Friday
Emerging roles of human prostatic Acid phosphatase
Monday
Integration of immunotherapy into the management of advanced prostate cancer.
ABSTRACT: Until recently, the only therapy shown to improve survival in men with metastatic castration-resistant prostate cancer (mCRPC) had been chemotherapy, usually reserved for symptomatic patients. However, sipuleucel-T, a cellular product directed toward a specific antigen, prostatic acid phosphatase, was Food and Drug Administration (FDA) approved in 2010 in the United States, based on phase 3 data showing improved overall survival in men with minimal or no symptoms due to mCRPC compared with placebo. Subsequently, several other promising immunotherapeutic approaches have advanced to study in the phase 3 setting, including ipilimumab and PROSTVAC. The demonstration of efficacy of immunotherapy in prostate cancer provides a new treatment option for men with no or few symptoms early in the course of mCRPC. Since sipuleucel-T was approved, several drugs that favorably impact survival have also been approved or are close to approval in the United States. These agents include cabazitaxel, abiraterone, radium-223, and MDV3100. There are many unresolved issues about sipuleucel-T, such as best timing in the course of mCRPC, the role for booster therapy, and the role of combinations with other active drugs, including other immune-modulating approaches. There are also many questions regarding sequencing of these new agents and, given the number of other promising agents in phase 3 trials, these questions will become more complicated, underscoring the need for better predictors of benefit for the individual patient.
Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
UROL ONCOL 2012 Sep;30(5 Suppl):S41-7. doi: 10.1016/j.urolonc.2012.06.0022012 Sep;30(5 Suppl):S41-7. doi: 10.1016/j.urolonc.2012.06.002
Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity as a biomarker for bone metastasis in non-small cell lung cancer patients
Background
Diagnosis and follow-up of bone metastasis (BMet) in non-small cell lung cancer (NSCLC) patients usually rely on symptoms and image studies. A serum marker of bone resorption may improve the quality of treatment in such patients. Tartrate-resistant acid phosphatase 5b (TRACP5b) is a specific marker for osteoclasts and we proposed it can be used as a marker of BMet in NSCLC patients.
Methods
In November 2002 till August 2008 serum samples were obtained from 141 newly diagnosed stage IIIA, IIIB or IV NSCLC patients and 41 normal subjects. All patients received baseline bone scintinography examination and evaluation of clinical symptoms as a standard of BMet diagnosis. Patients were divided into 2 groups by having BMet (Group I, n = 72) or not (Group II, n = 69). An in-house immunoassay using a TRACP-specific monoclonal antibody, 14G6, was used to measure the serum TRACP5b activity at pH 6.1.
Results
The mean serum TRACP5b activities of Group I, Group II and normal subjects were 3.50 ± 2.23 U/l, 2.09 ± 0.72 U/l and 2.33 ± 0.52 U/l, respectively. After adjusting for age, stage, gender, and histology in a generalized linear model, Group I has significantly higher TRACP5b activity than Group II (p < 0.001). The receiver operating characteristic analysis established a cutoff value of 2.551 U/l to identify BMet in NSCLC patients with a sensitivity of 63.9% and a specificity of 76.8%. TRACP5b activity declined in patients who responded to treatment (p = 0.047), and elevated in patients who developed new BMet (p = 0.05).
Conclusions
Serum TRACP5b activity test is a potentially useful adjunct in diagnosing and monitoring BMet in NSCLC. Further study is warranted to establish its real value in diagnosis and monitoring of BMet in NSCLC patients.
Diagnosis and follow-up of bone metastasis (BMet) in non-small cell lung cancer (NSCLC) patients usually rely on symptoms and image studies. A serum marker of bone resorption may improve the quality of treatment in such patients. Tartrate-resistant acid phosphatase 5b (TRACP5b) is a specific marker for osteoclasts and we proposed it can be used as a marker of BMet in NSCLC patients.
Methods
In November 2002 till August 2008 serum samples were obtained from 141 newly diagnosed stage IIIA, IIIB or IV NSCLC patients and 41 normal subjects. All patients received baseline bone scintinography examination and evaluation of clinical symptoms as a standard of BMet diagnosis. Patients were divided into 2 groups by having BMet (Group I, n = 72) or not (Group II, n = 69). An in-house immunoassay using a TRACP-specific monoclonal antibody, 14G6, was used to measure the serum TRACP5b activity at pH 6.1.
