REVIEW EDITORIAL For reprint orders, please contact: [email protected]
Is in vitro-acquired resistance to enzalutamide a useful model?
Carlo Buonerba1 & Giuseppe Di Lorenzo*,1,2
Prostate cancer is a major health concern among men worldwide, with an estimated 234,460 new cases diagnosed and 27,350 deaths in the USA alone in 2006 [1] . Significant advancements have been achieved in the fight against this deadly disease, both in terms of secondary prevention [2] and in the management of advanced prostate cancer resistant to castration [3] , namely, castration-resistant prostate cancer (CRPC). Overdiagnosis is a major drawback of screening, and demands patient informed consent, careful selection of patients to biopsy by the use of more refined tests than prostatespecific antigen (PSA) alone, such as PCA3 and prostate health index [4] , as well as appropriate use of active surveillance [2] . Treatment of CRPC has been elusive for many years, with conventional chemotherapy agents such as mitoxantrone and vinorelbine ineffective to prolong survival in Phase III trials [1] . At the present time, six agents have shown to prolong survival in CRPC, that is, two taxane agents (docetaxel and cabazitaxel), two hormonal agents (enzalutamide and
abiraterone), one radiopharmaceutical agent (radium-223) [5] and one immunotherapy agent (Sipuleucel-t) [6] . If all of these agents could be given sequentially in CRPC, 720 combinations are possible, hence the potential usefulness of retrospective studies and cell models to test cross resistance and sequential use of available agents. A number of small, retrospective studies have explored the effectiveness of third-line treatment in CRPC. While a similar survival of approximately 7–8 months was reported in 24 patients receiving docetaxel-abiraterone-cabazitaxel, and in 35 patients treated with the sequence docetaxel-abiraterone-enzalutamide, 30 patients treated with docetaxel-enzalutamide-abiraterone showed a median overall survival (OS) of approximately 11 months [7] . These data show that the expected treatment efficacy is lower in more advanced lines of therapy – a universal law in oncology. This can simply be explained with poorer performance status and increased disease burden, but it could also be the result of cross-resistance. In fact, taxanes may not
KEYWORDS
• abiraterone • acquired resistance to the therapy • cabazitaxel • castration-resistant prostate cancer • enzalutamide
“…with the multitude of effective therapeutic agents available in CRPC, large, prospective randomized controlled trials are required to … identify subpopulations of CRPC patients requiring a tailored approach.”
Medical Oncology Unit, Department of Clinical Medicine, Federico II University, Naples, Italy Genitourinary Cancer Section, Università Federico II, Napoli, Italy *Author for correspondence: Tel.: +39 081 746 3660; Fax: +39 081 220 3147; [email protected] 1 2
10.2217/FON.14.212 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(16), 2551–2553
part of
ISSN 1479-6694
2551
Editorial Buonerba & Di Lorenzo
“The diverse mechanisms
of resistance to enzalutamide should be explored and correlated to in vivo and in vitro efficacy of cabazitaxel.”
2552
work in CRPC as antimitotic agents, but they may exert their antineoplastic effect by inhibiting nuclear trafficking of the androgen receptor, so cabazitaxel and docetaxel could be cross resistant with abiraterone and enzalutamide [8,9] . This is particularly relevant, as approval of both enzalutamide and abiraterone was gained in chemo-naive patients without measuring the effect that delaying chemotherapy might have in a population of patients with metastatic CRPC [10] . In this regard, two study groups came to opposite conclusions. Van Soest et al. found that in cell lines resistant to abiraterone and enzalutamide, respectively, generated by continuous culturing of PC346C cells, cabazitaxel activity was significantly impaired. Furthermore, cabazitaxel appeared to inhibit nuclear translocation of the androgen receptor independently on its antimitotic effect [9] . Conversely, Al Nakouzi et al. [8] found that the enzalutamideresistant cell lines MR49C and MR49F and the enzalutamide-sensitive cell line CRPC-V16D were not differently sensitive to cabazitaxel. Furthermore, it was found that cabazitaxel had no independent effect on nuclear translocation of the androgen receptor, and that it mediated cell death by inducing a ‘mitotic catastrophe’. In this regard, we note that there is no demonstration that the in vitro model of resistance obtained in both studies is satisfactory to study clinically significant in vivo resistance. Furthermore, in this in vitro model no analysis has been performed to assess the mechanisms of resistance induced, which could vary according to the methods used (e.g., enzalutamide concentration) and could not reflect those occurring in vivo. For this reason, we suggest that an effort should be made to grow cell cultures obtained from a cohort of patients progressing on enzalutamide (resistance developed in vivo), if technically feasible. Efstathiou et al. studied in vivo resistance using immunohistochemistry and PCR on bone biopsy samples obtained from patients treated with enzalutamide, and found that PSA response was associated with androgen receptor subcellular localization shift from the nucleus, while resistance was strongly associated to presence of an androgen receptor V7 variant [11] . If individual patient biopsies could be used to grow cell lines or create animal models, it would be possible to correlate clinical activity of cabazitaxel to its in vitro activity to study mechanisms of resistance at an individual patient level and to seek agents capable of circumventing them.
