Male breast cancer is uncommon, accounting for less than 1% of all breast cancers. Carcinoma metastatic to the male breast is also unusual, with metastatic prostatic carcinoma being among the most common primary sites from which such tumours derive. Metastatic prostatic cancer and primary breast cancer may be histologically indistinguishable without immunohistochemistry because both often infiltrate with a cribriform architecture. Distinguishing between primary and metastatic disease within the breast is important because the treatment options for each are radically different. Following a case in which metastatic prostatic disease was initially wrongly diagnosed as primary breast cancer, a small series of male breast cancers was examined for expression of prostate specific antigen (PSA) and prostatic acid phosphatase to assess the usefulness of these markers in making this distinction. Focal expression of PSA was found in one of 11 cases of male breast cancer. These results indicate that PSA should be used with caution in this context.
breast cancer; male; prostate specific antigen
To understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland—but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance—allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.
Prostate cancer is the most common cancer in men in United States and the fifth most common cancer in men in Korea. Although the majority of patients with metastatic prostate cancer initially respond to androgen deprivation therapy, almost all patients will eventually progress to develop castration-resistant prostate cancer (CRPC). Treatment options for CRPC remain limited. Prostate cancer was considered unresponsive to chemotherapy until the mid-1990s, when mitoxantrone combined with prednisone was shown to play a role in the palliative treatment of patients with CRPC. In 2004, two large randomized clinical trials demonstrated for the first time a small but significant survival advantage of docetaxel-based chemotherapy compared with mitoxantrone in patients with metastatic CRPC. Recently, cabazitaxel was shown to improve survival in patients with metastatic CRPC who progressed after docetaxel-based chemotherapy. Sipuleucel-T was also demonstrated to improve overall survival in patients with asymptomatic or minimally symptomatic metastatic CRPC. Along with mitoxantrone and docetaxel, cabazitaxel and sipuleucel-T are now approved for use in metastatic CRPC by the US Food and Drug Administration. There have been multiple early-phase clinical trials of various agents for the treatment of CRPC, and some are in phase III development. This review focuses on the key clinical trials of various treatment options of CRPC currently in use and under investigation.
Drug therapy; Immunotherapy; Molecular targeted therapy; Prostatic neoplasms; Survival
Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues.
castrate resistant prostate cancer; immunotherapy; biomarkers; sipuleucel-T; immune response
The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory.
Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011) was 60 months, with median survival from RT 42 months.
Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.
Prostate cancer; Prostate radiation; Castrate refractory
Prostate circulating tumor cells (PCTCs) in circulation are shed from either a primary tumor or metastases, which are directly responsible for most prostate cancer deaths. Quantifying exfoliated PCTCs may serve as an indicator for the clinical management of prostate cancer, isolating and removing of PCTCs could potentially reduce prostate cancer metastasis, and culturing and characterizing captured PCTCs could facilitate the development of personalized treatment options. Prostate-specific membrane antigen (PSMA) is an established biomarker for prostate cancer being strongly expressed on prostate tumor cells associated with high-grade primary, androgen independent, and metastatic tumors.
Suspensions of PSMA+ (LNCaP) cells were pre-targeted with the irreversible PSMA inhibitor biotin-PEG12-CTT-54 to serve as a bait to capture PSMA+ cells using streptavidin-coated magnetic beads. Decreasing numbers of LNCaP cells were spiked into blood to determine the cell captured efficiency, recovery and viability.
High selectivity, recovery, and viability were achieved for the capture of PSMA+ cells in both model experiments with mixtures of LNCaP cells and WBCs as well as blood samples spiked with LNCaP cells. As low as 10 cells were captured from 1 mL of blood with nearly 90% viability. More importantly, captured cells could be subsequently propagated in vitro.
