcomes Enzalutamide resistance in castration resistant prostate cancer
Clinical Cancer Research, 2014Co-Authors: Nagalakshmi Nadiminty, Chad Schwartz, Christopher H. EvansAbstract:Purpose: Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration-resistant prostate cancer (CRPC) in patients who no longer respond to docetaxel. Despite these advances that provide temporary respite, resistance to Enzalutamide occurs frequently. Androgen receptor (AR) splice variants such as AR-V7 have recently been shown to drive castration-resistant growth and resistance to Enzalutamide. This study was designed to identify inhibitors of AR variants and test its ability to overcome resistance to Enzalutamide. Experimental Design: The drug screening was conducted using luciferase activity assay to determine the activity of AR-V7 after treatment with the compounds in the Prestwick Chemical Library, which contains about 1,120 FDA-approved drugs. The effects of the identified inhibitors on AR-V7 activity and Enzalutamide sensitivity were characterized in CRPC and Enzalutamide-resistant prostate cancer cells in vitro and in vivo . Results: Niclosamide, an FDA-approved antihelminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Niclosamide significantly downregulated AR-V7 protein expression by protein degradation through a proteasome-dependent pathway. Niclosamide also inhibited AR-V7 transcription activity and reduced the recruitment of AR-V7 to the PSA promoter. Niclosamide inhibited prostate cancer cell growth in vitro and tumor growth in vivo . Furthermore, the combination of niclosamide and Enzalutamide resulted in significant inhibition of Enzalutamide-resistant tumor growth, suggesting that niclosamide enhances Enzalutamide therapy and overcomes Enzalutamide resistance in CRPC cells. Conclusions: Niclosamide was identified as a novel inhibitor of AR variants. Our findings offer preclinical validation of niclosamide as a promising inhibitor of AR variants to treat, either alone or in combination with current antiandrogen therapies, patients with advanced prostate cancer, especially those resistant to Enzalutamide. Clin Cancer Res; 20(12); 3198–210. ©2014 AACR .
Allen C. Gao - One of the best experts on this subject based on the ideXlab platform.
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cross resistance among next generation antiandrogen drugs through the akr1c3 ar v7 axis in advanced prostate cancer
Molecular Cancer Therapeutics, 2020Co-Authors: Jinge Zhao, Joy C Yang, Wei Lou, Christopher H. Evans, Allen C. Gao, Cameron M Armstrong, Shu Ning, Alan P Lombard, Leandro S Dabronzo, Chengfei LiuAbstract:The next-generation antiandrogen drugs, XTANDI (Enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to Enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that Enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in Enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to Enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with Enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.
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Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells
Molecular cancer therapeutics, 2017Co-Authors: Ramakumar Tummala, Wei Lou, Allen C. Gao, Nagalakshmi NadimintyAbstract:Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, Enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and Arv567es have been implicated in the resistance to not only Enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies including ours suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to Enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes Enzalutamide-resistant prostate cancer cells to treatment with Enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes Enzalutamide-resistant prostate cancer cells to Enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation anti-androgen therapy.
