SPECIAL FOCUS y Prostate Cancer
Review
Precision medicine for prostate cancer Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by University of Cincinnati on 11/12/14 For personal use only.
Expert Rev. Anticancer Ther. 14(11), 1305–1315 (2014)
Myria Galazi1, Alejo Rodriguez-Vida1, Tony Ng2, Malcolm Mason3 and Simon Chowdhury*1 1 Department of Medical Oncology, Guy’s Hospital, London, SE1 9RT, UK 2 Richard Dimbleby Department of Cancer Research, King’s College London, SE1 1UL, UK 3 Institute of Cancer and Genetics, Cardiff University School of Medicine, CF14 2TL, UK *Author for correspondence: [email protected]
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Metastatic castration-resistant prostate cancer remains a lethal disease despite considerable progress in systemic therapy over the past decade. The recent advances in genomic sequencing have improved the molecular classification of prostate cancer. The translation of genomic data into clinically relevant prognostic and predictive biomarkers to guide therapy is still in its infancy and therapies for castration-resistant prostate cancer are still used empirically. We discuss these genomic aberrations in more detail, focusing on androgen receptor signaling, ETS transcription factor gene rearrangements and PTEN loss. The incorporation of this genomic data within early phase clinical trials is evolving and may prove significant in advancing personalized care in prostate cancer. KEYWORDS: androgen receptor • castration-resistant prostate cancer • ETS fusion gene rearrangements • PI3K/AKT/mTOR pathway • precision medicine • PTEN loss
Prostate cancer is the commonest cancer in men in the UK and the second most common cause of cancer-related death in men in the UK [1]. The disease exhibits remarkable heterogeneity in clinical behavior and outcome ranging from decades of indolence to lethal disease despite apparently similar histological features. Currently, androgen deprivation therapy (ADT) is the first-line therapy for metastatic disease. Response to therapy, however, is transient and patients invariably progress to castrationresistant prostate cancer (CRPC). The TAX327 trial established docetaxel plus prednisolone as first-line chemotherapy for CRPC [2]. Since then, there has been significant progress in the systemic treatment of prostate cancer with the approval of five new therapies for metastatic CRPC in the last 4 years. Cabazitaxel, sipuleucel-T, abiraterone acetate, enzalutamide and radium-223 have all demonstrated significant improvements in survival in Phase III trials [3–7]. However, all of these new therapies are given to relatively unselected patient groups with the only selection being based on clinical characteristics such as performance status. Despite these rapid advances, the management of prostate cancer is yet to embrace the personalized approach seen in other cancers such as malignant melanoma, breast and lung cancer. There are numerous challenges that exist in the clinic, especially with patient selection for therapies targeted against androgen 10.1586/14737140.2014.972948
synthesis and the androgen receptor (AR) signaling, and the implementation of rational combination regimes. The results obtained from array-based technologies and nextgeneration sequencing have enhanced our understanding of the pathways driving castration resistance, its molecular complexity and potential to guide therapeutics [8]. In particular, activation of the PI3K/AKT/mTOR pathway has been implicated in prostate cancer progression [9]. Precision oncology uses genomic data to facilitate rational treatment choices tailored to individual patients. The translation of basic science into clinically valuable biomarkers of prognostic and predictive significance is critical in the development of precision medicine in prostate cancer. Furthermore, there is increasing demand for the incorporation of genomic alterations as predictive biomarkers allowing patient stratification as part of innovative clinical trials. This review summarizes the evidence on the genomic events in prostate cancer and major targets for clinical intervention. In addition, we discuss innovative clinical trial design in an attempt to enhance individualized treatment in prostate cancer. AR signaling & the preclinical basis of treatment stratification
The growth of prostate cancer is largely dependent on androgens and therapies blocking the
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ISSN 1473-7140
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Review