Future Oncol. (2014) 10(16)
The conclusion that cabazitaxel preserves its effectiveness after enzalutamide appears justified on the grounds of clinical data presented by Al Nakouzi et al. [8] , who showed that out of 79 patients receiving cabazitaxel after doce taxel and abiraterone, a PSA decline ≥50% was achieved in 35% of patients, with a median progression-free survival and OS of 4.4 and 10.9 months, respectively. Nevertheless, it must be underlined that no recommendation can be extrapolated from these data, in the absence of a prospective, randomized controlled trial. In fact, as chemotherapy requires a better performance status, a patient progressing on cabazitaxel is more likely to be able to receive third-line enzalutamide or abiraterone, than vice versa. Pending prospective trials, preliminary evidence suggests that cabazitaxel may be particularly effective (vs hormonal therapy) in selected subpopulations of patients, such as those with primary refractoriness to docetaxel [12] , brain metastasis [13] and a high Gleason score at diagnosis [14] . In a Phase II study on ‘anaplastic’ prostate cancer, patients with seven clinical criteria, such as exclusive visceral or predominantly lytic bone metastases, low PSA levels with respect to tumor burden, poor response to androgen deprivation therapy or bulky tumor masses, received carboplatin plus docetaxel, followed by secondline cisplatin plus etoposide. A median OS of 16 months was achieved. If the mechanism of action of cabazitaxel is proven to be independent on the androgen receptor signaling as suggested in the work discussed above, then its combined use with a platinum agent could be explored in patients with ‘anaplastic’ features [15] . A Phase I study demonstrated that cabazitaxel can be safely combined with platinum agents [16] , which have shown activity in unselected populations of CRPC patients [17,18] . In conclusion, with the multitude of effective therapeutic agents available in CRPC, large, prospective randomized controlled trials are required to establish the best sequence of use and to identify subpopulations of CRPC patients requiring a tailored approach. The use of cell lines with resistance acquired in vitro should be replaced with the use of cell lines with resistance acquired in vivo, if technically feasible, for instance by the use of patient-derived tumor xenografts models [19] . The diverse mechanisms of resistance to enzalutamide should be explored and correlated to in vivo and in vitro efficacy of cabazitaxel.
future science group
Is in vitro-acquired resistance to enzalutamide a useful model? Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
References 1
2
3
4
5
6
Di Lorenzo G, Autorino R, Figg WD, De Placido S. Hormone-refractory prostate cancer: where are we going? Drugs 67(8), 1109–1124 (2007). Rescigno P, Buonerba C, Bellmunt J, Sonpavde G, De Placido S, Di Lorenzo G. New perspectives in the therapy of castration resistant prostate cancer. Curr. Drug Targets 13(13), 1676–1686 (2012). Schröder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 6, pii:S0140–S6736 (14), 60525–60520 (2014). Ferro M, Bruzzese D, Perdonà S et al. Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) significantly improve prostate cancer detection at initial biopsy in a total PSA range of 2–10 ng/ml. PLoS ONE 8(7), e67687 (2013). Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge®) for castrationresistant prostate cancer. BJU Int. 110(2 Pt 2), E99–E104 (2012). Borsò E, Boni G, Galli L et al. Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer. Future Oncol. 30, 1–9 (2014).
future science group
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
7
Buonerba C, Di Lorenzo G. Sequential therapies in castration-resistant prostate cancer. Future Oncol. 10(2), 153–155 (2014).
8
Al Nakouzi N, Le Moulec S, Albigès L et al. Cabazitaxel remains active in patients progressing after docetaxel followed by novel androgen receptor pathway targeted therapies. Eur. Urol. doi:10.1016/j.eururo.2014 (2014) (Epub ahead of print).
