Prostate News

Prostate Cancer and Prostatic Diseases (2008) 11, 108–111; doi:10.1038/pcan.2008.24

Changing biopsy patterns affect Clinical trial recommendations screening predictive value In 1999, the Prostate-Specific Antigen Working Group A large body of literature establishes the contribution of offered consensus recommendations for the conduct prostate-specific antigen (PSA) screening to the improve- of clinical trials. Their focus was on the development ment of prostate cancer detection. However, much of the of trials for patients with progressive disease who had data derived from the early and mid 1990s, and since undergone castration specifically with regard to the use then prostate biopsy practice patterns have changed of PSA level. A year later, the New Guidelines to significantly. Early on the predictive power of PSA Evaluate the Response to Treatment in Solid Tumors screening depended on the high prevalence of the criteria were introduced from a broader and interna- disease, the higher prevalence of high-grade disease tional group of researchers. Their focus was on standar- and the low likelihood of prostate cancer diagnosis in dizing the criteria used in clinical trials to assess tumor men with low PSA titers. Biopsy factors that affect the response for all solid tumors, whether arising in the changes in value of PSA screening include the increased prostate or elsewhere. However, if trial outcomes were number of biopsy cores obtained routinely and changes based solely on either of these two sets of criteria, none of in how pathologists interpret biopsy samples. To the approved treatments for prostate cancer would be examine the cause and effect relationships more care- available to such patients. To resolve this discrepancy, the fully, a group of researchers from Weill-Cornell Medical Group examined the previous criteria and emerging trial Center carried out a retrospective analysis of prostate data and report their recommendations in the Journal of biopsy samples from their institution. Their results Clinical Oncology. appear in Cancer. The Working Group identified six areas in need of Of the 3634 prostate biopsies performed at the consensus with regard to clinical trials for evaluating investigators’ institution between 1993 and 2005, 1607 drugs to treat prostate cancer: categorizing the clinical satisfied the inclusion and exclusion criteria and were spectrum from diagnosis to metastasis, defining thera- included in the study. Specimens were divided into three peutic objectives, establishing eligibility criteria for time cohorts: 1993 through 1997, 1998 through 2001 and enrollment, standardizing treatment duration, measur- 2002 through 2005. The number of biopsies performed, ing and reporting outcomes and developing phase III the percentage of positive biopsy results, and patient age clinical trials. In establishing enrollment criteria, they did not change significantly over time. However, emphasize the need to authenticate disease progres- significant changes that did occur over time included sion by establishing pretreatment assessments and decreased median PSA level in patients undergoing identifying standard criteria for establishing disease biopsy (from 7.0 to 5.5 ng/ml) and increased median progression for entry, as well as emphasizing the need number of biopsy cores obtained (from 8 to 14). to define clinical subtypes based on patterns of spread Significant changes in biopsy indication over time and to assess prognosis. With regard to treatment included a smaller percentage of biopsies performed duration, they stress the importance of ensuring a because of suspicious digital rectal examination (DRE) sufficient window of drug exposure and of reducing results (from 46 to 27%) and an increased percentage of the reliance on early changes in PSA levels as well as the patients undergoing biopsy because of a PSA titer need to confirm time-to-event outcomes. Their recom- between 2.5 and 3.99 ng/ml (from 8 to 13%). The authors mendations have two overall objectives: (1) to control, conclude that biopsy practice patterns have improved relieve or eliminate the disease manifestations that are the detection of prostate cancer in men with normal DRE present when treatment is initiated; and (2) to prevent results, in particular in those whose PSA levels are or delay those disease manifestations that are expected between 2.5 and 3.99 ng/ml. These conclusions suggest to occur. that the predictive value of PSA testing with normal DRE results is lost. Original research paper Original research paper Scher HI et al. Design and end points of clinical trials for Schwartz MJ et al. Negative influence to changing biopsy patients with progressive prostate cancer and castrate practice patterns on the predictive value of prostate- levels of testosterone: recommendations of the Prostate specific antigen for cancer detection on prostate biopsy. Cancer Clinical Trials Working Group. J Clin Oncol 2008; Cancer 2008; e-pub ahead of print 10 March. 