Editorial
Prostate stem cell antigen – novel biomarker and therapeutic target? Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by National Taiwan University on 01/15/15 For personal use only.
Expert Rev. Anticancer Ther. 14(1), 5–7 (2014)
Pedro Barga˜o Santos Department of Urology, Hospital Prof. Doutor Fernando Fonseca and Hospital CUF Descobertas, Lisbon, Portugal
Prostate stem cell antigen gene was originally identified through an analysis of genes upregulated in the human prostate cancer LAPC-4 xenograft model. PSCA was named inaccurately since it is not a marker for a stem cell population nor is it exclusively expressed in the prostate. The function of PSCA in normal cellular processes or carcinogenesis is currently unknown. Prostate cancer specificity
Hitendra RH Patel Author for correspondence: University Hospital North Norway, Tromso, Norway [email protected]
This article is intended as an accompaniment to the following review article which also appears in the issue: Prostate stem cell antigen and cancer risk, mechanisms and therapeutic implications by Xueling Yang, Zhi Guo, Ya Liu, Tongguo Si, Haipeng Yu, Bo Li, Wei Tian
Prostate cancer (CaP) is the most commonly diagnosed non-dermatological malignancy and the second leading cause of cancer-related death in American men [1]. Radical prostatectomy is one of the most common treatments for organ confined or localized CaP in the world. Radical prostatectomy and radiation therapy result in an overall rate of 5–10 years disease-free survival. There have been advances in the treatment of primary localized CaP with surgery and/ or radiation therapy; however there has been limited progress for therapeutic options for metastatic, hormone-refractory disease or local treatment failure [2–4]. The most widely used treatment in the latter case has been androgen deprivation therapy, which initially shows a therapeutic response, but eventually patients develop androgen-independent CaP within 12–18 months, with an associated rising prostate-specific antigen (PSA). Chemotherapeutic agents and anticancer drugs such as docetaxel are used for treating androgen independent or hormone-refractory CaP, but this is a palliative option. Clinical experience with the US FDA approved CaP vaccine, sipuleucel-T (ProvengeÒ) is limited but it has some survival benefit, although health economics are not fully studied. Second-line treatment options are limited and most patients who present with metastases die within 5 years of diagnosis [5]. There is
currently no effective cure for advanced and metastatic CaP. One potential and very promising strategy for this problem is immunotherapy. Cancer immunotherapeutics use the patient’s immune system to detect and kill cancer cells by targeting cancerassociated proteins expressed by tumor cells. To that end, prostate stem cell antigen (PSCA) represents an ideal choice because it is highly expressed by a large proportion of human prostate tumors, including metastatic and hormone-refractory, but has limited expression in normal tissues [6,7]. This expression profile also makes it a potential diagnostic and prognostic biomarker for CaP. Through a blood screening and analysis of expression levels in prostate biopsies, PSCA may be diagnostic for an undiagnosed CaP or provide clues concerning the aggressiveness and/or propensity to metastasize established prostate cancer tumors. Prostate stem cell antigen
PSCA gene was originally identified through an analysis of genes upregulated in the human CaP LAPC-4 xenograft model [8], is located on chromosome 8q24.2 and encodes a 123 amino acid cell surface protein with 30% homology to stem cell antigen type 2 (SCA-2), an immature lymphocyte cell surface marker. It is because of this relatively weak homology that PSCA was named inaccurately since it is not a marker for a stem cell population nor is it
KEYWORDS: cancer • immunotherapy • mechanisms • prostate stem cell antigen
www.expert-reviews.com
10.1586/14737140.2014.870481
Ó 2014 Informa UK Ltd
ISSN 1473-7140
5
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by National Taiwan University on 01/15/15 For personal use only.