Galazi, Rodriguez-Vida, Ng, Mason & Chowdhury
AR signaling pathway are effective for most patients. However, several mechanisms can restore AR signaling and promote the development of CRPC. These include amplification, gain-offunction AR mutations, splice variants and overexpression of AR or its coactivators. For example, AR amplification is observed in 50% of patients with metastatic disease and can occur through focal amplification of gain of the entire Xchromosome [8]. The use of selective and potent AR-targeted therapies such as the androgen biosynthesis inhibitor abiraterone acetate and the AR inhibitor enzalutamide has radically changed systemic therapy leading to significant improvements in overall survival (OS) and progression-free survival (PFS) [5,6]. These results further demonstrate that continued AR inhibition is important in the castrate-resistant state. However, these second-generation AR-targeted agents are largely used in an unselected manner for patients with castrate-resistant disease. Strategies to select those patients most likely to benefit and also to identify primary and acquired resistance are needed to increase the probability of response to treatment and clinical benefit. The H874Y AR somatic mutation leads to increase of the AR binding capacity for testosterone and other mutations in the ligand-binding domain of AR allow activation by other steroid hormones [10,11]. The AR mutation F876L leads to resistance to enzalutamide and may explain resistance to treatment in the subgroup of patients that express this. The F876L mutation in AR demonstrated obliteration of antagonistic activity of enzalutamide, hence leading to agonist switch activity to AR in several prostate cancer cell lines [12]. Through these resistance mechanisms prostate cancer in the castration-resistant setting remains dependent on the AR axis. Furthermore, recent preclinical evidence has demonstrated that expression of the glucocorticoid receptor (GR) is also associated with resistance to enzalutamide and the novel antiandrogen ARN509. Data have shown that AR inhibition induces strong GR expression in androgen-resistant prostate cancer cells. GR is thought to confer anti-androgen resistance via several target genes. The serum glucocorticoid-induced kinase 1 was found to be among the most upregulated and several other genes, for example, PMEPA1 and SNAI2 were found to be repressed [13]. AR splice variants appear to be an important potential mechanism in resistant disease. Splicing has been documented to play a significant role in the regulation of cancer-associated genes and is the process in which exons are selectively excised from the pre-mRNA, resulting in different combinations of exons in the final translated mRNA [14,15]. Loss of fidelity and variation of the splicing process is thought to occur during tumor progression and further understanding of the process of aberrant splicing as well as characterization of splice variants may be used as potential therapeutic targets. Recent findings indicate that the AR is expressed as C-terminal-truncated AR splice variants, which are constitutively active in driving ARregulated transcription and promoting tumor progression even under castrate conditions. ADT induces AR RNA transcription 1306
and higher levels of the splice variant AR-V7 are observed [16]. Splice variant AR3 (also termed AR-V7) is the most studied and lacks the ligand-binding domain in androgen-resistant prostate cancer cells. AR3 has been found to be significantly upregulated during prostate cancer progression, leading to activation of AR reporter genes [17]. It has been suggested that AR3 may play a role in prostate cancer growth in the castration-resistant state through activation of AR and AKT1 gene. Microarray analysis of gene expression showed that activation of AR3 plays a role in upregulation of AKT1 expression and of the AKT pathway at the transcriptional level during prostate cancer progression [18]. AR-V7 is a truncated form of the AR lacking the ligandbinding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. The hypothesis that the splice variant AR-V7 may be associated with primary resistance to abiraterone acetate and enzalutamide has been recently studied using quantitative reversetranscription PCR. The presence or absence of AR-V7 in circulating tumor cells (CTCs) from 31 patients with metastatic CRPC starting treatment with abiraterone acetate or enzalutamide was examined. AR-V7 status was found to be correlated with prostate-specific antigen (PSA) response