Prostate cancers that ‘Wnt’ respond to abiraterone

Prostate cancers that ‘Wnt’ respond to abiraterone Wnt/β-catenin (Wnt) signalling is involved in cancer cell self-renewal, epidermal to mesenchymal transition and growth signalling. Furthermore, the interplay between Wnt pathway components and androgen receptor (AR) signalling have been well documented [1]. Linkage studies in prostate cancer have demonstrated an association between Wnt pathway genes and reduced prostate-specific antigen-free survival [2] and prostate cancer progression [3]. RNA-sequencing of circulating tumour cells has implicated non-canonical Wnt pathway activation in resistance to AR antagonism [4], and large-scale sequencing efforts have revealed genomic aberrations in the Wnt signalling pathway in approximately 20% of castration-resistant prostate cancer (CRPC) metastases obtained by biopsy or at rapid autopsy [5, 6]. In this edition of Annals of Oncology, Wang et al. report the PROMOTE single-centre trial designed to identify associations with primary resistance to abiraterone using molecular analyses of tumour biopsies obtained before treatment from progressing pre-chemotherapy metastatic CRPC patients [7]. This prospectively defined and well-characterised study population is an important resource. Specifically, Wang et al. enrolled 92 men and succeeded in performing a combination of whole-exome and/or whole-transcriptome sequencing on tumours from 86. Of note, 72% of biopsies were from bone metastases, putatively more clinically representative than most recent endeavours that were enriched for soft tissue disease. Patients were dichotomised by progression at 12 weeks of therapy (non-responders versus responders) and associations with mutated genes, copy number aberrations and transcriptional profiles were determined. For these analyses, the authors selected 98 genes with recurrent mutations in two or more tumours in their and the Grasso and Robinson’s datasets. They also restricted copy number evaluation to tumours with a minimum 15% tumour purity and transcriptomic analyses to skeletal metastases. Activating mutations in the Wnt pathway were enriched in abiraterone non-responders compared with responders (56.3 versus 17.1%, P = 0.001), and patients were twice as likely (HR 2.07, CI 1.08–3.97, P = 0.03) to be resistant to abiraterone if they had gene expression aberrations of the pathway. Another strength of the current study is that the investigators functionally tested chemical inhibition of Wnt signalling in combination with abiraterone in abiraterone-sensitive and abiraterone-resistant patient-derived prostate cancer organoids. In keeping with their prediction, inhibition of Wnt had little effect in the abiraterone-sensitive (normal Wnt) model, but in the abiraterone-resistant model (aberrant Wnt), cell death was seen with Wnt inhibitor monotherapy and partial induction of sensitivity when combined with abiraterone. Future work could further support the association between aberrant Wnt signalling and abiraterone resistance using an orthogonal approach such as CRISPR-CASP9 genome editing to activate the Wnt pathway. It should also be noted that abiraterone may be acting as an AR antagonist in in vitro models, rather than by inhibiting androgen synthesis [8], in this case also competing with pregnenolone added as a CYP17 substrate. These findings nonetheless still implicate Wnt pathway signalling in resistance to AR inhibition. The results of drug screens in organoid or patient-derived xenograft models have been correlated with clinical responses [9, 10], but the lack of stromal and immunological interactions are a limitation that could be overcome by developing co-culture systems or using the next generation of humanised mouse models. Low tumour purity can markedly reduce the detection of mutations and copy number changes in clinical samples. Traditional visual or image analysis of tumour purity is being replaced by computational methods. In the current study, the inferred tumour purity was low (median 33%) although the high mean sequencing coverage of 258× should help to limit the false-negative rate. Low tumour purity has previously been correlated to some clinicopathological entities in prostate cancer [11] and Wang et al. build on this by presenting a trend to higher tumour purity in non-responders compared to responders (36% versus 22%, P = 0.09). Low tumour purity implies that non-tumour cells or tumour microenviroment (TME) predominates in the sample. It is well recognised that paracrine Wnt signals from the TME can contribute to prostate tumour progression [4]. In mouse models, Wnt signalling has been implicated as modulating the TME-inflammatory response [12], and similarly, we have recently demonstrated in a cohort of high-risk localised or hormone-naive metastatic prostate cancer patients that activated Wnt signalling correlated with low CD8/FoxP3 ratio, consistent with a dysfunctional T-cell response and tumour escape [13]. While a convincing association