26: 1148–1159. AR, black men and prostate cancer a group of British researchers carried out an extensive 109 review of the literature and report their results in the Among the known risk factors for prostate cancer are a British Journal of Cancer. family history of the disease and African ancestry. Thus, The authors searched eighteen electronic databases, the search for genetic risk factors is ongoing, and one of which produced 935 citations, from which 22 reports of the most studied genes in this regard is the androgen 17 studies (for a total of 3627 randomized patients) were receptor (AR) gene. In particular, research has shown an included in the analysis of effectiveness and safety. An inverse relationship between the lengths of the CAG and additional three studies, with a total of 82 patients, were GGN repeats in the gene and AR activity levels. Indeed, examined to analyze the relationship with either effec- studies comparing the distribution of allele sizes for tiveness or safety and dose of estrogen. The study these repeat polymorphisms in different populations characterizes the included trials as ‘generally poorly demonstrated shorter repeat lengths, overall, in men of reported or of poor quality’ and examines three studies African versus those of European descent. However, in particular, for a total of 1394 patients, that used only limited studies have examined the association polyestradiol phosphate, 240 mg/month. Given the between these AR repeat polymorphisms and the risk dearth of evidence of good quality that the authors of prostate cancer in black men. Writing in the Journal of discovered in their review, they were not able to draw Human Genetics, Lange and associates report their results any clear conclusions regarding the effectiveness and from an examination of this association, the first such safety of parenteral estrogen compared with other types study to do so. of hormone therapy. Indeed, the researchers call for The investigators used data from the Flint Men’s studies that directly compare the adverse event profile of Health Study, a community-based study of prostate parenteral estrogen with that of LHRH, with particular cancer in black men 40–79 years of age, which recruited attention paid to the accurate assessment of cardio- 730 men to participate in 1996. Of those 730 men, vascular morbidity and mortality, especially with regard genotype data for at least one of the AR repeats were to existing cardiovascular disease status and the meta- available for 131 patients with prostate cancer and 340 static status of the prostate cancer. controls. The mean number of repeats was similar for cases and controls for both repeats: CAG, 19.92 for cases and 19.91 for controls; GGN, 15.76 for cases and 15.41 Review article for controls. The authors conclude that their investiga- tions showed no significant evidence of an association Norman G et al. Parenteral estrogen in the treatment of between the shorter alleles for the two polymorphisms prostate cancer: a systematic review. Br J Cancer 2008; 98: and an increased risk of prostate cancer in this popula- 697–707. tion of African-American men. Further, they suggest that their results using AR CAG and GGN repeat lengths are not independent and that future studies should consider modeling the effects of the two repeats together as well The effect of PSA screening as separately. Among all cancers, PSA is one of the few molecular markers used routinely to detect, stratify the risk of and monitor a common disease. Although PSA is specific to the prostate, it is not specific to prostate cancer; indeed, Original research paper BPH and other benign diseases of the prostate also result Lange EM et al. The androgen receptor CAG and GGN in increased levels of PSA. In fact, most men with repeat polymorphisms and prostate cancer susceptibility increased levels of PSA do not have prostate cancer. The in African-American men: results from the Flint Men’s effect of PSA screening on treatment and prognosis has Health Study. J Hum Genet 2008; 53: 220–226. been profound since its inception in the early 1990s. In a recent issue of Nature Reviews Cancer, Lilja and colleagues examine the current evidence for the association between PSA level and risk of prostate cancer, disease outcome Is parenteral estrogen effective? and recurrence. They also examine the use of PSA screening for the long-term prediction of prostate cancer Androgen deprivation therapy is one of the few treat- and the use of PSA derivatives to improve PSA testing. ment options when prostate cancer is not amenable to The authors begin by evaluating the evidence regard- potentially curative therapy. Thus, many approaches to ing the biology of PSA, noting in particular that the two achieving a reduction in the circulating levels of human kallikrein genes that show major changes androgens exist, including surgical options (for example, through mammalian evolution, KLK3 and KLK2, have orchidectomy) and medical options. The medical options been found in primates and that the latter also has been are several and include treatment with luteinizing found in dogs, which is notable because dogs and hormone-releasing hormone (LHRH) and oral estrogen humans are two of the few species in which prostate therapy. Indeed, these medical options are as effective as cancer and BPH develop spontaneously. With regard to orchidectomy in achieving castrate levels of testosterone. the role of PSA in early detection and screening of the However, the side effects of medical androgen depriva- disease, the investigators note that it strongly discrimi- tion therapy increasingly are a cause for concern because nates different disease stages: PSA levels are higher in of long-term toxicity, specifically osteoporosis and patients with localized disease than in those who are cardiovascular system toxicity. To investigate the clinical cancer free, are associated with stage and grade of effectiveness and safety of parenteral estrogen therapy, localized disease and are higher in those with metastatic