rates (‡50% decline from baseline maintained for ‡4 weeks), PSA-PFS and clinical/radiographic PFS. From the 31 enrolled patients receiving enzalutamide, the AR-V7-positive patients (n = 12) had markedly inferior PSA response rates (0 vs 52.6%; p = 0.004), PSA-PFS (median 1.4 vs 5.9 months; p < 0.001) and PFS (median 2.1 vs 6.1 months; p < 0.001). Similarly, in the abiraterone acetate group (n = 31), AR-V7-positive patients (n = 6) had significantly inferior PSA response rates (0 vs 68.0%; p = 0.004), PSA-PFS (median 1.3 months vs not reached; p < 0.001) and PFS (median 2.3 months vs not reached; p < 0.001). Further research is needed to confirm these preliminary findings, which suggest that AR-V7 in CTCs of metastatic CRPC patients is associated with primary resistance to abiraterone acetate and enzalutamide [19]. Current data suggest that aberrant AR splice variant expression may be a novel mechanism of metastatic CRPC progression and may serve as predictive biomarker of patient response to treatment, predict AR-targeted therapy resistance as well as lead to development of AR splice variant domain inhibitors. The identification of antisense oligonucleotides, fragments of single-stranded DNA molecules, as potential therapeutic agents, has evolved through developments in sequencing the human genome. The mechanism of action of oligonucleotides is via the induction of mRNA degradation and inhibition of splicing leading to genetic modulation of protein expression [20]. OGX-427 is a second-generation antisense oligonucleotide that inhibits heat shock protein 27 (Hsp27) expression in vitro and in vivo leading to apoptosis, inhibition of tumor growth and AR activity and sensitization of cells to chemotherapy [21]. A Phase II study in 74 patients with metastatic CRPC who progressed on abiraterone is randomizing patients between OGX-427 with abiraterone or continuing abiraterone alone to Expert Rev. Anticancer Ther. 14(11), (2014)
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Precision medicine for prostate cancer
evaluate PFS at day 60, PSA and disease response and CTC enumeration. This trial is still recruiting patients and the results are eagerly anticipated [22,23]. Another Phase II trial in chemotherapy-naı¨ve patients with metastatic CRPC randomized patients to receive OGX-427 with prednisolone (n = 17) versus prednisolone alone (n = 15). This study is evaluating the proportion of patients who are progression free at 12 weeks, the PSA decline, measurable disease response and CTC enumeration. Preliminary results from this study have reported a ‡50% decline in PSA during treatment in 41% of patients in the OGX-427 and prednisolone arm versus 20% in the prednisolone-only arm. Furthermore, partial responses were seen in 38% of the OGX-427 and prednisolone patients versus 0% in the prednisolone-only group and CTC conversion from ‡5 to 50% of patients and provide potential therapeutic targets. • New predictive biomarkers are required for assessment of disease response to treatment.
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Precision medicine for prostate cancer
prostate cancer cells through combinatorial activation of the mutant androgen receptor and mitogen-activated protein kinase pathways. Mol Cancer Res 2008;6:1507-20
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Review
Enzalutamide Plus Everolimus in Men With Metastatic Castrate-Resistant Prostate Cancer. Available from: http://clinicaltrials. gov/show/NCT02125084 Pasireotide (SOM230) With or Without Everolimus in Treating Patients With Hormone Resistant, Chemotherapy Naive Prostate Cancer. Available from: http:// clinicaltrials.gov/show/NCT01313559 Everolimus as First-Line Therapy in Treating Patients With Prostate Cancer. Available from: http://clinicaltrials.gov/show/ NCT00976755
informahealthcare.com
94.
Dual mTOR Inhibitor MLN0128 in Advanced Castration-Resistant Prostate Cancer (CRPC) Patients. Available from: http://clinicaltrials.gov/show/NCT02091531
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A Study Combining ABT-888, Oral PARP Inhibitor, With Temozolomide in Patients With Metastatic Prostate Cancer. Available from: http://clinicaltrials.gov/show/ NCT01085422
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TOPARP: a Phase II Trial of Olaparib in Patients With Advanced Castration
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Precision medicine for prostate cancer Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by University of Cincinnati on 11/12/14 For personal use only.