between Wnt signalling and abiraterone primary resistance is reported in this discovery cohort, the negative predictive value, even if confirmed in independent validation sets, is insufficient for clinical decision making. Moreover, nearly one in five Wnt aberrant patients responded. Prostate cancer mouse models suggest that Wnt signalling requires additional events (e.g. PTEN loss) for oncogenesis [14], and similarly, abiraterone resistance may also be multi-genomic. AR aberrations detected in blood, both genomic (copy number gain or point mutations) and splice variants (mRNA or protein), have shown strong associations with primary resistance [15–17]. In the current study, tumour biopsy AR-V7 transcript levels also associated with primary resistance. It is therefore probable that a biomarker suite would provide the most accurate prediction of response. Overall, the PROMOTE data provide a strong rationale for testing of Wnt inhibitors (several agents currently in early clinical trial testing) alone or in combination with abiraterone in abiraterone-resistant biomarker-selected patients. Funding ML is supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre (no grant numbers apply). Cancer Research UK Advanced Clinician Scientist Fellowship (A22744) to GA. Disclosure The ICR developed abiraterone and therefore has a commercial interest in this agent. GA is on the ICR list of rewards to inventors for abiraterone. ML has received educational grants from BMS & Sanofi, travel support from Janssen, Astellas, Bayer and MSD and honorarium from Janssen. GA has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Ventana, ESSA Pharmaceuticals and Sanofi-Aventis and grant support from Janssen, AstraZeneca and Arno. References 1 Murillo-Garzon V, Kypta R. WNT signalling in prostate cancer. Nat Rev Urol  2017; 14( 11): 683– 696. Google Scholar CrossRef Search ADS PubMed  2 Huang SP, Ting WC, Chen LM et al.   Association analysis of Wnt pathway genes on prostate-specific antigen recurrence after radical prostatectomy. Ann Surg Oncol  2010; 17( 1): 312– 322. Google Scholar CrossRef Search ADS PubMed  3 Geng JH, Lin VC, Yu CC et al.   Inherited variants in Wnt pathway genes influence outcomes of prostate cancer patients receiving androgen deprivation therapy. IJMS  2016; 17( 12): E1970. Google Scholar CrossRef Search ADS PubMed  4 Miyamoto DT, Zheng Y, Wittner BS et al.   RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science  2015; 349( 6254): 1351– 1356. Google Scholar CrossRef Search ADS PubMed  5 Robinson D, Van Allen EM, Wu YM et al.   Integrative clinical genomics of advanced prostate cancer. Cell  2015; 161( 5): 1215– 1228. Google Scholar CrossRef Search ADS PubMed  6 Grasso CS, Wu YM, Robinson DR et al.   The mutational landscape of lethal castration-resistant prostate cancer. Nature  2012; 487( 7406): 239– 243. Google Scholar CrossRef Search ADS PubMed  7 Wang L, Dehm SM, Hillman DW et al.   A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate–prednisone. Ann Oncol  2018; 29( 2): 352– 360. 8 Richards J, Lim AC, Hay CW et al.   Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res  2012; 72( 9): 2176– 2182. Google Scholar CrossRef Search ADS PubMed  9 Izumchenko E, Paz K, Ciznadija D et al.   Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors. Ann Oncol  2017; 28( 10): 2595– 2605. Google Scholar CrossRef Search ADS PubMed  10 Saeed K, Rahkama V, Eldfors S et al.   Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant prostate cancer. Eur Urol  2017; 71( 3): 319– 327. Google Scholar CrossRef Search ADS PubMed  11 Aran D, Camarda R, Odegaard J et al.   Comprehensive analysis of normal adjacent to tumor transcriptomes. Nat Commun  2017; 8( 1): 1077. Google Scholar CrossRef Search ADS PubMed  12 Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature  2015; 523( 7559): 231– 235. Google Scholar CrossRef Search ADS PubMed  13 Linch M, Goh G, Hiley C et al.   Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol  2017; 28( 10): 2472– 2480. Google Scholar CrossRef Search ADS PubMed  14 Francis JC, Thomsen MK, Taketo MM et al.   beta-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma. PLoS Genet  2013; 9( 1): e1003180. Google Scholar CrossRef Search ADS PubMed  15 Conteduca V, Wetterskog D, Sharabiani MTA et al.   Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Oncol  2017; 28( 7): 1508– 1516. Google Scholar CrossRef Search ADS PubMed  16 Antonarakis ES, Lu C, Luber B et al.   Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol  2017; 35( 19): 2149– 2156. Google Scholar CrossRef Search ADS PubMed  17 Scher HI, Lu D, Schreiber NA et al.   Association of ar-v7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol  2016; 2( 11): 1441– 1449. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Prostate cancers that ‘Wnt’ respond to abiraterone

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Oxford University Press
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© The Author(s) 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