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Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation
The Prostate, 2015Co-Authors: Ramakumar Tummala, Nagalakshmi Nadiminty, Wei Lou, Christopher H. Evans, Allen C. GaoAbstract:BACKGROUND Prostate cancer (PCa) is androgen-dependent initially and progresses to a castration-resistant state after androgen deprivation therapy. Treatment options for castration-resistant PCa include the potent second-generation anti-androgen Enzalutamide or CYP17A1 inhibitor abiraterone. Recent clinical observations point to the development of resistance to these therapies which may be mediated by constitutively active alternative splice variants of the androgen receptor (AR). METHODS Sensitivity of LNCaP cells overexpressing Lin28 (LN-Lin28) to Enzalutamide, abiraterone, or bicalutamide was compared to that of control LN-neo cells using cell growth assays, proliferation assays using MTT, anchorage-dependent clonogenic ability assays and soft agar assays. Ability of LN-Lin28 cells to maintain AR activation after treatment with Enzalutamide, abiraterone, or bicalutamide was tested using immunofluorescence, Western blotting, ChIP assays, and qRT-PCR. Importance of Lin28 in Enzalutamide resistance was assessed by the downregulation of Lin28 expression in C4-2B and 22Rv1 cells chronically treated with Enzalutamide. Requirement for sustained AR signaling in LN-Lin28 cells was examined by the downregulation of either full length AR or AR-V7 using siRNA. RESULTS We show that Lin28 promotes the development of resistance to currently used targeted therapeutics by enhancing the expression of AR splice variants such as AR-V7. PCa cells overexpressing Lin28 exhibit resistance to treatment with Enzalutamide, abiraterone, or bicalutamide. Downregulation of Lin28 resensitizes Enzalutamide-resistant PCa cells to Enzalutamide treatment. We also show that the upregulation of splicing factors such as hnRNPA1 by Lin28 may mediate the enhanced generation of AR splice variants in Lin28-expressing cells. CONCLUSIONS Our findings suggest that Lin28 plays a key role in the acquisition of resistance to AR-targeted therapies by PCa cells and establish the importance of Lin28 in PCa progression. Prostate 76:445–455, 2016. © 2015 Wiley Periodicals, Inc.
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P52 Activation and Enzalutamide Therapy in Prostate Cancer
2015Co-Authors: Allen C. GaoAbstract:Abstract : There has been a major focus on the androgen receptor (AR) pathway as the principal therapeutic target for CRPC including recently approved therapies such as next-generation antiandrogen Enzalutamide and abiraterone. Despite these advances that provide temporary respite, almost all patients will go on to die from progressive and resistant prostate cancer. Therefore, there is an urgent need to identify resistant pathways that perpetuate disease progression. We provided preliminary data demonstrating that p52 increases AR variant V7 (AR-V7) expression and enhances prostate cancer cell resistance to next generation antiandrogen Enzalutamide treatment. We hypothesize that overexpression of p52 signaling activates resistance pathways to Enzalutamide and co-targeting p52 will overcome treatment resistance. In this project, we will examine the potential mechanisms underlying p52-mediated treatment resistance (Aim 1). Aim 2 will validate the efficacy of co-targeting p52 to overcome treatment resistance to Enzalutamide. We hope to identify the mechanisms of adaptive/resistant pathways that are responsible for Enzalutamide resistance, and provide a rationale for therapeutic co-targeting to overcome Enzalutamide resistance.
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antiandrogens inhibit abcb1 efflux and atpase activity and reverse docetaxel resistance in advanced prostate cancer
Clinical Cancer Research, 2015Co-Authors: Yezi Zhu, Wei Lou, Chengfei Liu, Cameron M Armstrong, Amandeep Sandher, Allen C. GaoAbstract:Purpose: Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and Enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel. Experimental Design: ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and Enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo . Results: We found that bicalutamide and Enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, whereas Enzalutamide inhibited ABCB1 efflux activity by approximately 60%. Both bicalutamide and Enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and Enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel-resistant and androgen receptor (AR)–negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel-resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status. Conclusions: We identified a novel mechanism of action for antiandrogens such as bicalutamide and Enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and Enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/Enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer. Clin Cancer Res; 21(18); 4133–42. ©2015 AACR .
J S De Bono - One of the best experts on this subject based on the ideXlab platform.
