| 1. |
- Aad, G., et al.
(författare)
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- 2013
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Anand, Aseem, et al.
(författare)
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Automated Bone Scan Index to Optimize Prostate Cancer Working Group Radiographic Progression Criteria for Men With Metastatic Castration-Resistant Prostate Cancer
- 2022
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Ingår i: Clinical Genitourinary Cancer. - : Elsevier BV. - 1558-7673. ; 20:3, s. 270-277
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Radiographic progression-free survival (rPFS) by Prostate Cancer Working Group (PCWG) criteria is a radiographic endpoint. The automated bone scan index (aBSI) quantifies osseous disease burden on bone scintigraphy as a percentage of total skeletal weight. Using the aBSI, we sought to quantify increase in tumor burden represented by PCWG progression criteria, and to determine the interval increase that best associates with overall survival (OS). Patient and Methods: Retrospective analysis of trials using androgen receptor axis–targeted drugs for metastatic castration resistant prostate cancer patients (mCRPC). aBSI increase in bone disease was assessed from baseline scan to time-to-progression (per PCWG criteria). Threshold for time to aBSI increase were explored and the association between each time-to-threshold and OS was computed. Results: A total of 169 mCPRC patients had bone scans available for aBSI analysis. Of these, 90 (53%) had progression in bone meeting PCWG criteria. Total aBSI increase in patients meeting PCWG criteria was 1.22 (interquartile range [IQR]: 0.65-2.49), with a median relative increase of 109% (IQR: 40%-377%). Median aBSI at baseline was 3.1 (IQR: 1.3-7.1). The best association between OS and time-to-progression occurred with an absolute increase in aBSI equal to 0.6 (Kendall's tau 0.52). Conclusion: An absolute increase of 0.6 or more in aBSI from the first follow-up scan results in the highest association with OS in patients with mCRPC. The rPFS by PCWG, identified progression at nearly twice this tumor burden, suggesting that aBSI may be used to further develop the PCWG criteria without degrading its association with OS.
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| 3. |
- Beer, Tomasz M, et al.
(författare)
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Enzalutamide in metastatic prostate cancer before chemotherapy
- 2014
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:5, s. 33-424
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
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| 4. |
- Gallagher, David J., et al.
(författare)
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Susceptibility Loci Associated with Prostate Cancer Progression and Mortality
- 2010
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:10, s. 2819-2832
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools. Experimental Design: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs. Results: On univariate analysis, two SNPs were associated (P < 0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer specific mortality. Applying a Bonferroni correction (P < 0.0017), one association with biochemical recurrence (P = 0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (P < 0.0005 by both univariate and multivariable analysis). Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer-specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. Clin Cancer Res; 16(10); 2819-32. (C) 2010 AACR.
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| 5. |
- Knutsson, Anki, et al.
(författare)
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Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE-/- mice
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE-/- mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0-3.1), 0.2% (IQR 0-4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.
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| 6. |
- McDevitt, Michael R., et al.
(författare)
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Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
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| 7. |
- Nazarian, Arpi, et al.
(författare)
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Inhibition of Circulating Dipeptidyl Peptidase 4 Activity in Patients with Metastatic Prostate Cancer
- 2014
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Ingår i: Molecular & Cellular Proteomics. - 1535-9484. ; 13:11, s. 3082-3096
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.
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| 8. |
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| 9. |
- Shaffer, David R, et al.
(författare)
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Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:7, s. 2023-2029
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To better direct targeted therapies to the patients with tumors that express the target, there is an urgent need for blood-based assays that provide expression information on a consistent basis in real time with minimal patient discomfort. We aimed to use immunomagnetic-capture technology to isolate and analyze circulating tumor cells (CTC) from small volumes of peripheral blood of patients with advanced prostate cancer. EXPERIMENTAL DESIGN: Blood was collected from 63 patients with metastatic prostate cancer. CTCs were isolated by the Cell Search system, which uses antibodies to epithelial cell adhesion marker and immunomagnetic capture. CTCs were defined as nucleated cells positive for cytokeratins and negative for CD45. Captured cells were analyzed by immunofluorescence, Papanicolau staining, and fluorescence in situ hybridization. RESULTS: Most patients (65%) had 5 or more CTCs per 7.5 mL blood sample. Cell counts were consistent between laboratories (c = 0.99) and did not change significantly over 72 or 96 h of storage before processing (c = 0.99). Their identity as prostate cancer cells was confirmed by conventional cytologic analysis. Molecular profiling, including analysis of epidermal growth factor receptor (EGFR) expression, chromosome ploidy, and androgen receptor (AR) gene amplification, was possible for all prostate cancer patients with >or=5 CTCs. CONCLUSIONS: The analysis of cancer-related alterations at the DNA and protein level from CTCs is feasible in a hospital-based clinical laboratory. The alterations observed in EGFR and AR suggest that the methodology may have a role in clinical decision making.
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| 10. |
- Thorek, Daniel L J, et al.
(författare)
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Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:367
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Tidskriftsartikel (refereegranskat)abstract
- Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.
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