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1569-8041
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10.1093/annonc/mdx785
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Abstract

Wnt/β-catenin (Wnt) signalling is involved in cancer cell self-renewal, epidermal to mesenchymal transition and growth signalling. Furthermore, the interplay between Wnt pathway components and androgen receptor (AR) signalling have been well documented [1]. Linkage studies in prostate cancer have demonstrated an association between Wnt pathway genes and reduced prostate-specific antigen-free survival [2] and prostate cancer progression [3]. RNA-sequencing of circulating tumour cells has implicated non-canonical Wnt pathway activation in resistance to AR antagonism [4], and large-scale sequencing efforts have revealed genomic aberrations in the Wnt signalling pathway in approximately 20% of castration-resistant prostate cancer (CRPC) metastases obtained by biopsy or at rapid autopsy [5, 6]. In this edition of Annals of Oncology, Wang et al. report the PROMOTE single-centre trial designed to identify associations with primary resistance to abiraterone using molecular analyses of tumour biopsies obtained before treatment from progressing pre-chemotherapy metastatic CRPC patients [7]. This prospectively defined and well-characterised study population is an important resource. Specifically, Wang et al. enrolled 92 men and succeeded in performing a combination of whole-exome and/or whole-transcriptome sequencing on tumours from 86. Of note, 72% of biopsies were from bone metastases, putatively more clinically representative than most recent endeavours that were enriched for soft tissue disease. Patients were dichotomised by progression at 12 weeks of therapy (non-responders versus responders) and associations with mutated genes, copy number aberrations and transcriptional profiles were determined. For these analyses, the authors selected 98 genes with recurrent mutations in two or more tumours in their and the Grasso and Robinson’s datasets. They also restricted copy number evaluation to tumours with a minimum 15% tumour purity and transcriptomic analyses to skeletal metastases. Activating mutations in the Wnt pathway were enriched in abiraterone non-responders compared with responders (56.3 versus 17.1%, P = 0.001), and patients were twice as likely (HR 2.07, CI 1.08–3.97, P = 0.03) to be resistant to abiraterone if they had gene expression aberrations of the pathway. Another strength of the current study is that the investigators functionally tested chemical inhibition of Wnt signalling in combination with abiraterone in abiraterone-sensitive and abiraterone-resistant patient-derived prostate cancer organoids. In keeping with their prediction, inhibition of Wnt had little effect in the abiraterone-sensitive (normal Wnt) model, but in the abiraterone-resistant model (aberrant Wnt), cell death was seen with Wnt inhibitor monotherapy and partial induction of sensitivity when combined with abiraterone. Future work could further support the association between aberrant Wnt signalling and abiraterone resistance using an orthogonal approach such as CRISPR-CASP9 genome editing to activate the Wnt pathway. It should also be noted that abiraterone may be acting as an AR antagonist in in vitro models, rather than by inhibiting androgen synthesis [8], in this case also competing with pregnenolone added as a CYP17 substrate. These findings nonetheless still implicate Wnt pathway signalling in resistance to AR inhibition. The results of drug screens in organoid or patient-derived xenograft models have been correlated with clinical responses [9, 10], but the lack of stromal and immunological interactions are a limitation that could be overcome by developing co-culture systems or using the next generation of humanised mouse models. Low tumour purity can markedly reduce the detection of mutations and copy number changes in clinical samples. Traditional visual or image analysis of tumour purity is being replaced by computational methods. In the current study, the inferred tumour purity was low (median 33%) although the high mean sequencing coverage of 258× should help to limit the false-negative rate. Low tumour purity has previously been correlated to some clinicopathological entities in prostate cancer [11] and Wang et al. build on this by presenting a trend to higher tumour purity in non-responders compared to responders (36% versus 22%, P = 0.09). Low tumour purity implies that non-tumour cells or tumour microenviroment (TME) predominates in the sample. It is well recognised that paracrine Wnt signals from the TME can contribute to prostate tumour progression [4]. In mouse models, Wnt signalling has been implicated as modulating the TME-inflammatory response [12], and similarly, we have recently demonstrated in a cohort of high-risk localised or hormone-naive metastatic prostate cancer patients that activated Wnt signalling correlated