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Enzalutamide antitumour activity against metastatic castration resistant prostate cancer previously treated with docetaxel and abiraterone a multicentre analysis
European Urology, 2015Co-Authors: Klaus Brasso, Axel S. Merseburger, David Lorente, Frederik Birkebaek Thomsen, Andres J Schrader, Sebastian Schmid, Margitta Retz, Christoph A J Von Klot, Martin Boegemann, J S De BonoAbstract:Abstract Background The degree of antitumour activity of Enzalutamide following disease progression on docetaxel and abiraterone remains controversial. Objective To examine the effect of Enzalutamide in patients progressing following taxane-based chemotherapy and abiraterone. Design, setting, and participants Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of Enzalutamide. Outcome measurements and statistical analysis The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. Results and limitations We identified 137 patients who prior to Enzalutamide had progressed following a median of eight cycles of docetaxel and seven courses of abiraterone. The median time on Enzalutamide was 3.2 mo; median OS from the time patients started Enzalutamide was 8.3 mo (95% confidence interval, 6.8–9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively. Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p =0.001 and 12.6 vs 7.4 mo; p =0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. Conclusions Median OS on Enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with Enzalutamide in this setting had longer survival. Patient summary Enzalutamide produces modest prostate-specific antigen (PSA) responses in patients progressing following chemotherapy and abiraterone. Despite a modest PSA response, survival may still be improved.
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is there an antiandrogen withdrawal syndrome with Enzalutamide
BJUI, 2015Co-Authors: Alejo Rodriguezvida, Diletta Bianchini, Mieke Van Hemelrijck, Simon Hughes, Zafar Malik, Thomas Powles, Amit Bahl, Sarah Rudman, Heather Payne, J S De BonoAbstract:Objective To examine prostate-specific antigen (PSA) levels after Enzalutamide discontinuation to assess whether an antiandrogen withdrawal syndrome (AAWS) exists with Enzalutamide. Methods We retrospectively identified 30 consecutive patients with metastatic prostate cancer who were treated with Enzalutamide after docetaxel. Post-discontinuation PSA results were available for all patients and were determined at 2-weekly intervals until starting further anticancer systemic therapy. PSA withdrawal response was defined as a PSA decline by >= 50% from the last on-treatment PSA, with a confirmed decrease >= 3 weeks later. Patient characteristics were evaluated in relation to the AAWS using univariate logistic regression analysis. Results The median (range) patient age was 70.5 (56-86) years and the median (range) follow-up was 9.0 (0.5-16) months. The most common metastatic sites were the bone (86.7%) and lymph nodes (66.7%). Most patients (70%) had previously received abiraterone and 12 patients (40%) had also received cabazitaxel. The median (range) treatment duration with Enzalutamide was 3.68 (1.12-21.39) months. PSA levels after Enzalutamide withdrawal were monitored for a median (range) time of 35 (10-120) days. Only one patient (3.3%) had a confirmed PSA response >= 50% after Enzalutamide discontinuation. One patient (3.3%) had a confirmed PSA response of between 30 and 50% and another patient (3.3%) had an unconfirmed PSA response of between 30 and 50%. The median overall survival was 15.5 months (95% CI 8.1-24.7). None of the factors analysed in the univariate analysis were significant predictors of PSA decline after Enzalutamide discontinuation. Conclusions This retrospective study provides the first evidence that Enzalutamide may have an AAWS in a minority of patients with metastatic castration-resistant prostate cancer. Further studies are needed to confirm the existence of an Enzalutamide AAWS and to assess its relevance in prostate cancer management.
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antitumour activity of Enzalutamide mdv3100 in patients with metastatic castration resistant prostate cancer crpc pre treated with docetaxel and abiraterone
European Journal of Cancer, 2014Co-Authors: Diletta Bianchini, David Lorente, Alejo Rodriguezvida, Aurelius Omlin, Carmel Pezaro, Roberta Ferraldeschi, Andrea Zivi, Gerhardt Attard, Simon Chowdhury, J S De BonoAbstract:BACKGROUND: The new generation anti-androgen Enzalutamide and the potent CYP17 inhibitor abiraterone have both demonstrated survival benefits in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. Preliminary data on the antitumour activity of abiraterone after Enzalutamide have suggested limited activity. The antitumour activity and safety of Enzalutamide after abiraterone in metastatic CRPC patients is still unknown. PATIENTS AND METHODS: We retrospectively identified patients treated with docetaxel and abiraterone prior to Enzalutamide to investigate the activity and safety of Enzalutamide in a more advanced setting. Prostate specific antigen (PSA), radiological and clinical assessments were analysed. RESULTS: 39 patients with metastatic CRPC were identified for this analysis (median age 70years, range: 54-85years). Overall 16 patients (41%) had a confirmed PSA decline of at least 30%. Confirmed PSA declines of ⩾50% and ⩾90% were achieved in 5/39 (12.8%) and 1/39 (2.5%) respectively. Of the 15 patients who responded to abiraterone, two (13.3%) also had a confirmed ⩾50% PSA decline on subsequent Enzalutamide. Among the 22 abiraterone-refractory patients, two (9%) achieved a confirmed ⩾50% PSA decline on Enzalutamide. CONCLUSION: Our preliminary case series data suggest limited activity of Enzalutamide in the post-docetaxel and post-abiraterone patient population.