9
Editorial
van Soest RJ, van Royen ME, de Morrée ES et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur. J. Cancer 49(18), 3821–3830 (2013).
10 Di Lorenzo G, Buonerba C. Words of
wisdom: Re: Abiraterone in metastatic prostate cancer without previous chemotherapy. Eur. Urol. 63(5), 961 (2013). 11 Efstathiou E, Titus M, Wen S et al. Molecular
characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur. Urol. doi:10.1016/j.eururo.2014.05.005 (2014) (Epub ahead of print). 12 Di Lorenzo G, Bracarda S, Buonerba C, Aieta
M, Mirone V. Poor survival in prostate cancer patients with primary refractoriness to docetaxel. Eur. Urol. 65, 505–507 (2014). 13 De Placido S, Rescigno P, Federico P et al.
Cabazitaxel in castration resistant prostate
cancer with brain metastases: 3 case reports. World J. Clin. Cases 2, 228–231 (2014). 14 Buonerba C, Pond GR, Sonpavde G et al.
Potential value of Gleason score in predicting the benefit of cabazitaxel in metastatic castration-resistant prostate cancer. Future Oncol. 9, 889–897 (2013). 15 Aparicio AM, Harzstark AL, Corn PG et al.
Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin. Cancer Res. 19(13), 3621–3630 (2013). 16 Lockhart AC, Sundaram S, Sarantopoulos
J. Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors. Invest. New Drugs 32(6), 1236–1245 (2014). 17 Buonerba C, Federico P, D’Aniello C et al.
Phase II trial of cisplatin plus prednisone in docetaxel-refractory castration-resistant prostate cancer patients. Cancer Chemother. Pharmacol. 67, 1455–1461 (2011). 18 Buonerba C, Federico P, Bosso D et al.
Carboplatin plus etoposide in heavily pretreated castration-resistant prostate cancer patients. Future Oncol. 10, 1353–1360 (2014). 19 Malaney P, Nicosia SV, Davé V. One mouse,
one patient paradigm: new avatars of personalized cancer therapy. Cancer Lett. 344(1), 1–12 (2014).
www.futuremedicine.com
2553
Is in vitro-acquired resistance to enzalutamide a useful model?
Carlo Buonerba1 & Giuseppe Di Lorenzo*,1,2
Prostate cancer is a major health concern among men worldwide, with an estimated 234,460 new cases diagnosed and 27,350 deaths in the USA alone in 2006 [1] . Significant advancements have been achieved in the fight against this deadly disease, both in terms of secondary prevention [2] and in the management of advanced prostate cancer resistant to castration [3] , namely, castration-resistant prostate cancer (CRPC). Overdiagnosis is a major drawback of screening, and demands patient informed consent, careful selection of patients to biopsy by the use of more refined tests than prostatespecific antigen (PSA) alone, such as PCA3 and prostate health index [4] , as well as appropriate use of active surveillance [2] . Treatment of CRPC has been elusive for many years, with conventional chemotherapy agents such as mitoxantrone and vinorelbine ineffective to prolong survival in Phase III trials [1] . At the present time, six agents have shown to prolong survival in CRPC, that is, two taxane agents (docetaxel and cabazitaxel), two hormonal agents (enzalutamide and
abiraterone), one radiopharmaceutical agent (radium-223) [5] and one immunotherapy agent (Sipuleucel-t) [6] . If all of these agents could be given sequentially in CRPC, 720 combinations are possible, hence the potential usefulness of retrospective studies and cell models to test cross resistance and sequential use of available agents. A number of small, retrospective studies have explored the effectiveness of third-line treatment in CRPC. While a similar survival of approximately 7–8 months was reported in 24 patients receiving docetaxel-abiraterone-cabazitaxel, and in 35 patients treated with the sequence docetaxel-abiraterone-enzalutamide, 30 patients treated with docetaxel-enzalutamide-abiraterone showed a median overall survival (OS) of approximately 11 months [7] . These data show that the expected treatment efficacy is lower in more advanced lines of therapy – a universal law in oncology. This can simply be explained with poorer performance status and increased disease burden, but it could also be the result of cross-resistance. In fact, taxanes may not
KEYWORDS
• abiraterone • acquired resistance to the therapy • cabazitaxel • castration-resistant prostate cancer • enzalutamide
“…with the multitude of effective therapeutic agents available in CRPC, large, prospective randomized controlled trials are required to … identify subpopulations of CRPC patients requiring a tailored approach.”