This methodology for the detection, isolation, and culture of PCTCs from peripheral blood can serve as an effective tool for the detection of metastatic prostate cancer, treatment monitoring, and the development of personalized therapy based on the responsiveness of PCTCs to chemotherapeutic strategies.
prostate cancer; circulating tumor cells; PSMA; prostate-specific membrane antigen; flow cytometry; magnetic bead
Prostate cancer is the most common cancer among men in American and the second leading cause of cancer death. The treatment options employed for patients with advanced and metastatic prostate cancer are limited. As a critical mediator of oncogenic signaling, STAT3 is active in 82% of patients with prostate cancer. STAT3 has become a very important molecular target for prostate cancer therapy since it upregulates the oncogenes encoding apoptosis inhibitors, cell-cycle regulators, and inducers of angiogenesis. However, no anti-tumor drug whose primary mode of action is to target STAT3 has yet reached the clinic. To this end, we have laid the initial groundwork to develop the STAT3-inhibiting G-quartet oligodeoxynucleotide (GQ-ODN), T40214, for treatment of prostate cancers.
We employed in vitro and in vivo assays, including western blots, EMSA, cell cycle analysis, TUNEL and xenograft models, to determine the drug efficacy and mechanism of T40214/PEI complex.
The results demonstrated that (i) T40214 significantly inhibited STAT3 activation and induced apoptosis in both androgen-dependent and androgen-independent prostate cancer cells; (ii) T40214 delivered by PEI (ployethylenimine) significantly suppressed prostate tumor growth in tumor-bearning nude mice due to that T40214 inhibited STAT3 activation and then greatly promoted apoptosis, reduced angiogenesis and cell proliferation in prostate tumors.
Our studies suggested that STAT3 is a critical oncogenic signal, which strongly influences the progression of prostate cancers and that T40214/PEI complex is a promising candidate for treatment of patients with prostate tumors and represents a novel strategy for prostate cancer therapy.
If metastatic prostate cancer gets resistant to antiandrogen therapy, there are few treatment options, because prostate cancer is not very sensitive to cytostatic agents. Temozolomide (TMZ) as an orally applicable chemotherapeutic substance has been proven to be effective and well tolerated with occasional moderate toxicity especially for brain tumors and an application to prostate cancer cells seemed to be promising. Unfortunately, TMZ was inefficient in the treatment of symptomatic progressive hormone-refractory prostate cancer (HRPC). The reasons could be a low sensitivity against TMZ the short plasma half-life of TMZ, non-adapted application regimens and additionally, the aneuploid DNA content of prostate cancer cells suggesting different sensitivity against therapeutical interventions e.g. radiation therapy or chemotherapy. Considerations to improve this unsatisfying situation resulted in the realization of higher local TMZ concentrations, sufficient to kill cells regardless of intrinsic cellular sensitivity and cell DNA-index. Therefore, we reformulated the TMZ by ligation to a peptide-based carrier system called TMZ-BioShuttle for intervention. The modular-composed carrier consists of a transmembrane transporter (CPP), connected to a nuclear localization sequence (NLS) cleavably-bound, which in turn was coupled with TMZ. The NLS-sequence allows an active delivery of the TMZ into the cell nucleus after transmembrane passage of the TMZ-BioShuttle and intra-cytoplasm enzymatic cleavage and separation from the CPP. This TMZ-BioShuttle could contribute to improve therapeutic options exemplified by the hormone refractory prostate cancer. The next step was to syllogize a qualified method monitoring cell toxic effects in a high sensitivity under consideration of the ploidy status. The high-resolution flow cytometric analysis showed to be an appropriate system for a better detection and distinction of several cell populations dependent on their different DNA-indices as well as changes in proliferation of cell populations after chemotherapeutical treatment.
TMZ-BioShuttle; Prostate Cancer Cells; Flow Cytometry
Although most prostate cancers respond well to initial treatments, a fraction of prostate cancers are more aggressive and will recur and metastasize. At that point, there are few treatment options available. Significant efforts have been made to identify biomarkers that will identify these more aggressive cancers to tailor a more vigorous treatment in order to improve outcome. Polycomb Group protein Enhancer of Zeste 2 (EZH2) was found to be overexpressed in metastatic prostate tumors, and is considered an excellent candidate for such a biomarker. Scattered studies have found that EZH2 overexpression causes neoplastic transformation, invasion, and growth of prostate cells. However, these studies utilized different systems and cell lines, and so are difficult to correlate with one another.