Nagalakshmi Nadiminty - One of the best experts on this subject based on the ideXlab platform.
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Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells
Molecular cancer therapeutics, 2017Co-Authors: Ramakumar Tummala, Wei Lou, Allen C. Gao, Nagalakshmi NadimintyAbstract:Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, Enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and Arv567es have been implicated in the resistance to not only Enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies including ours suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to Enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes Enzalutamide-resistant prostate cancer cells to treatment with Enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes Enzalutamide-resistant prostate cancer cells to Enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation anti-androgen therapy.
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Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation
The Prostate, 2015Co-Authors: Ramakumar Tummala, Nagalakshmi Nadiminty, Wei Lou, Christopher H. Evans, Allen C. GaoAbstract:BACKGROUND Prostate cancer (PCa) is androgen-dependent initially and progresses to a castration-resistant state after androgen deprivation therapy. Treatment options for castration-resistant PCa include the potent second-generation anti-androgen Enzalutamide or CYP17A1 inhibitor abiraterone. Recent clinical observations point to the development of resistance to these therapies which may be mediated by constitutively active alternative splice variants of the androgen receptor (AR). METHODS Sensitivity of LNCaP cells overexpressing Lin28 (LN-Lin28) to Enzalutamide, abiraterone, or bicalutamide was compared to that of control LN-neo cells using cell growth assays, proliferation assays using MTT, anchorage-dependent clonogenic ability assays and soft agar assays. Ability of LN-Lin28 cells to maintain AR activation after treatment with Enzalutamide, abiraterone, or bicalutamide was tested using immunofluorescence, Western blotting, ChIP assays, and qRT-PCR. Importance of Lin28 in Enzalutamide resistance was assessed by the downregulation of Lin28 expression in C4-2B and 22Rv1 cells chronically treated with Enzalutamide. Requirement for sustained AR signaling in LN-Lin28 cells was examined by the downregulation of either full length AR or AR-V7 using siRNA. RESULTS We show that Lin28 promotes the development of resistance to currently used targeted therapeutics by enhancing the expression of AR splice variants such as AR-V7. PCa cells overexpressing Lin28 exhibit resistance to treatment with Enzalutamide, abiraterone, or bicalutamide. Downregulation of Lin28 resensitizes Enzalutamide-resistant PCa cells to Enzalutamide treatment. We also show that the upregulation of splicing factors such as hnRNPA1 by Lin28 may mediate the enhanced generation of AR splice variants in Lin28-expressing cells. CONCLUSIONS Our findings suggest that Lin28 plays a key role in the acquisition of resistance to AR-targeted therapies by PCa cells and establish the importance of Lin28 in PCa progression. Prostate 76:445–455, 2016. © 2015 Wiley Periodicals, Inc.
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intracrine androgens and akr1c3 activation confer resistance to Enzalutamide in prostate cancer
Cancer Research, 2015Co-Authors: Joy C Yang, Nagalakshmi Nadiminty, Nilesh W. Gaikwad, Christopher P EvansAbstract:The introduction of Enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to Enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed Enzalutamide resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene expression analysis showed that steroid biosynthesis pathway is activated in Enzalutamide resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in Enzalutamide resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in Enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in Enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized Enzalutamide resistant prostate cancer cells to Enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to Enzalutamide. Furthermore, the combination of indomethacin and Enzalutamide resulted in significant inhibition of Enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with Enzalutamide resistance, targeting intracrine androgens and AKR1C3 will overcome Enzalutamide resistance and improve survival of advanced prostate cancer patients.