Expert Rev. Anticancer Ther. 14(11), 1305–1315 (2014)
Myria Galazi1, Alejo Rodriguez-Vida1, Tony Ng2, Malcolm Mason3 and Simon Chowdhury*1 1 Department of Medical Oncology, Guy’s Hospital, London, SE1 9RT, UK 2 Richard Dimbleby Department of Cancer Research, King’s College London, SE1 1UL, UK 3 Institute of Cancer and Genetics, Cardiff University School of Medicine, CF14 2TL, UK *Author for correspondence: [email protected]
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Metastatic castration-resistant prostate cancer remains a lethal disease despite considerable progress in systemic therapy over the past decade. The recent advances in genomic sequencing have improved the molecular classification of prostate cancer. The translation of genomic data into clinically relevant prognostic and predictive biomarkers to guide therapy is still in its infancy and therapies for castration-resistant prostate cancer are still used empirically. We discuss these genomic aberrations in more detail, focusing on androgen receptor signaling, ETS transcription factor gene rearrangements and PTEN loss. The incorporation of this genomic data within early phase clinical trials is evolving and may prove significant in advancing personalized care in prostate cancer. KEYWORDS: androgen receptor • castration-resistant prostate cancer • ETS fusion gene rearrangements • PI3K/AKT/mTOR pathway • precision medicine • PTEN loss
Prostate cancer is the commonest cancer in men in the UK and the second most common cause of cancer-related death in men in the UK [1]. The disease exhibits remarkable heterogeneity in clinical behavior and outcome ranging from decades of indolence to lethal disease despite apparently similar histological features. Currently, androgen deprivation therapy (ADT) is the first-line therapy for metastatic disease. Response to therapy, however, is transient and patients invariably progress to castrationresistant prostate cancer (CRPC). The TAX327 trial established docetaxel plus prednisolone as first-line chemotherapy for CRPC [2]. Since then, there has been significant progress in the systemic treatment of prostate cancer with the approval of five new therapies for metastatic CRPC in the last 4 years. Cabazitaxel, sipuleucel-T, abiraterone acetate, enzalutamide and radium-223 have all demonstrated significant improvements in survival in Phase III trials [3–7]. However, all of these new therapies are given to relatively unselected patient groups with the only selection being based on clinical characteristics such as performance status. Despite these rapid advances, the management of prostate cancer is yet to embrace the personalized approach seen in other cancers such as malignant melanoma, breast and lung cancer. There are numerous challenges that exist in the clinic, especially with patient selection for therapies targeted against androgen 10.1586/14737140.2014.972948
synthesis and the androgen receptor (AR) signaling, and the implementation of rational combination regimes. The results obtained from array-based technologies and nextgeneration sequencing have enhanced our understanding of the pathways driving castration resistance, its molecular complexity and potential to guide therapeutics [8]. In particular, activation of the PI3K/AKT/mTOR pathway has been implicated in prostate cancer progression [9]. Precision oncology uses genomic data to facilitate rational treatment choices tailored to individual patients. The translation of basic science into clinically valuable biomarkers of prognostic and predictive significance is critical in the development of precision medicine in prostate cancer. Furthermore, there is increasing demand for the incorporation of genomic alterations as predictive biomarkers allowing patient stratification as part of innovative clinical trials. This review summarizes the evidence on the genomic events in prostate cancer and major targets for clinical intervention. In addition, we discuss innovative clinical trial design in an attempt to enhance individualized treatment in prostate cancer. AR signaling & the preclinical basis of treatment stratification
The growth of prostate cancer is largely dependent on androgens and therapies blocking the
2014 Informa UK Ltd
ISSN 1473-7140
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Galazi, Rodriguez-Vida, Ng, Mason & Chowdhury
