Saposin C stimulates growth and invasion,activates p42/44 and SAPK/JNK signaling pathways of MAPK and upregulates uPA/uPAR expression in prostate cancer and stromal cells

Aim:To determine the effect of saposin C (a known trophic domain of prosaposin) on proliferation,migration and invasion,as well as its effect on the expression of urokinase plasmonogen activator (uPA),its receptor (uPAR) and matrix metalloproteinases (MMP)-2 and -9 in normal and malignant prostate cells.In addition,we tested whether saposin C can activate p42/44 and stress-activated protein kinase/c-Jun NH_2-terminal kinase (SAPK/JNK) signal transduction pathways of the mitogen-activated protein kinase (MAPK) superfamily.Methods:We employed West- ern blot analysis,phospho-specific antibodies,cell proliferation assay,reverse transcriptase-polymerase chain reaction, in vitro kinase assays and migration and invasion to determine the effect of saposin C on various biological behaviors of prostate stromal and cancer cells.Results:Saposin C,in a cell type-specific manner,upregulates uPA/uPAR and immediate early gene c-Jun expression,stimulates cell proliferation,migration and invasion and activates p42/44 and SAPK/JNK MAPK pathways in prostate stromal and cancer cells.Normal prostate epithelial cells were not responsive to saposin C treatment in the above studies.Conclusion:Saposin C functions as a multipotential modulator of diverse biological activities in prostate cancer and stromal cells.These results strongly suggest that saposin C functions as a potent growth factor for prostatic cells and may contribute to prostate carcinogenesis and/or the development of hormone-refractory prostate cancer.

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

Potential synergistic implications for stromal-targeted radiopharmaceuticals in bone-metastatic prostate cancer

Genetic heterogeneity and chemotherapy-resistant ＇stem cells＇ represent two of the most pressing issues in devising new strategies for the treatment of advanced prostate cancer. Though curative strategies have long been present for men with localized disease, metastatic prostate cancer is currently incurable. Though substantial improvements in outcomes are now possible through the utilization of newly approved therapies, novel combinations are clearly needed. Herein we describe potentially synergistic interactions between bone stromal-targeted radiopharmaceuticals and other therapies for treatment of bone-metastatic prostate cancer. Radiation has long been known to synergize with cytotoxic chemotherapies and recent data also suggest the possibility of synergy when combining radiation and immune-based strategies. Combination therapies will be required to substantially improve survival for men with castrate-resistant metastatic prostate cancer and we hypothesize that bone-targeted radiopharmaceuticals will play an important role in this Drocess.

Treatment sequencing in metastatic castrate-resistant prostate cancer

Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer （mCRPC）. Front-line therapeutic options for mCRPC include docetaxel, sipuleuceI-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.

Radium-223 in metastatic castration resistant prostate cancer

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer （mCRPC）. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleuceI-T, cabazitaxel, abiraterone, enzalutamide and （most recently） radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer （e.g. samarium-153 and strontium-89）, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

Management of localized prostate cancer： the pendulum swings （back to the middle）

Herein, we discuss 18-year follow-up data from the Scandinavian ProstateCancer Group-4 （SPCG-4） trial, a randomized study comparing observation and radical prostatectomy （RP） in patients with localized prostate cancer. The results of this study are contrasted with another study employing a similar randomization, the Prostate Cancer Intervention Versus Observation Trial （PIVOT）. We highlight several key differences in study eligibility and enrollment that may account for distinct results, and describe how these datasets impact the complex landscape of therapy for localized prostate cancer.

Reappraisal of glucocorticoids in castrate-resistant prostate cancer

Recent reports and discussions of .preclinical prostate cancer models have emphasized the possibility that enzalutamide resistance may be mediated by glucocorticoid receptors （GR）.In both in vitro and xenograft animal studies, it is possible to show that the GR is up-regulated in prostate cancer cell lines and that dexamethasone reverses enzalutamide induced growth inhibition. In these model systems, GR agonists can induce a subset of androgen receptor target genes including prostate-specific antigen. These investigators also report a correlation between GR expression in patient-derived prostate cancer specimens and clinical response to enzalutamide. The authors discuss the possibility that these findings have important clinical relevance. We note that the current clinical evidence for GR mediating drug resistance or disease progression in patients with castrate-resistant prostate cancer （CRPC） is very limited at best.

Randomized studies of PSA screening： an opinion

The issue of prostate cancer screening with prostate-specific antigen （PSA） has been contentious for nearly two decades due to lack of data from randomized trials, but that has now changed. A brief review of the available data is warranted as there is finally some clarity on this critically important topic. Knowing what to ignore, as well as what to focus on, is critical for understanding the current data.