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niclosamide inhibits androgen receptor variants expression and overcomes Enzalutamide resistance in castration resistant prostate cancer
Clinical Cancer Research, 2014Co-Authors: Nagalakshmi Nadiminty, Chad Schwartz, Christopher H. EvansAbstract:Purpose: Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration-resistant prostate cancer (CRPC) in patients who no longer respond to docetaxel. Despite these advances that provide temporary respite, resistance to Enzalutamide occurs frequently. Androgen receptor (AR) splice variants such as AR-V7 have recently been shown to drive castration-resistant growth and resistance to Enzalutamide. This study was designed to identify inhibitors of AR variants and test its ability to overcome resistance to Enzalutamide. Experimental Design: The drug screening was conducted using luciferase activity assay to determine the activity of AR-V7 after treatment with the compounds in the Prestwick Chemical Library, which contains about 1,120 FDA-approved drugs. The effects of the identified inhibitors on AR-V7 activity and Enzalutamide sensitivity were characterized in CRPC and Enzalutamide-resistant prostate cancer cells in vitro and in vivo . Results: Niclosamide, an FDA-approved antihelminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Niclosamide significantly downregulated AR-V7 protein expression by protein degradation through a proteasome-dependent pathway. Niclosamide also inhibited AR-V7 transcription activity and reduced the recruitment of AR-V7 to the PSA promoter. Niclosamide inhibited prostate cancer cell growth in vitro and tumor growth in vivo . Furthermore, the combination of niclosamide and Enzalutamide resulted in significant inhibition of Enzalutamide-resistant tumor growth, suggesting that niclosamide enhances Enzalutamide therapy and overcomes Enzalutamide resistance in CRPC cells. Conclusions: Niclosamide was identified as a novel inhibitor of AR variants. Our findings offer preclinical validation of niclosamide as a promising inhibitor of AR variants to treat, either alone or in combination with current antiandrogen therapies, patients with advanced prostate cancer, especially those resistant to Enzalutamide. Clin Cancer Res; 20(12); 3198–210. ©2014 AACR .
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nf κb2 p52 induces resistance to Enzalutamide in prostate cancer role of androgen receptor and its variants
Molecular Cancer Therapeutics, 2013Co-Authors: Nagalakshmi Nadiminty, Joy C Yang, Ramakumar Tummala, Wei Lou, Christopher H. Evans, Chengfei Liu, Allen C. GaoAbstract:Resistance of prostate cancer (CaP) cells to the next generation anti-androgen, Enzalutamide, may be mediated by a multitude of survival signaling pathways. In this study we tested whether increased expression of NF-κB2/p52 induces CaP cell resistance to Enzalutamide and whether this response is mediated by aberrant androgen receptor (AR) activation and AR splice variant production. LNCaP cells stably expressing NF-κB2/p52 exhibited higher survival rates compared to controls when treated with Enzalutamide. C4-2B and CWR22Rv1 cells chronically treated with Enzalutamide were found to express higher levels of NF-κB2/p52. Downregulation of NF-κB2/p52 in CWR22Rv1 cells chronically treated with Enzalutamide rendered them more sensitive to cell growth inhibition by Enzalutamide. Analysis of the expression levels of AR splice variants by qRT-PCR and Western blotting revealed that LNCaP cells expressing p52 exhibit higher expression of AR splice variants. Downregulation of expression of NF-κB2/p52 in VCaP and CWR22Rv1 cells by shRNA abolished expression of splice variants. Downregulation of expression of either full length AR or the splice variant AR-V7 led to an increase in sensitivity of CaP cells to Enzalutamide. These results collectively demonstrate that resistance to Enzalutamide may be mediated by NF-κB2/p52 via activation of AR and its splice variants.