AR signaling pathway are effective for most patients. However, several mechanisms can restore AR signaling and promote the development of CRPC. These include amplification, gain-offunction AR mutations, splice variants and overexpression of AR or its coactivators. For example, AR amplification is observed in 50% of patients with metastatic disease and can occur through focal amplification of gain of the entire Xchromosome [8]. The use of selective and potent AR-targeted therapies such as the androgen biosynthesis inhibitor abiraterone acetate and the AR inhibitor enzalutamide has radically changed systemic therapy leading to significant improvements in overall survival (OS) and progression-free survival (PFS) [5,6]. These results further demonstrate that continued AR inhibition is important in the castrate-resistant state. However, these second-generation AR-targeted agents are largely used in an unselected manner for patients with castrate-resistant disease. Strategies to select those patients most likely to benefit and also to identify primary and acquired resistance are needed to increase the probability of response to treatment and clinical benefit. The H874Y AR somatic mutation leads to increase of the AR binding capacity for testosterone and other mutations in the ligand-binding domain of AR allow activation by other steroid hormones [10,11]. The AR mutation F876L leads to resistance to enzalutamide and may explain resistance to treatment in the subgroup of patients that express this. The F876L mutation in AR demonstrated obliteration of antagonistic activity of enzalutamide, hence leading to agonist switch activity to AR in several prostate cancer cell lines [12]. Through these resistance mechanisms prostate cancer in the castration-resistant setting remains dependent on the AR axis. Furthermore, recent preclinical evidence has demonstrated that expression of the glucocorticoid receptor (GR) is also associated with resistance to enzalutamide and the novel antiandrogen ARN509. Data have shown that AR inhibition induces strong GR expression in androgen-resistant prostate cancer cells. GR is thought to confer anti-androgen resistance via several target genes. The serum glucocorticoid-induced kinase 1 was found to be among the most upregulated and several other genes, for example, PMEPA1 and SNAI2 were found to be repressed [13]. AR splice variants appear to be an important potential mechanism in resistant disease. Splicing has been documented to play a significant role in the regulation of cancer-associated genes and is the process in which exons are selectively excised from the pre-mRNA, resulting in different combinations of exons in the final translated mRNA [14,15]. Loss of fidelity and variation of the splicing process is thought to occur during tumor progression and further understanding of the process of aberrant splicing as well as characterization of splice variants may be used as potential therapeutic targets. Recent findings indicate that the AR is expressed as C-terminal-truncated AR splice variants, which are constitutively active in driving ARregulated transcription and promoting tumor progression even under castrate conditions. ADT induces AR RNA transcription 1306
and higher levels of the splice variant AR-V7 are observed [16]. Splice variant AR3 (also termed AR-V7) is the most studied and lacks the ligand-binding domain in androgen-resistant prostate cancer cells. AR3 has been found to be significantly upregulated during prostate cancer progression, leading to activation of AR reporter genes [17]. It has been suggested that AR3 may play a role in prostate cancer growth in the castration-resistant state through activation of AR and AKT1 gene. Microarray analysis of gene expression showed that activation of AR3 plays a role in upregulation of AKT1 expression and of the AKT pathway at the transcriptional level during prostate cancer progression [18]. AR-V7 is a truncated form of the AR lacking the ligandbinding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. The hypothesis that the splice variant AR-V7 may be associated with primary resistance to abiraterone acetate and enzalutamide has been recently studied using quantitative reversetranscription PCR. The presence or absence of AR-V7 in circulating tumor cells (CTCs) from 31 patients with metastatic CRPC starting treatment with abiraterone acetate or enzalutamide was examined. AR-V7 status was found to be correlated with prostate-specific antigen (PSA) response rates (‡50% decline from baseline maintained for ‡4 weeks), PSA-PFS and clinical/radiographic