Editorial
˜ o Santos & Patel Barga
exclusively expressed in the prostate. The function of PSCA in normal cellular processes or carcinogenesis is currently unknown; however, PSCA homologs fall in a variety of possible functions. It has been previously shown that GPI-anchored proteins, like PSCA, play a role in T-cell activation [9]. Interestingly, a recent study showed that PSCA homozygous knockout mice are viable, with both male and female mice fertile into adulthood with normal litter size and gender distribution [10]. These data suggest that PSCA in mice is not critical for either normal development or urogenital function. Furthermore in the same study, PSCA homozygous knockout mice did not have an increased incidence of cancer formation, even when they were further subjected to c-radiation. Thus, animal models may be of less importance when studying PSCA. Clinical perspective
Unfortunately, over time it has become clear that the clinical application for PSA is not ideal for cancer detection and treatment, and therefore, significant effort continues to be devoted to the discovery and development of novel biomarkers [11]. Due to increased PSCA expression in CaP, particularly its correlation with Gleason score [12] and upregulation in metastasis [13], it has become one of many CaP therapeutic targets. In the initial study using PSCA as a CaP biomarker, a cost-effective and RTPCR screen from a milliliter of blood detected PSCA mRNA in 13.8% of CaP cases [14]. Notably, stage IV patients with positive PSCA mRNA correlated with a lower disease-free survival than those with negative PSCA mRNA, suggesting that PSCA may be promising for the molecular staging of CaP. Interestingly, in a study of men with benign prostatic hyperplasia treated with transurethral resection of the prostate were screened for PSCA mRNA expression and subsequent CaP [15]. In total, the PSCA mRNA expression was not particularly strong in the BPH tissues, with 93 of 288 (32.3%) cases positive for PSCA. However, in the 93 patients with positive expression for PSCA mRNA, 23.7% subsequently developed clinical CaP over the follow-up period versus only 1.0% of the 195 patients with negative expression for PSCA mRNA. Of note, the level of positive expression of PSCA mRNA was directly proportional to the Gleason score and clinical stage of the resulting CaP. In 2009, a study by Wu et al. [16] found a presence of a distinct single nucleotide polymorphism rs2294008 in the PSCA promoter region and its association with increased bladder cancer References 1
Jemal A, Siegal R, Ward E et al. Cancer statistics. CA Cancer J. Clin. 58, 71–96 (2008).
2
Garnick M, Fair W. Prostate cancer: emerging concepts: part I. Ann. Intern. Med. 125, 118–125 (1996).
3
Crawford ED, Rosenblum M, Ziada A, Lange PH. Overview: hormone refractory prostate cancer. Urology 54, 1–7 (1999).
6
susceptibility. Recently, Gakis and Stenzl [17] described the localization of this single nucleotide polymorphism in the androgenresponsive element of the PSCA promoter and showed its importance in the novel theory on the sex-steroid-dependent progression of muscle-invasive bladder cancer. Future perspective
PSCA seems to have significant potential as a diagnostic, prognostic and therapeutic tool in the management of CaP patients, also because of its limited expression in normal tissues. Through analysis of blood samples or biopsies, PSCA may allow physicians and researchers to adapt treatments to best anticipate individual tumor characteristics and design appropriate therapies, including immunotherapy. In vitro and in vivo studies have shown that PSCA immunotherapy can be not only safe but also quite effective in the treatment of CaP. Animal models that replicate human prostatic disease have allowed PSCA to be validated as a therapeutic target in many approaches and clinical trials have proven the safety of PSCA immunotherapy, thus giving hope for future successes. The field is now prepared to move forward with trials elucidating the efficacy of PSCA as a clinical tool. In 2012, Morris et al. [18] from Memorial Sloan–Kettering Cancer Center, undertook the first-in-human Phase I/IIA study to evaluate the safety and pharmacokinetics of AGS-PSCA, a fully human monoclonal antibody-directed PSCA in progressive castrationresistant prostate cancer. Based on animal models, an appropriate vaccination strategy with PSCA as the immune target should be initiated in a human clinical trial. At the same time, PSCA could be further evaluated in a diagnostic and prognostic scenario to better identify the relevant risks of a particular tumor in a given patient. There is still the possibility that PSCA vaccination could be initiated in a preventative setting, at first evidence of a pre-malignant lesion, therefore becoming part of a paradigm shift in tumor immunotherapy. 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 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.
4
Tjoa B, Murphy G. Progress in active specific immunotherapy of prostate cancer. Semin. Surg. Oncol. 18, 80–87 (2000).
5
Kozlowski JM, Ellis WJ, Grayhack JT. Advanced prostatic carcinoma. Early versus late endocrine therapy. Urol. Clin. North Am. 18(1), 15–24 (1991).
6
Reiter RE, Gu Z, Watabe T et al. Witte, Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer.
Proc. Natl Acad. Sci. USA 95, 1735–1740 (1998). 7
Ross S, Spencer S, Holcomb I et al. Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate. Cancer Res. 62, 2546–2553 (2002).
8
Murphy WM, Soloway MS, Jukkola AF, Crabtree MN, Ford KS. Urinary cytology and bladder cancer. The cellular features of
Expert Rev. Anticancer Ther. 14(1), (2014)
Prostate stem cell antigen – novel biomarker & therapeutic target?
prostate cancer. Oncogene 19, 1288–1296 (2000).
transitional cell neoplasms. Cancer 53, 1555 (1984). 9
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by National Taiwan University on 01/15/15 For personal use only.