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cross resistance among next generation antiandrogen drugs through the akr1c3 ar v7 axis in advanced prostate cancer
Molecular Cancer Therapeutics, 2020Co-Authors: Jinge Zhao, Joy C Yang, Wei Lou, Christopher H. Evans, Allen C. Gao, Cameron M Armstrong, Shu Ning, Alan P Lombard, Leandro S Dabronzo, Chengfei LiuAbstract:The next-generation antiandrogen drugs, XTANDI (Enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to Enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that Enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in Enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to Enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with Enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.
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cross resistance among next generation anti androgen drugs through the akr1c3 ar v7 axis in advanced prostate cancer
Molecular Cancer Therapeutics, 2020Co-Authors: Jinge Zhao, Joy C Yang, Cameron M Armstrong, Shu Ning, Alan P Lombard, Leandro S Dabronzo, Christopher P EvansAbstract:The next generation anti-androgen drugs, XTANDI® (Enzalutamide), ZYTIGA® (Abiraterone acetate), ERLEADA™ (Apalutamide) and NUBEQA (Darolutamide) extend survival times and improve quality of life in advanced prostate cancer patients. Despite these advances, resistance occurs frequently and there is currently no definitive cure for Castration-Resistant Prostate Cancer (CRPC). Our previous studies identified that similar mechanisms of resistance to Enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here we show that Enzalutamide and abiraterone resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in Enzalutamide resistant cells re-sensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 re-sensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression which confers resistance to Enzalutamide, abiraterone and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with Enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second generation AR-targeted therapies in advanced prostate cancer.
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intracrine androgens and akr1c3 activation confer resistance to Enzalutamide in prostate cancer
Cancer Research, 2015Co-Authors: Joy C Yang, Nagalakshmi Nadiminty, Nilesh W. Gaikwad, Christopher P EvansAbstract:The introduction of Enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to Enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed Enzalutamide resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene expression analysis showed that steroid biosynthesis pathway is activated in Enzalutamide resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in Enzalutamide resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in Enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in Enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized Enzalutamide resistant prostate cancer cells to Enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to Enzalutamide. Furthermore, the combination of indomethacin and Enzalutamide resulted in significant inhibition of Enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with Enzalutamide resistance, targeting intracrine androgens and AKR1C3 will overcome Enzalutamide resistance and improve survival of advanced prostate cancer patients.
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nf κb2 p52 induces resistance to Enzalutamide in prostate cancer role of androgen receptor and its variants
Molecular Cancer Therapeutics, 2013Co-Authors: Nagalakshmi Nadiminty, Joy C Yang, Ramakumar Tummala, Wei Lou, Christopher H. Evans, Chengfei Liu, Allen C. GaoAbstract:Resistance of prostate cancer (CaP) cells to the next generation anti-androgen, Enzalutamide, may be mediated by a multitude of survival signaling pathways. In this study we tested whether increased expression of NF-κB2/p52 induces CaP cell resistance to Enzalutamide and whether this response is mediated by aberrant androgen receptor (AR) activation and AR splice variant production. LNCaP cells stably expressing NF-κB2/p52 exhibited higher survival rates compared to controls when treated with Enzalutamide. C4-2B and CWR22Rv1 cells chronically treated with Enzalutamide were found to express higher levels of NF-κB2/p52. Downregulation of NF-κB2/p52 in CWR22Rv1 cells chronically treated with Enzalutamide rendered them more sensitive to cell growth inhibition by Enzalutamide. Analysis of the expression levels of AR splice variants by qRT-PCR and Western blotting revealed that LNCaP cells expressing p52 exhibit higher expression of AR splice variants. Downregulation of expression of NF-κB2/p52 in VCaP and CWR22Rv1 cells by shRNA abolished expression of splice variants. Downregulation of expression of either full length AR or the splice variant AR-V7 led to an increase in sensitivity of CaP cells to Enzalutamide. These results collectively demonstrate that resistance to Enzalutamide may be mediated by NF-κB2/p52 via activation of AR and its splice variants.