In this study, a comprehensive evaluation of the phenotypic effects of EZH2 in a panel of five prostate cancer cell lines was performed. By using multiple cell lines, and examining overexpression and knockdown of EZH2 concurrently, a broad view of EZH2's role in prostate cancer was achieved.
Overexpression of EZH2 led to more aggressive behaviors in all prostate cell lines tested. In contrast, downregulation of EZH2 reduced invasion and tumorigenicity of androgen-independent cell lines CWR22Rv1, PC3, and DU145, but not of androgen-dependent cell lines LAPC4 and LNCaP.
Findings from this study suggest androgen-independent prostate tumors are more dependent on EZH2 expression than androgen-dependent tumors. Our observations provide an explanation for the strong correlation between EZH2 overexpression and advanced stage, aggressive prostate cancers.
EZH2; Prostate; Cancer; Growth; Aggression
Prostate cancer dissemination is difficult to detect in the clinic, and few treatment options exist for patients with advanced-stage disease. Our aim was to investigate the role of tumor lymphangiogenesis during metastasis. Further, we implemented a noninvasive molecular imaging technique to facilitate the assessment of the metastatic process. The metastatic potentials of several human prostate cancer xenograft models, LAPC-4, LAPC-9, PC3 and CWR22Rv-1 were compared. The cells were labeled with luciferase, a bioluminescence imaging reporter gene, to enable optical imaging. After tumor implantation the animals were examined weekly during several months for the appearance of metastases. Metastatic lesions were confirmed by immunohistochemistry. Additionally, the angiogenic and lymphangiogenic profiles of the tumors were characterized. To confirm the role of lymphangiogenesis in mediating metastasis, the low-metastatic LAPC-9 tumor cells were engineered to overexpress VEGF-C, and the development of metastases was evaluated. Our results show CWR22Rv-1 and PC3 tumor cell lines to be more metastatic than LAPC-4, which in turn disseminates more readily than LAPC-9. The difference in metastatic potential correlated with the endogenous production levels of lymphangiogenic growth factor VEGF-C and the presence of tumor lymphatics. In agreement, induced overexpression of VEGF-C in LAPC-9 enhanced tumor lymphangiogenesis leading to the development of metastatic lesions. Taken together, our studies, based on a molecular imaging approach for semiquantitative detection of micrometastases, point to an important role of tumor lymphatics in the metastatic process of human prostate cancer. In particular, VEGF-C seems to play a key role in prostate cancer metastasis.
lymphatics; vascular endothelial growth factor; lung; luciferase; lymph node
Hormonal deprivation therapy is well established for the treatment of locally advanced and metastatic prostate cancer, as well as the adjuvant treatment of some patients with localized disease. Long-acting gonadotropin releasing hormone (GnRH) agonists have become a mainstay of androgen deprivation therapy, due to their efficacy, tolerability, and convenience of use. One-month, 3-month, and 4-month depot leuprorelin formulations are well established and widely used to this end. Recently, a 6-month depot leuprorelin has been approved for use in advanced and metastatic prostate cancer patients. With similar efficacy and side effect profiles to earlier formulations, 6-month depot leuprorelin is a convenient treatment option for these patients. This review will highlight the role of GnRH agonists in the treatment of prostate cancer with a focus on the clinical efficacy, pharmacology, and patient-focused outcomes of the newer 6-month 45 mg depot leuprorelin formulation in comparison to available shorter-acting products.
prostate cancer; leuprorelin; hormonal deprivation therapy
The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the past year, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel with prednisone and abiraterone acetate with prednisone), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are showing preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, which represents part 1 of a two-part series on metastatic CRPC, we will summarize the mechanisms of resistance to hormonal and chemotherapies and discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options following docetaxel administration, as well as prognostic factors in this post-docetaxel state. As docetaxel remains the standard initial systemic therapy for men with metastatic CRPC for both palliative and life-prolonging purposes, knowledge of these evolving standards will help to optimize delivery of care and long-term outcomes.