Results
The mean serum TRACP5b activities of Group I, Group II and normal subjects were 3.50 ± 2.23 U/l, 2.09 ± 0.72 U/l and 2.33 ± 0.52 U/l, respectively. After adjusting for age, stage, gender, and histology in a generalized linear model, Group I has significantly higher TRACP5b activity than Group II (p < 0.001). The receiver operating characteristic analysis established a cutoff value of 2.551 U/l to identify BMet in NSCLC patients with a sensitivity of 63.9% and a specificity of 76.8%. TRACP5b activity declined in patients who responded to treatment (p = 0.047), and elevated in patients who developed new BMet (p = 0.05).
Conclusions
Serum TRACP5b activity test is a potentially useful adjunct in diagnosing and monitoring BMet in NSCLC. Further study is warranted to establish its real value in diagnosis and monitoring of BMet in NSCLC patients.
Serum Tartrate Resistant Acid Phosphatase as Prognostic Marker of Survival
Abstract
Background: Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) activity is a marker of osteoclast number and is elevated in breast cancer (BC) patients with extensive bone metastasis, which might in turn reflect the tumour burden.
We tested the hypothesis that baseline serum TRACP 5b activity and its interval change are potential prognostic markers of survival in BC patients with bone metastasis.
Methods: We analyzed the data from previous prospective studies. A total of 100 patients with newly diagnosed bone metastasis were included. Cox proportional regression model was used to evaluate the correlation between the overall
survival time (OS) and baseline serum TRACP 5b activity and its interval changes. The least significant change (LSC) of TRACP 5b was calculated from data obtained from 15 patients with early BC.
Results: Estrogen receptor status (Hazard Ratio (HR) = 0.397; p = 0.003) and visceral metastasis (HR = 0.492; p = 0.0045)were significantly correlated with OS. The OS was significantly shorter in those patients with higher baseline TRACP 5b
activity based on a cut-off value to delineate the highest tertile (HR = 3.524; p < 0.0001). Further analysis demonstrated that among patients in the highest tertile, OS was significantly longer in those patients who had achieved a decrease of
serum TRACP 5b activity greater than the LSC (38.59%) (p = 0.0015).
Conclusions: We found that TRACP 5b activity and its interval change after treatment bore a prognostic role in BC patients with bone metastasis and a high baseline serum TRACP 5b activity. Further prospective phase II study is necessary to confirm these results
Background: Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) activity is a marker of osteoclast number and is elevated in breast cancer (BC) patients with extensive bone metastasis, which might in turn reflect the tumour burden.
We tested the hypothesis that baseline serum TRACP 5b activity and its interval change are potential prognostic markers of survival in BC patients with bone metastasis.
Methods: We analyzed the data from previous prospective studies. A total of 100 patients with newly diagnosed bone metastasis were included. Cox proportional regression model was used to evaluate the correlation between the overall
survival time (OS) and baseline serum TRACP 5b activity and its interval changes. The least significant change (LSC) of TRACP 5b was calculated from data obtained from 15 patients with early BC.
Results: Estrogen receptor status (Hazard Ratio (HR) = 0.397; p = 0.003) and visceral metastasis (HR = 0.492; p = 0.0045)were significantly correlated with OS. The OS was significantly shorter in those patients with higher baseline TRACP 5b
activity based on a cut-off value to delineate the highest tertile (HR = 3.524; p < 0.0001). Further analysis demonstrated that among patients in the highest tertile, OS was significantly longer in those patients who had achieved a decrease of
serum TRACP 5b activity greater than the LSC (38.59%) (p = 0.0015).
Conclusions: We found that TRACP 5b activity and its interval change after treatment bore a prognostic role in BC patients with bone metastasis and a high baseline serum TRACP 5b activity. Further prospective phase II study is necessary to confirm these results
Wednesday
Structural and functional analysis of human prostatic acid phosphatase
Prostatic acid phosphatase (PAP) is the most abundant phosphatase in human prostate tissue/secretions. PAP is a clinically important protein for its relevance as a biomarker of prostate carcinoma. Furthermore, it has a potential role in fertilization. We describe here most of the features of PAP including gene regulation, gene/protein structure, functions, its role in tumor progression and evolutionary features.