Medical Oncology Unit, Department of Clinical Medicine, Federico II University, Naples, Italy Genitourinary Cancer Section, Università Federico II, Napoli, Italy *Author for correspondence: Tel.: +39 081 746 3660; Fax: +39 081 220 3147; [email protected] 1 2
10.2217/FON.14.212 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(16), 2551–2553
part of
ISSN 1479-6694
2551
Editorial Buonerba & Di Lorenzo
“The diverse mechanisms
of resistance to enzalutamide should be explored and correlated to in vivo and in vitro efficacy of cabazitaxel.”
2552
work in CRPC as antimitotic agents, but they may exert their antineoplastic effect by inhibiting nuclear trafficking of the androgen receptor, so cabazitaxel and docetaxel could be cross resistant with abiraterone and enzalutamide [8,9] . This is particularly relevant, as approval of both enzalutamide and abiraterone was gained in chemo-naive patients without measuring the effect that delaying chemotherapy might have in a population of patients with metastatic CRPC [10] . In this regard, two study groups came to opposite conclusions. Van Soest et al. found that in cell lines resistant to abiraterone and enzalutamide, respectively, generated by continuous culturing of PC346C cells, cabazitaxel activity was significantly impaired. Furthermore, cabazitaxel appeared to inhibit nuclear translocation of the androgen receptor independently on its antimitotic effect [9] . Conversely, Al Nakouzi et al. [8] found that the enzalutamideresistant cell lines MR49C and MR49F and the enzalutamide-sensitive cell line CRPC-V16D were not differently sensitive to cabazitaxel. Furthermore, it was found that cabazitaxel had no independent effect on nuclear translocation of the androgen receptor, and that it mediated cell death by inducing a ‘mitotic catastrophe’. In this regard, we note that there is no demonstration that the in vitro model of resistance obtained in both studies is satisfactory to study clinically significant in vivo resistance. Furthermore, in this in vitro model no analysis has been performed to assess the mechanisms of resistance induced, which could vary according to the methods used (e.g., enzalutamide concentration) and could not reflect those occurring in vivo. For this reason, we suggest that an effort should be made to grow cell cultures obtained from a cohort of patients progressing on enzalutamide (resistance developed in vivo), if technically feasible. Efstathiou et al. studied in vivo resistance using immunohistochemistry and PCR on bone biopsy samples obtained from patients treated with enzalutamide, and found that PSA response was associated with androgen receptor subcellular localization shift from the nucleus, while resistance was strongly associated to presence of an androgen receptor V7 variant [11] . If individual patient biopsies could be used to grow cell lines or create animal models, it would be possible to correlate clinical activity of cabazitaxel to its in vitro activity to study mechanisms of resistance at an individual patient level and to seek agents capable of circumventing them.
Future Oncol. (2014) 10(16)
The conclusion that cabazitaxel preserves its effectiveness after enzalutamide appears justified on the grounds of clinical data presented by Al Nakouzi et al. [8] , who showed that out of 79 patients receiving cabazitaxel after doce taxel and abiraterone, a PSA decline ≥50% was achieved in 35% of patients, with a median progression-free survival and OS of 4.4 and 10.9 months, respectively. Nevertheless, it must be underlined that no recommendation can be extrapolated from these data, in the absence of a prospective, randomized controlled trial. In fact, as chemotherapy requires a better performance status, a patient progressing on cabazitaxel is more likely to be able to receive third-line enzalutamide or abiraterone, than vice versa. Pending prospective trials, preliminary evidence suggests that cabazitaxel may be particularly effective (vs hormonal therapy) in selected subpopulations of patients, such as those with primary refractoriness to docetaxel [12] , brain metastasis [13] and a high Gleason score at diagnosis [14] . In a Phase II study on ‘anaplastic’ prostate cancer, patients with seven clinical criteria, such as exclusive visceral or predominantly lytic bone metastases, low PSA levels with respect to tumor burden, poor response to androgen deprivation therapy or bulky tumor masses, received carboplatin plus docetaxel, followed by secondline cisplatin plus etoposide. A median OS of 16 months was achieved. If the mechanism of action of cabazitaxel is proven to be independent on the androgen receptor signaling as suggested in the work discussed above, then its combined use with a platinum agent could be explored in patients with ‘anaplastic’ features [15] . A Phase I study demonstrated that cabazitaxel can be safely combined with platinum agents [16] , which have shown activity in unselected populations of CRPC patients [17,18] . In conclusion, with the multitude of effective therapeutic agents available in CRPC, large, prospective randomized controlled trials are required to establish the best sequence of use and to identify subpopulations of CRPC patients requiring a tailored approach. The use of cell lines with resistance acquired in vitro should be replaced with the use of cell lines with resistance acquired in vivo, if technically feasible, for instance by the use of patient-derived tumor xenografts models [19] . The diverse mechanisms of resistance to enzalutamide should be explored and correlated to in vivo and in vitro efficacy of cabazitaxel.