castrate-resistant prostate cancer; docetaxel-refractory; cabazitaxel; abiraterone; sipuleucel-T
The three main treatment options for primary prostate cancer are surgery, radiation, and active surveillance. Surgical and radiation intervention for prostate cancer can be associated with significant morbidity. Therefore, accurate stratification predictive of outcome for prostate cancer patients is essential for appropriate treatment decisions. Nomograms that use clinical and pathologic variables are often used for risk prediction. Favorable outcomes exist even among men classified by nomograms as being at high risk of recurrence.
Previously, we identified a set of DNA-based biomarkers termed Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) and have shown that they can predict risk of recurrence with 80% accuracy. Here, we examined the risk prediction ability of GEMCaP in a high-risk cohort and compared it to a Kattan nomogram.
We determined that the GEMCaP genotype alone is comparable with the nomogram, and that for a subset of cases with negative lymph nodes improves upon it.
Thus, GEMCaP shows promise for predicting unfavorable outcomes for negative lymph node high-risk cases, where the nomogram falls short, and suggests that addition of GEMCaP to nomograms may be warranted.
This article discusses radical prostatectomy as a treatment option for high-risk prostate cancer in men older than 70 years.
Prostate cancer affects a high proportion of men over 70 years of age, who are likely to have high-risk disease and a substantial risk of prostate-cancer-specific death. With life expectancy increasing worldwide, the burden of prostate cancer is also expected to rise. Thus, effective management of this high-risk senior patient group is increasingly important. Radical prostatectomy can increase survival and decrease the risk of metastatic progression. Postsurgery complications are affected more by comorbidity than by age. In patients without comorbidities, surgery is associated with a low risk of mortality. Advanced age may increase the likelihood of incontinence following radical prostatectomy, but patients with higher risk disease are no more likely to experience this complication compared with lower risk groups. Treatment decisions should be made after considering the health status and life expectancy of the individual patient. If eligible, the patient should be offered radical prostatectomy as a potentially curative treatment, without a rigid restriction to a certain chronological age.
Curative therapy; Cancer-specific mortality; Localized disease; High risk
Genome-wide association studies (GWAS) have identified multiple novel prostate cancer predisposition loci. Whether these common genetic variants are associated with incident metastatic prostate cancer or with recurrence after surgical treatment for clinically localized prostate cancer is uncertain.
Twelve SNPs were selected for study in relation to prostate metastatic cancer and recurrence, based on their genome-wide association with prostate cancer in the Cancer Genetic Markers of Susceptibility (CGEMS) (1, 2). To assess risk for metastatic disease, we compared genotypes for the 12 SNPs by logistic regression of 470 incident metastatic prostate cancer cases and 1945 controls in 3 case-control studies. To assess the relationship of these SNPs to risk for prostate cancer recurrence, we used Cox regression in a cohort of 1412 men treated for localized prostate cancer, including 328 recurrences, and used logistic regression in a case-case study, comparing 450 recurrent versus 450 nonrecurrent prostate cancer cases. Study-specific RRs for risk of metastatic disease and recurrence were summarized using meta-analysis, with inverse variance weights.
MSMB rs10993994 (per variant allele summary RR=1.24, 95% CI=1.05-1.48), 8q24 rs4242382 (RR=1.40, 95% CI=1.13-1.75) and 8q24 rs6983267 (RR=0.67, 95% CI=0.50-0.89) were associated with risk for metastatic prostate cancer. None of the 12 SNPs was associated with prostate cancer recurrence.
SNPs in MSMB and 8q24 which predispose to prostate cancer overall are associated with risk for metastatic prostate cancer, the most lethal form of this disease. SNPs predictive of prostate cancer recurrence were not identified, among the predisposition SNPs. GWAS specific to these two phenotypes may identify additional phenotype-specific genetic determinants.