10
11
12
Presky D, Low M, Shevach E. Role of phosphatidylinositol-anchored proteins in T cell activation. J. Immunol. 144, 860–868 (1990).
13
Moore ML, Teitell MA, Kim Y et al. Deletion of PSCA increases metastasis of TRAMP-induced prostate tumors without altering primary tumor formation. Prostate 68, 139–151 (2008).
14
Parekh DJ, Ankerst DP, Troyer D, Srivastava S, Thompson IM. Biomarkers for prostate cancer detection. J. Urol. 178, 2252–2259 (2007). Gu Z, Thomas G, Yamashiro J et al. Reiter, Prostate stem cell antigen (PSCA) expression increases with high Gleason score, advanced stage and bone metastasis in
www.expert-reviews.com
15
Watabe T, Lin M, Ide H et al. Growth, regeneration, and tumorigenesis of the prostate activates the PSCA promoter. Proc. Natl Acad. Sci. USA 99, 401–406 (2002). Hara N, Kasahara T, Kawasaki T, Bilim V, Obara K, Takahashi K, Tomita Y. Reverse transcription-polymerase chain reaction detection of prostate-specific antigen prostate-specific membrane antigen, and prostate stem cell antigen in one milliliter of peripheral blood: value for the staging of prostate cancer. Clin. Cancer Res. 8, 1794–1799 (2002). Zhigang Z, Wenlu S. The association of prostate stem cell antigen (PSCA) mRNA expression and subsequent prostate cancer risk in men with benign prostatic
Editorial
hyperplasia following transurethral resection of the prostate. Prostate 68, 190–199 (2008). 16
Wu X, Ye Y, LA Kiemeney, Sulem P. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat. Genet. 41(9), 991–995 (2009).
17
Gakis G, Stenzl A. Gender-specific differences in muscle-invasive bladder cancer: the concept of sex steroid sensitivity. World J. Urol. 31(5), 1059–1064 (2013).
18
Morris MJ, Eisenberger MA, Pili R et al. A phase I/IIA study of AGS-PSCA for castration-resistant prostate cancer. Ann. Oncol. 23(10), 2714–2719 (2012).
7
Prostate stem cell antigen – novel biomarker and therapeutic target? Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by National Taiwan University on 01/15/15 For personal use only.
Expert Rev. Anticancer Ther. 14(1), 5–7 (2014)
Pedro Barga˜o Santos Department of Urology, Hospital Prof. Doutor Fernando Fonseca and Hospital CUF Descobertas, Lisbon, Portugal
Prostate stem cell antigen gene was originally identified through an analysis of genes upregulated in the human prostate cancer LAPC-4 xenograft model. PSCA was named inaccurately since it is not a marker for a stem cell population nor is it exclusively expressed in the prostate. The function of PSCA in normal cellular processes or carcinogenesis is currently unknown. Prostate cancer specificity
Hitendra RH Patel Author for correspondence: University Hospital North Norway, Tromso, Norway [email protected]
This article is intended as an accompaniment to the following review article which also appears in the issue: Prostate stem cell antigen and cancer risk, mechanisms and therapeutic implications by Xueling Yang, Zhi Guo, Ya Liu, Tongguo Si, Haipeng Yu, Bo Li, Wei Tian
Prostate cancer (CaP) is the most commonly diagnosed non-dermatological malignancy and the second leading cause of cancer-related death in American men [1]. Radical prostatectomy is one of the most common treatments for organ confined or localized CaP in the world. Radical prostatectomy and radiation therapy result in an overall rate of 5–10 years disease-free survival. There have been advances in the treatment of primary localized CaP with surgery and/ or radiation therapy; however there has been limited progress for therapeutic options for metastatic, hormone-refractory disease or local treatment failure [2–4]. The most widely used treatment in the latter case has been androgen deprivation therapy, which initially shows a therapeutic response, but eventually patients develop androgen-independent CaP within 12–18 months, with an associated rising prostate-specific antigen (PSA). Chemotherapeutic agents and anticancer drugs such as docetaxel are used for treating androgen independent or hormone-refractory CaP, but this is a palliative option. Clinical experience with the US FDA approved CaP vaccine, sipuleucel-T (ProvengeÒ) is limited but it has some survival benefit, although health economics are not fully studied. Second-line treatment options are limited and most patients who present with metastases die within 5 years of diagnosis [5]. There is