future science group
Is in vitro-acquired resistance to enzalutamide a useful model? Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
References 1
2
3
4
5
6
Di Lorenzo G, Autorino R, Figg WD, De Placido S. Hormone-refractory prostate cancer: where are we going? Drugs 67(8), 1109–1124 (2007). Rescigno P, Buonerba C, Bellmunt J, Sonpavde G, De Placido S, Di Lorenzo G. New perspectives in the therapy of castration resistant prostate cancer. Curr. Drug Targets 13(13), 1676–1686 (2012). Schröder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 6, pii:S0140–S6736 (14), 60525–60520 (2014). Ferro M, Bruzzese D, Perdonà S et al. Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) significantly improve prostate cancer detection at initial biopsy in a total PSA range of 2–10 ng/ml. PLoS ONE 8(7), e67687 (2013). Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge®) for castrationresistant prostate cancer. BJU Int. 110(2 Pt 2), E99–E104 (2012). Borsò E, Boni G, Galli L et al. Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer. Future Oncol. 30, 1–9 (2014).
future science group
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
7
Buonerba C, Di Lorenzo G. Sequential therapies in castration-resistant prostate cancer. Future Oncol. 10(2), 153–155 (2014).
8
Al Nakouzi N, Le Moulec S, Albigès L et al. Cabazitaxel remains active in patients progressing after docetaxel followed by novel androgen receptor pathway targeted therapies. Eur. Urol. doi:10.1016/j.eururo.2014 (2014) (Epub ahead of print).
9
Editorial
van Soest RJ, van Royen ME, de Morrée ES et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur. J. Cancer 49(18), 3821–3830 (2013).
10 Di Lorenzo G, Buonerba C. Words of
wisdom: Re: Abiraterone in metastatic prostate cancer without previous chemotherapy. Eur. Urol. 63(5), 961 (2013). 11 Efstathiou E, Titus M, Wen S et al. Molecular
characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur. Urol. doi:10.1016/j.eururo.2014.05.005 (2014) (Epub ahead of print). 12 Di Lorenzo G, Bracarda S, Buonerba C, Aieta
M, Mirone V. Poor survival in prostate cancer patients with primary refractoriness to docetaxel. Eur. Urol. 65, 505–507 (2014). 13 De Placido S, Rescigno P, Federico P et al.
Cabazitaxel in castration resistant prostate
cancer with brain metastases: 3 case reports. World J. Clin. Cases 2, 228–231 (2014). 14 Buonerba C, Pond GR, Sonpavde G et al.
Potential value of Gleason score in predicting the benefit of cabazitaxel in metastatic castration-resistant prostate cancer. Future Oncol. 9, 889–897 (2013). 15 Aparicio AM, Harzstark AL, Corn PG et al.
Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin. Cancer Res. 19(13), 3621–3630 (2013). 16 Lockhart AC, Sundaram S, Sarantopoulos
J. Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors. Invest. New Drugs 32(6), 1236–1245 (2014). 17 Buonerba C, Federico P, D’Aniello C et al.
Phase II trial of cisplatin plus prednisone in docetaxel-refractory castration-resistant prostate cancer patients. Cancer Chemother. Pharmacol. 67, 1455–1461 (2011). 18 Buonerba C, Federico P, Bosso D et al.
Carboplatin plus etoposide in heavily pretreated castration-resistant prostate cancer patients. Future Oncol. 10, 1353–1360 (2014). 19 Malaney P, Nicosia SV, Davé V. One mouse,
one patient paradigm: new avatars of personalized cancer therapy. Cancer Lett. 344(1), 1–12 (2014).
www.futuremedicine.com
2553