Therapeutic options for patients with metastatic castration-resistant prostate cancer are increasing, spurring an urgent need to better understand which treatments are best for individual patients. The recent approval of a first-in-class agent, sipuleucel-T, has intensified this need. This therapeutic cancer vaccine has demonstrated a survival advantage in 2 phase III trials, but does not alter progression in the short term. Therefore, a new therapeutic approach for patients with metastatic castration-resistant prostate cancer is taking shape, based on broader understanding of available therapies. This new clinical approach seeks to maximize patient benefit from treatment, minimize associated toxicities, and may have far-reaching implications for other therapeutic cancer vaccines currently in clinical development.
prostate cancer; therapeutic cancer vaccines; emerging therapies; treatment paradigm
After Taxotere fails, treatment options for metastatic prostate cancer are limited. The three drugs with FDA approval in this setting, Jevtana, Provenge and Zytiga, are associated with median survivals of less than 2 years. In part, the impact on survival is the result of low response rates, indicating a significant proportion of patients exhibiting de novo resistance to these agents. An alternate approach is to let treatment selection be governed by gene expression profiling so that the treatment is tailored to the specific patient. Here, we report a case of metastatic prostate cancer with a dramatic response to treatment selected based on molecular profiling. This patient had failed LHRH agonist, bicalutamide, Taxotere, and doxorubicin. Molecular profiling showed overexpression of the androgen receptor and he had a dramatic response of measurable disease to second-line hormonal therapy with ketoconazole, estrogen and Leukine.
Prostate; Molecular profiling; Post-chemotherapy response
To highlight the role of psychosocial variables in treatment decision making for patients with localized prostate cancer and how family physicians can be of most help to such patients in facilitating good treatment choices.
QUALITY OF EVIDENCE
PubMed was searched, and articles relevant to the psychosocial aspects of localized prostate cancer treatment decision making were included. Articles were excluded when they clearly specified inclusion of men with metastatic disease. This is not a systematic review, and recommendations made are drawn from studies of level II or III evidence.
The optimal strategy for managing localized prostate cancer has not been established and currently includes a number of potential options: active surveillance, radical prostatectomy, external beam radiotherapy, brachytherapy, and cryoablation. Consequently, men often struggle during the decision-making process, and some later regret their decisions. With an increased awareness of the psychosocial aspects of patient decision making, family physicians can help patients make better decisions.
Family physicians can help minimize the decisional regret experienced by patients after treatment by encouraging patients to consider their values and social supports, as well as the accuracy and appropriateness of the information used in the decision-making process.
The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the last 2 years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel, and abiraterone acetate), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimize delivery of care and long term outcomes in men with advanced CRPC.
castration-resistant prostate cancer; novel therapies; drug development; sipuleucel-T; cabazitaxel; abiraterone; denosumab; orteronel; MDV3100; ipilimumab
This review examines the development and efficacy of novel treatment options for advanced prostate cancer and discusses novel therapies that are on the horizon. Since the introduction of docetaxel as the standard treatment for patients with metastatic castration-resistant prostate cancer (CRPC), a number of different agents have been tested but failed to demonstrate improvement in overall survival (OS). Recently, three novel compounds have demonstrated OS benefit and one other showed reduction in skeletal-related events (SREs). Sipuleucel-T, a novel vaccine, was approved by the US regulatory authorities in April 2010 for patients with early advanced prostate cancer. A new taxane, cabazitaxel, and abiraterone acetate, an androgen biosynthesis inhibitor, have shown an OS benefit in advanced CRPC after docetaxel, leading to drug approval. A new bone-targeting agent, denosumab, a receptor activator of nuclear factor κB ligand (RANKL) antagonist, showed a modest reduction in SREs in comparison to zoledronic acid in patients with bone metastases. Other promising novel agents are currently being tested in the clinical setting of advanced CRPC. These include, androgen receptor inhibitors (MDV3100), androgen biosynthesis inhibitors, angiogenesis inhibitors (thalidomide, lenalidomine, aflibercept, tasquinimod), a novel form of radiotherapy (radium-223), and immune-modulating compounds (PROSTVAC-VF). Improvements in progression-free survival and OS rates, observed with novel agents, in metastatic prostate cancer have led to a shift in treatment paradigm. The challenge will be to position the current established and expected novel treatments in the new landscape of metastatic prostate cancer and to determine at what point and time in the disease course they can best be administered.