PFS. From the 31 enrolled patients receiving enzalutamide, the AR-V7-positive patients (n = 12) had markedly inferior PSA response rates (0 vs 52.6%; p = 0.004), PSA-PFS (median 1.4 vs 5.9 months; p < 0.001) and PFS (median 2.1 vs 6.1 months; p < 0.001). Similarly, in the abiraterone acetate group (n = 31), AR-V7-positive patients (n = 6) had significantly inferior PSA response rates (0 vs 68.0%; p = 0.004), PSA-PFS (median 1.3 months vs not reached; p < 0.001) and PFS (median 2.3 months vs not reached; p < 0.001). Further research is needed to confirm these preliminary findings, which suggest that AR-V7 in CTCs of metastatic CRPC patients is associated with primary resistance to abiraterone acetate and enzalutamide [19]. Current data suggest that aberrant AR splice variant expression may be a novel mechanism of metastatic CRPC progression and may serve as predictive biomarker of patient response to treatment, predict AR-targeted therapy resistance as well as lead to development of AR splice variant domain inhibitors. The identification of antisense oligonucleotides, fragments of single-stranded DNA molecules, as potential therapeutic agents, has evolved through developments in sequencing the human genome. The mechanism of action of oligonucleotides is via the induction of mRNA degradation and inhibition of splicing leading to genetic modulation of protein expression [20]. OGX-427 is a second-generation antisense oligonucleotide that inhibits heat shock protein 27 (Hsp27) expression in vitro and in vivo leading to apoptosis, inhibition of tumor growth and AR activity and sensitization of cells to chemotherapy [21]. A Phase II study in 74 patients with metastatic CRPC who progressed on abiraterone is randomizing patients between OGX-427 with abiraterone or continuing abiraterone alone to Expert Rev. Anticancer Ther. 14(11), (2014)
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Precision medicine for prostate cancer
evaluate PFS at day 60, PSA and disease response and CTC enumeration. This trial is still recruiting patients and the results are eagerly anticipated [22,23]. Another Phase II trial in chemotherapy-naı¨ve patients with metastatic CRPC randomized patients to receive OGX-427 with prednisolone (n = 17) versus prednisolone alone (n = 15). This study is evaluating the proportion of patients who are progression free at 12 weeks, the PSA decline, measurable disease response and CTC enumeration. Preliminary results from this study have reported a ‡50% decline in PSA during treatment in 41% of patients in the OGX-427 and prednisolone arm versus 20% in the prednisolone-only arm. Furthermore, partial responses were seen in 38% of the OGX-427 and prednisolone patients versus 0% in the prednisolone-only group and CTC conversion from ‡5 to 50% of patients and provide potential therapeutic targets. • New predictive biomarkers are required for assessment of disease response to treatment.
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Precision medicine for prostate cancer
prostate cancer cells through combinatorial activation of the mutant androgen receptor and mitogen-activated protein kinase pathways. Mol Cancer Res 2008;6:1507-20
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Tivantinib in treating patients with metastatic prostate cancer. Available from: http://clinicaltrials.gov/show/NCT01519414
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OGX-427 in castration resistant prostate cancer patients. Available from: http:// clinicaltrials.gov/show/NCT01120470
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Resistant Prostate Cancer. Available from: http://clinicaltrials.gov/show/NCT01682772
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ARN 509 Plus Everolimus in Men With Progressive Metastatic Castration-Resistant Prostate Cancer After Treatment With Abiraterone Acetate. Available from: http:// clinicaltrials.gov/show/NCT02106507
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Dual mTOR Inhibitor MLN0128 in Advanced Castration-Resistant Prostate Cancer (CRPC) Patients. Available from: http://clinicaltrials.gov/show/NCT02091531
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A Study Combining ABT-888, Oral PARP Inhibitor, With Temozolomide in Patients With Metastatic Prostate Cancer. Available from: http://clinicaltrials.gov/show/ NCT01085422
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TOPARP: a Phase II Trial of Olaparib in Patients With Advanced Castration
1315