currently no effective cure for advanced and metastatic CaP. One potential and very promising strategy for this problem is immunotherapy. Cancer immunotherapeutics use the patient’s immune system to detect and kill cancer cells by targeting cancerassociated proteins expressed by tumor cells. To that end, prostate stem cell antigen (PSCA) represents an ideal choice because it is highly expressed by a large proportion of human prostate tumors, including metastatic and hormone-refractory, but has limited expression in normal tissues [6,7]. This expression profile also makes it a potential diagnostic and prognostic biomarker for CaP. Through a blood screening and analysis of expression levels in prostate biopsies, PSCA may be diagnostic for an undiagnosed CaP or provide clues concerning the aggressiveness and/or propensity to metastasize established prostate cancer tumors. Prostate stem cell antigen
PSCA gene was originally identified through an analysis of genes upregulated in the human CaP LAPC-4 xenograft model [8], is located on chromosome 8q24.2 and encodes a 123 amino acid cell surface protein with 30% homology to stem cell antigen type 2 (SCA-2), an immature lymphocyte cell surface marker. It is because of this relatively weak homology that PSCA was named inaccurately since it is not a marker for a stem cell population nor is it
KEYWORDS: cancer • immunotherapy • mechanisms • prostate stem cell antigen
www.expert-reviews.com
10.1586/14737140.2014.870481
Ó 2014 Informa UK Ltd
ISSN 1473-7140
5
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by National Taiwan University on 01/15/15 For personal use only.
Editorial
˜ o Santos & Patel Barga
exclusively expressed in the prostate. The function of PSCA in normal cellular processes or carcinogenesis is currently unknown; however, PSCA homologs fall in a variety of possible functions. It has been previously shown that GPI-anchored proteins, like PSCA, play a role in T-cell activation [9]. Interestingly, a recent study showed that PSCA homozygous knockout mice are viable, with both male and female mice fertile into adulthood with normal litter size and gender distribution [10]. These data suggest that PSCA in mice is not critical for either normal development or urogenital function. Furthermore in the same study, PSCA homozygous knockout mice did not have an increased incidence of cancer formation, even when they were further subjected to c-radiation. Thus, animal models may be of less importance when studying PSCA. Clinical perspective
Unfortunately, over time it has become clear that the clinical application for PSA is not ideal for cancer detection and treatment, and therefore, significant effort continues to be devoted to the discovery and development of novel biomarkers [11]. Due to increased PSCA expression in CaP, particularly its correlation with Gleason score [12] and upregulation in metastasis [13], it has become one of many CaP therapeutic targets. In the initial study using PSCA as a CaP biomarker, a cost-effective and RTPCR screen from a milliliter of blood detected PSCA mRNA in 13.8% of CaP cases [14]. Notably, stage IV patients with positive PSCA mRNA correlated with a lower disease-free survival than those with negative PSCA mRNA, suggesting that PSCA may be promising for the molecular staging of CaP. Interestingly, in a study of men with benign prostatic hyperplasia treated with transurethral resection of the prostate were screened for PSCA mRNA expression and subsequent CaP [15]. In total, the PSCA mRNA expression was not particularly strong in the BPH tissues, with 93 of 288 (32.3%) cases positive for PSCA. However, in the 93 patients with positive expression for PSCA mRNA, 23.7% subsequently developed clinical CaP over the follow-up period versus only 1.0% of the 195 patients with negative expression for PSCA mRNA. Of note, the level of positive expression of PSCA mRNA was directly proportional to the Gleason score and clinical stage of the resulting CaP. In 2009, a study by Wu et al. [16] found a presence of a distinct single nucleotide polymorphism rs2294008 in the PSCA promoter region and its association with increased bladder cancer References 1
Jemal A, Siegal R, Ward E et al. Cancer statistics. CA Cancer J. Clin. 58, 71–96 (2008).
2
Garnick M, Fair W. Prostate cancer: emerging concepts: part I. Ann. Intern. Med. 125, 118–125 (1996).
3
Crawford ED, Rosenblum M, Ziada A, Lange PH. Overview: hormone refractory prostate cancer. Urology 54, 1–7 (1999).