abiraterone; cabazitaxel; castration-resistant prostate cancer; MDV3100; sipuleucel-T; denosumab; zoledronic acid
Prostate-derived Ets factor (PDEF) is expressed in tissues of high epithelial content including prostate, although its precise function has not been fully established. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is, at present, no effective treatment for intervention in metastatic prostate cancer. These facts underline the need to develop new approaches for early diagnosis of aggressive prostate cancer patients, and mechanism based anti-metastasis therapies that will improve the outlook for hormone-refractory prostate cancer. In this study we evaluated role of prostate-derived Ets factor (PDEF) in prostate cancer.
We observed decreased PDEF expression in prostate cancer cell lines correlated with increased aggressive phenotype, and complete loss of PDEF protein in metastatic prostate cancer cell lines. Loss of PDEF expression was confirmed in high Gleason Grade prostate cancer samples by immuno-histochemical methods. Reintroduction of PDEF profoundly affected cell behavior leading to less invasive phenotypes in three dimensional cultures. In addition, PDEF expressing cells had altered cell morphology, decreased FAK phosphorylation and decreased colony formation, cell migration, and cellular invasiveness. In contrast PDEF knockdown resulted in increased migration and invasion as well as clonogenic activity. Our results also demonstrated that PDEF downregulated MMP9 promoter activity, suppressed MMP9 mRNA expression, and resulted in loss of MMP9 activity in prostate cancer cells. These results suggested that loss of PDEF might be associated with increased MMP9 expression and activity in aggressive prostate cancer. To confirm results we investigated MMP9 expression in clinical samples of prostate cancer. Results of these studies show increased MMP9 expression correlated with advanced Gleason grade. Taken together our results demonstrate decreased PDEF expression and increased MMP9 expression during the transition to aggressive prostate cancer.
These studies demonstrate for the first time negative regulation of MMP9 expression by PDEF, and that PDEF expression was lost in aggressive prostate cancer and was inversely associated with MMP9 expression in clinical samples of prostate cancer. Based on these exciting results, we propose that loss of PDEF along with increased MMP9 expression should serve as novel markers for early detection of aggressive prostate cancer.
Prostate cancer (PC) is the leading cause of cancer and the second leading cause of cancer-death among men in the Western world. About 10–20% of men with PC present with metastatic disease at diagnosis, while 20–30% of patients diagnosed with localized disease will eventually develop metastases. Although most respond to initial androgen-deprivation therapy (ADT), progression to castration-resistant PC (CRPC) is universal. In 2004 the docetaxel/prednisone regimen was approved for the management of patients with metastatic CRPC, becoming the standard first-line therapy. Recent advances have now led to an unprecedented number of new drug approvals within the past years, providing many new treatment options for patients with metastatic CRPC. Four new drugs have received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. The data supporting the approval of each of these agents are described in this review, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies.
prostate cancer; castration-resistance; sipuleucel-T; cabazitaxel; abiraterone; denosumab
Clinical decision for primary treatment for prostate cancer is dictated by variables with insufficient specificity. Early detection of prostate cancer likely to develop rapid recurrence could support neo-adjuvant therapeutics and adjuvant options prior to frank biochemical recurrence. This study compared markers in serum and urine of patients with rapidly recurrent prostate cancer to recurrence-free patients after radical prostatectomy. Based on previous identification of urinary sarcosine as a metastatic marker, we tested whether methionine metabolites in urine and serum could serve as pre-surgical markers for aggressive disease.