with low CD8/FoxP3 ratio, consistent with a dysfunctional T-cell response and tumour escape [13]. While a convincing association between Wnt signalling and abiraterone primary resistance is reported in this discovery cohort, the negative predictive value, even if confirmed in independent validation sets, is insufficient for clinical decision making. Moreover, nearly one in five Wnt aberrant patients responded. Prostate cancer mouse models suggest that Wnt signalling requires additional events (e.g. PTEN loss) for oncogenesis [14], and similarly, abiraterone resistance may also be multi-genomic. AR aberrations detected in blood, both genomic (copy number gain or point mutations) and splice variants (mRNA or protein), have shown strong associations with primary resistance [15–17]. In the current study, tumour biopsy AR-V7 transcript levels also associated with primary resistance. It is therefore probable that a biomarker suite would provide the most accurate prediction of response. Overall, the PROMOTE data provide a strong rationale for testing of Wnt inhibitors (several agents currently in early clinical trial testing) alone or in combination with abiraterone in abiraterone-resistant biomarker-selected patients. Funding ML is supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre (no grant numbers apply). Cancer Research UK Advanced Clinician Scientist Fellowship (A22744) to GA. Disclosure The ICR developed abiraterone and therefore has a commercial interest in this agent. GA is on the ICR list of rewards to inventors for abiraterone. ML has received educational grants from BMS & Sanofi, travel support from Janssen, Astellas, Bayer and MSD and honorarium from Janssen. GA has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Ventana, ESSA Pharmaceuticals and Sanofi-Aventis and grant support from Janssen, AstraZeneca and Arno. References 1 Murillo-Garzon V, Kypta R. WNT signalling in prostate cancer. Nat Rev Urol  2017; 14( 11): 683– 696. Google Scholar CrossRef Search ADS PubMed  2 Huang SP, Ting WC, Chen LM et al.   Association analysis of Wnt pathway genes on prostate-specific antigen recurrence after radical prostatectomy. Ann Surg Oncol  2010; 17( 1): 312– 322. Google Scholar CrossRef Search ADS PubMed  3 Geng JH, Lin VC, Yu CC et al.   Inherited variants in Wnt pathway genes influence outcomes of prostate cancer patients receiving androgen deprivation therapy. IJMS  2016; 17( 12): E1970. Google Scholar CrossRef Search ADS PubMed  4 Miyamoto DT, Zheng Y, Wittner BS et al.   RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science  2015; 349( 6254): 1351– 1356. Google Scholar CrossRef Search ADS PubMed  5 Robinson D, Van Allen EM, Wu YM et al.   Integrative clinical genomics of advanced prostate cancer. Cell  2015; 161( 5): 1215– 1228. Google Scholar CrossRef Search ADS PubMed  6 Grasso CS, Wu YM, Robinson DR et al.   The mutational landscape of lethal castration-resistant prostate cancer. Nature  2012; 487( 7406): 239– 243. Google Scholar CrossRef Search ADS PubMed  7 Wang L, Dehm SM, Hillman DW et al.   A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate–prednisone. Ann Oncol  2018; 29( 2): 352– 360. 8 Richards J, Lim AC, Hay CW et al.   Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res  2012; 72( 9): 2176– 2182. Google Scholar CrossRef Search ADS PubMed  9 Izumchenko E, Paz K, Ciznadija D et al.   Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors. Ann Oncol  2017; 28( 10): 2595– 2605. Google Scholar CrossRef Search ADS PubMed  10 Saeed K, Rahkama V, Eldfors S et al.   Comprehensive drug testing of patient-derived conditionally reprogrammed cells from castration-resistant prostate cancer. Eur Urol  2017; 71( 3): 319– 327. Google Scholar CrossRef Search ADS PubMed  11 Aran D, Camarda R, Odegaard J et al.   Comprehensive analysis of normal adjacent to tumor transcriptomes. Nat Commun  2017; 8( 1): 1077. Google Scholar CrossRef Search ADS PubMed  12 Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature  2015; 523( 7559): 231– 235. Google Scholar CrossRef Search ADS PubMed  13 Linch M, Goh G, Hiley C et al.   Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol  2017; 28( 10): 2472– 2480. Google Scholar CrossRef Search ADS PubMed  14 Francis JC, Thomsen MK, Taketo MM et al.   beta-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma. PLoS Genet  2013; 9( 1): e1003180. Google Scholar CrossRef Search ADS PubMed  15 Conteduca V, Wetterskog D, Sharabiani MTA et al.   Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Oncol  2017; 28( 7): 1508– 1516. Google Scholar CrossRef Search ADS PubMed  16 Antonarakis ES, Lu C, Luber B et al.   Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol  2017; 35( 19): 2149– 2156. Google Scholar CrossRef Search ADS PubMed  17 Scher HI, Lu D, Schreiber NA et al.   Association of ar-v7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol  2016; 2( 11): 1441– 1449. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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