6
susceptibility. Recently, Gakis and Stenzl [17] described the localization of this single nucleotide polymorphism in the androgenresponsive element of the PSCA promoter and showed its importance in the novel theory on the sex-steroid-dependent progression of muscle-invasive bladder cancer. Future perspective
PSCA seems to have significant potential as a diagnostic, prognostic and therapeutic tool in the management of CaP patients, also because of its limited expression in normal tissues. Through analysis of blood samples or biopsies, PSCA may allow physicians and researchers to adapt treatments to best anticipate individual tumor characteristics and design appropriate therapies, including immunotherapy. In vitro and in vivo studies have shown that PSCA immunotherapy can be not only safe but also quite effective in the treatment of CaP. Animal models that replicate human prostatic disease have allowed PSCA to be validated as a therapeutic target in many approaches and clinical trials have proven the safety of PSCA immunotherapy, thus giving hope for future successes. The field is now prepared to move forward with trials elucidating the efficacy of PSCA as a clinical tool. In 2012, Morris et al. [18] from Memorial Sloan–Kettering Cancer Center, undertook the first-in-human Phase I/IIA study to evaluate the safety and pharmacokinetics of AGS-PSCA, a fully human monoclonal antibody-directed PSCA in progressive castrationresistant prostate cancer. Based on animal models, an appropriate vaccination strategy with PSCA as the immune target should be initiated in a human clinical trial. At the same time, PSCA could be further evaluated in a diagnostic and prognostic scenario to better identify the relevant risks of a particular tumor in a given patient. There is still the possibility that PSCA vaccination could be initiated in a preventative setting, at first evidence of a pre-malignant lesion, therefore becoming part of a paradigm shift in tumor immunotherapy. 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 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.
4
Tjoa B, Murphy G. Progress in active specific immunotherapy of prostate cancer. Semin. Surg. Oncol. 18, 80–87 (2000).
5
Kozlowski JM, Ellis WJ, Grayhack JT. Advanced prostatic carcinoma. Early versus late endocrine therapy. Urol. Clin. North Am. 18(1), 15–24 (1991).
6
Reiter RE, Gu Z, Watabe T et al. Witte, Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer.
Proc. Natl Acad. Sci. USA 95, 1735–1740 (1998). 7
Ross S, Spencer S, Holcomb I et al. Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate. Cancer Res. 62, 2546–2553 (2002).
8
Murphy WM, Soloway MS, Jukkola AF, Crabtree MN, Ford KS. Urinary cytology and bladder cancer. The cellular features of
Expert Rev. Anticancer Ther. 14(1), (2014)
Prostate stem cell antigen – novel biomarker & therapeutic target?
prostate cancer. Oncogene 19, 1288–1296 (2000).
transitional cell neoplasms. Cancer 53, 1555 (1984). 9
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by National Taiwan University on 01/15/15 For personal use only.
10
11
12
Presky D, Low M, Shevach E. Role of phosphatidylinositol-anchored proteins in T cell activation. J. Immunol. 144, 860–868 (1990).
13
Moore ML, Teitell MA, Kim Y et al. Deletion of PSCA increases metastasis of TRAMP-induced prostate tumors without altering primary tumor formation. Prostate 68, 139–151 (2008).
14
Parekh DJ, Ankerst DP, Troyer D, Srivastava S, Thompson IM. Biomarkers for prostate cancer detection. J. Urol. 178, 2252–2259 (2007). Gu Z, Thomas G, Yamashiro J et al. Reiter, Prostate stem cell antigen (PSCA) expression increases with high Gleason score, advanced stage and bone metastasis in
www.expert-reviews.com
15
Watabe T, Lin M, Ide H et al. Growth, regeneration, and tumorigenesis of the prostate activates the PSCA promoter. Proc. Natl Acad. Sci. USA 99, 401–406 (2002). Hara N, Kasahara T, Kawasaki T, Bilim V, Obara K, Takahashi K, Tomita Y. Reverse transcription-polymerase chain reaction detection of prostate-specific antigen prostate-specific membrane antigen, and prostate stem cell antigen in one milliliter of peripheral blood: value for the staging of prostate cancer. Clin. Cancer Res. 8, 1794–1799 (2002). Zhigang Z, Wenlu S. The association of prostate stem cell antigen (PSCA) mRNA expression and subsequent prostate cancer risk in men with benign prostatic
Editorial
hyperplasia following transurethral resection of the prostate. Prostate 68, 190–199 (2008). 16
Wu X, Ye Y, LA Kiemeney, Sulem P. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat. Genet. 41(9), 991–995 (2009).
17
Gakis G, Stenzl A. Gender-specific differences in muscle-invasive bladder cancer: the concept of sex steroid sensitivity. World J. Urol. 31(5), 1059–1064 (2013).
18
Morris MJ, Eisenberger MA, Pili R et al. A phase I/IIA study of AGS-PSCA for castration-resistant prostate cancer. Ann. Oncol. 23(10), 2714–2719 (2012).
7