Urine and serum samples (n = 54 and 58, respectively), collected at the time of prostatectomy were divided into subjects who developed biochemical recurrence within 2 years and those who remained recurrence-free after 5 years. Multiple methionine metabolites were measured in urine and serum by GC-MS. The role of serum metabolites and clinical variables (biopsy Gleason grade, clinical stage, serum prostate specific antigen [PSA]) on biochemical recurrence prediction were evaluated. Urinary sarcosine and cysteine levels were significantly higher (p = 0.03 and p = 0.007 respectively) in the recurrent group. However, in serum, concentrations of homocysteine (p = 0.003), cystathionine (p = 0.007) and cysteine (p<0.001) were more abundant in the recurrent population. The inclusion of serum cysteine to a model with PSA and biopsy Gleason grade improved prediction over the clinical variables alone (p<0.001).
Higher serum homocysteine, cystathionine, and cysteine concentrations independently predicted risk of early biochemical recurrence and aggressiveness of disease in a nested case control study. The methionine metabolites further supplemented known clinical variables to provide superior sensitivity and specificity in multivariable prediction models for rapid biochemical recurrence following prostatectomy.
Metastatic involvement of the skeleton is a frequent consequence of advanced prostate cancer. These skeletal metastases cause a number of debilitating complications and are refractory to current treatments. New therapeutic options are being explored, including conditionally replicating adenoviruses (CRAds). CRAds are engineered to selectively replicate in and destroy tumor cells and can be “armed” with exogenous transgenes for enhanced potency. We hypothesized that a CRAd armed with osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, would inhibit the progression of prostate cancer bone metastases by directly lysing tumor cells and by reducing osteoclast activity. Although prostate cancer bone metastases are predominantly osteoblastic in nature, increased osteoclast activity is critical for the growth of these lesions. Ad5-Δ24-sOPG-Fc-RGD is a CRAd that carries a fusion of the ligand-binding domains of OPG and the Fc region of human IgG1 in place of the viral E3B genes. To circumvent low tumor cell expression of the native adenoviral receptor, an arginine-glycine-aspartic acid (RGD) peptide insertion within the viral fiber knob allows infection of cells expressing αv integrins. A 24-base pair deletion (Δ24) within viral E1A limits replication to cells with aberrant retinoblastoma cell cycle regulator/tumor suppressor expression. We have confirmed that Ad5-Δ24-sOPG-Fc-RGD replicates within and destroys prostate cancer cells and, in both murine and human coculture models, that infection of prostate cancer cells inhibits osteoclastogenesis in vitro. In a murine model, progression of advanced prostate cancer bone metastases was inhibited by treatment with Ad5-Δ24-sOPG-Fc-RGD but not by an unarmed control CRAd.
Adenovirus; bone metastasis; oncolytic virus; osteoprotegerin; prostate cancer; virotherapy
The risk of significant morbidity and mortality often outweighs the benefit of surgical resection as palliative treatment for patients with high systemic disease burden, poor cardiopulmonary status, and previous spinal surgeries. Minimally invasive surgical (MIS) approaches to decompressing metastatic epidural cord compression (MECC) can address these issues and thereby make palliation a feasible option for these patients.
We present the cases of three consecutively collected patients with severe neurological compromise secondary to lumbar epidural metastases who underwent MIS decompression and achieved improved functional outcome and quality of life. The first patient is a 23-year-old female with metastatic Ewing's sarcoma who presented with 2 weeks of a right foot drop and radiculopathic pain. The next case is that of a 71-year-old male with metastatic prostate cancer who presented with significant radiculopathic L5-S1 pain and severe motor deficits in his lower extremities. The last case is that of a 73-year-old male with metastatic hepatocellular carcinoma who presented with worsening left leg weakness, paresthesia, and dysethesia. Postoperatively, each patient experienced significant improvement and almost complete enduring return of function, strength, and resolution of pain.
We demonstrate that MIS approaches to spinal decompression as palliative treatment for metastatic disease is a viable treatment in patients with a focal symptomatic lesion and comes with the benefits of decreased surgical morbidity inherent to the minimally invasive approach as well as excellent functional outcomes.
Epidural metastases; Ewing's sarcoma; metastatic; palliation; spinal decompression