Long-term survival of participants in the prostate ：ancer prevention trial

The Prostate Cancer Prevention Trial （PCPT） is a seminal study in the field of urology. More than 10years after its initial publication, updated data from this trial continue to shape our understanding of prostate cancer. Among the major findings from the PCPT has been the demonstration that prostate cancer is common in men with prostate-specific antigen （PSA） once thought to be in the normal range,~ finasteride prevents the development of benign prostatic hypertrophy,2 it increases the sensitivity of PSA3 and digital rectal examination.4 Furthermore the PCPT helped to establish the link between erectile dysfunction and cardiovascular disease,5 and perhaps most importantly finasteride demonstrated a 25% relative risk reduction in the diagnosis of prostate cancer compared with placebo.

Implications of the prostate intervention versus observation trial （PIVOT）

PSA screening improves early detection of prostate cancer but can lead to overtreatment if all of these cancers are treated. The first randomized treatment study for men with PSA detected cancers has now been reported.

Stromal targeted therapy in bone metastatic prostate cancer： promise delivered

The ability of epithelial neoplasms to evade both hormonal and cytotoxic therapies is self-evident as the common carcinomas （lung, stomach, breast, colon and prostate） at their metastatic stage are rarely curable with current therapies. Though the precise reasons for incurability are debated,

Denosumab in bone-metastatic prostate cancer： known effects on skeletal＇related events but unknown effects on quality of life

The purpose of new pharmaceuticals is to improve how patients feel, function or survive. Exceptions exist when surrogates are developed and we know that those surrogates correlate well with one of the above. Hypercholesterolemia is a well-accepted example. We know that high cholesterol is a reasonable indicator that results in increased risk of strokes and heart attacks. Thus, we treat hypercholesterolemia in hopes that our patients＇ health will improve.

Twists and turns on the way to progress in metastatic castrate-resistant prostate cancer

Harnessing the body＇s immune system for the treatment of metastatic cancer has been a dream since the late 19th century [1]. Since that time progress has been intermittent and mostly disappointing. Interferon and Interleukin-2 represented steps forward but in retrospect the steps were not large and rarely are these agents used in the clinic today except as the control arm of randomized studies designed to demonstrate that a new drug is better.

Experimental therapeutics in prostate cancer： where are Ne now and where do we need to go

The explosion of new therapeutics in metastatic castrate-resistant prostatecancer （mCRPC） is unprecedented, but much more work needs to be done before we are satisfied. Six phase III trials with an overall survival impact have now been reported （Table 1）.1-6 Four of these trials were exclusively or predominantly in the mCRPC post-docetaxel space （MDV3100, abiraterone, 223radium and cabazitaxel）. The 223radium trial also uniquely offered therapy to patients who were unsuitable for or refused docetaxel. The sipuleucel-T trial focused on mCRPC patients who were asymptomatic or minimally symptomatic; most of these patients were chemotherapy naive.

前列腺癌治疗: ^(177)Lu-PSMA-617的注意事项、观点和局限性

^(177)Lu-前列腺特异膜抗原(PSMA)-617的临床Ⅲ期VISION研究对前列腺癌的诊疗及临床管理具有广泛影响。转移性前列腺癌诊疗领域发展迅速,具有多种成熟的治疗方法,包括化疗、激素治疗、免疫治疗、放射性药物及靶向治疗。现行诊疗方案来源于一系列重要的关键性临床Ⅲ期试验,这些试验通常采用总生存期为研究终点。为了更好地理解在去势抵抗性前列腺癌患者中进行的VISION研究,有必要彻底了解该研究设计的决策基础及内容。因此该文将介绍VISION临床Ⅲ期试验的关键要素以及这些要素对监管决策和临床实践的影响。研究的纳入和排除标准以及治疗、评估和终点事件等也将重点介绍。令人印象深刻的是,VISION试验对只有少数治疗方案可选择的晚期前列腺癌患者仍能明显提高生存期。除了取得的重大进展外,该研究也存在重大的局限性。^(177)Lu-PSMA-617将对前列腺癌治疗产生深远的影响。基于VISION数据,2022年3月23日美国食品与药品监督管理局(FDA)批准177Lu-PSMA-617用于前列腺癌的治疗。

Cancer-derived C-terminus-extended p53 mutation confers dominant-negative effect on its wild-type counterpart

The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert ‘dominant-negative’ effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named ‘p53-374*48’ and ‘p53-393*78’) as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity.

Androgen receptor variant-7： an important predictive biomarker in castrate resistant prostate cancer

The recent manuscript in New England Journal of Medicine by Antonarakis et al. has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 （AR-V7）, in circulating tumor cells （CTCs） from metastatic castrate-resistant prostate cancer （mCRPC） patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen （PSA） responses.