PAP has phosphatase activity and is an extensively studied biomarker of prostate cancer. The major action of PAP is to dephosphorylate macromolecules with the help of catalytic residues (His12 and Asp258) that are located in the cleft between two domains. This article will be of great interest to all those scientists who are working in the area of prostate pathophysiology
Authors: Hassan, Md Imtaiyaz1; Aijaz, Afnan; Ahmad, Faizan
Source: Expert Review of Anticancer Therapy, Volume 10, Number 7, July 2010 , pp. 1055-1068(14)
PAP has phosphatase activity and is an extensively studied biomarker of prostate cancer. The major action of PAP is to dephosphorylate macromolecules with the help of catalytic residues (His12 and Asp258) that are located in the cleft between two domains. This article will be of great interest to all those scientists who are working in the area of prostate pathophysiology
Authors: Hassan, Md Imtaiyaz1; Aijaz, Afnan; Ahmad, Faizan
Source: Expert Review of Anticancer Therapy, Volume 10, Number 7, July 2010 , pp. 1055-1068(14)
Thursday
Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)
Abstract
In semen, proteolytic peptide fragments from prostatic acid phosphatase can form amyloid fibrils termed SEVI (semen-derived enhancer of viral infection). These fibrils greatly enhance human immunodeficiency virus (HIV) infectivity by increasing the attachment of virions to target cells. Therefore, SEVI may have a significant impact on whether HIV is successfully transmitted during sexual contact.
Here, we demonstrate that surfen, a small molecule heparan sulfate proteoglycan antagonist, inhibits both SEVI- and semen-mediated enhancement of HIV type 1 infection. Surfen interferes with the binding of SEVI to both target cells and HIV type 1 virions but does not deaggregate SEVI fibrils. Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency.
Nadia R. Roan‡, Stefanie Sowinski‡, Jan Münch§, Frank Kirchhoff§ and Warner C. Greene‡¶,1
In semen, proteolytic peptide fragments from prostatic acid phosphatase can form amyloid fibrils termed SEVI (semen-derived enhancer of viral infection). These fibrils greatly enhance human immunodeficiency virus (HIV) infectivity by increasing the attachment of virions to target cells. Therefore, SEVI may have a significant impact on whether HIV is successfully transmitted during sexual contact.
Here, we demonstrate that surfen, a small molecule heparan sulfate proteoglycan antagonist, inhibits both SEVI- and semen-mediated enhancement of HIV type 1 infection. Surfen interferes with the binding of SEVI to both target cells and HIV type 1 virions but does not deaggregate SEVI fibrils. Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency.
Nadia R. Roan‡, Stefanie Sowinski‡, Jan Münch§, Frank Kirchhoff§ and Warner C. Greene‡¶,1
Tuesday
Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer
Genitourinary Cancer
Purpose: Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.
Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 µg, 500 µg, or 1,500 µg plasmid DNA, coadministered intradermally with 200 µg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.
Results: No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).
Conclusion: The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
Supported by Grant No. K23 RR16489 from the National Institutes of Health (NIH; D.G.M., E.J.D.), by a production grant from the NIH National Gene Vector Laboratory Program, by the NIH National Center for Research Resources Clinical and Translational Science Award program (1UL1RR025011), and Grant No. W81XWH-05-1-0404 from the US Army Medical Research and Materiel Command Prostate Cancer Research Program (D.G.M., E.J.D., J.G.D., D.L.H., J.C.E.).
C. G. Drake
Immunotherapy for Prostate Cancer: Walk, Don't Run
J. Clin. Oncol., September 1, 2009; 27(25): 4035 - 4037.
Purpose: Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.
Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 µg, 500 µg, or 1,500 µg plasmid DNA, coadministered intradermally with 200 µg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.
Results: No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).
Conclusion: The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
Supported by Grant No. K23 RR16489 from the National Institutes of Health (NIH; D.G.M., E.J.D.), by a production grant from the NIH National Gene Vector Laboratory Program, by the NIH National Center for Research Resources Clinical and Translational Science Award program (1UL1RR025011), and Grant No. W81XWH-05-1-0404 from the US Army Medical Research and Materiel Command Prostate Cancer Research Program (D.G.M., E.J.D., J.G.D., D.L.H., J.C.E.).
C. G. Drake
Immunotherapy for Prostate Cancer: Walk, Don't Run
J. Clin. Oncol., September 1, 2009; 27(25): 4035 - 4037.
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