Prostate Cancer and Prostatic Diseases 110 compared with those with localized disease. Evidence TREK-1: a novel marker also indicates that although PSA level is a sensitive indicator of recurrence after radical prostatectomy, it is Given the widespread prevalence of prostate cancer in less useful as an indicator after radiotherapy. To improve the US and the palliative nature of treatment after the the accuracy of screening, many researchers are explo- disease spreads, the search for novel molecular targets ring the possibility of combining conventional PSA in the diagnosis and treatment is as important as ever. A testing with PSA derivatives, such as PSA density. In group of researchers at Columbia University, writing in examining the future of PSA research, the authors note Cancer Research, present the results of their investigation the possibility of anticancer drugs being developed that into TREK-1, a lipid-sensitive member of the potassium are linked to an inhibitory peptide that is removed by channel family that is voltage and time dependent. PSA-activated cleavage. The authors chose TREK-1 as the target of their investigation because of its differential regulation by different lipid metabolites in normal or malignant prostate epithe- Review article lium, which may alter the function of this potassium channel and may result in changes in cell proliferation. Lilja H et al. Prostate-specific antigen and prostate cancer: First, the authors investigated the expression of TREK-1 prediction, detection and monitoring. Nat Rev Cancer in both human prostate tissues and cell lines, including 2008; e-pub ahead of print 13 March 2008. normal prostate epithelium and the PC3 prostate cancer cell line. They found that 78% of nontumoral tissue samples, including BPH samples, showed weak and Does hypoxia protect tumors? heterogenous TREK-1 expression, whereas all prostatic intraepithelial lesions and invasive prostatic carcinomas Although intuitively, inefficient blood flow may seem expressed TREK-1 in a high proportion of tumor cells. like a flaw in solid tumor structure, in fact, evidence They also observed that increased proliferation in normal suggests that the tumor vasculature may act as a cells is induced by overexpression of TREK-1. Second, protective net against destruction. In prostate tumors, the investigators overexpressed TREK-1 heterologously both immunomolecular imaging and physical measure- and used a dominant-negative TREK-1 to knock down its ment of molecular markers of hypoxia have provided endogenous expression. Their evaluation of these evidence of tumor hypoxia. Reviewing more than 200 changes in normal prostate epithelium and the PC3 cell articles for Cancer Treatment Reviews, a group of Irish lines showed that proliferation was reduced to a near- researchers examined the evidence regarding the occur- normal level. The researchers conclude that increased rence, role and routine clinical importance of hypoxia in TREK-1 expression can occur in early-stage prostate prostate tumors. In particular, they focused on the cancer. Further, this overexpression and its correlation molecular pathways involved in the induction of gene with disease stage and grade, make this potassium expression in response to hypoxia. channel a potential tumor marker and novel target for The authors first examine the clinical relevance of therapy. They recommend that future studies also should hypoxia in prostate cancer, noting that recognition of the investigate the presence of TREK-1 in other types of role of hypoxia in disease progression may facilitate cancer. the identification of new biomarkers we well as the development of novel therapies. The key to examining hypoxia is understanding its molecular signature, hypoxia- inducible factor 1. Whether hypoxia acts as a shield against Original research paper cellular destruction may be accomplished by facilitating et al reduced oxidative defense, influencing tumor progression, Voloshyna I . TREK-1 is a novel molecular target in Cancer Res 68 promoting gene instability and protecting the tumor from prostate cancer. 2008; : 1197–1203. the induction of apoptosis. Further, evidence suggests that hypoxia also may act as a shield against androgen deprivation by inducing androgen hypersensitivity and Isosilybin B causes AR degradation triggering androgen resistance. The researchers also examine the evidence indicating that hypoxia may protect When prostate cancer becomes locally advanced or tumors from both chemotherapy agents and radiation metastatic, few treatment options exist; the most com- insult. Hypoxia is emerging as a common feature of mon treatment is surgical or chemical ablation of prostate tumors, which appear able to turn the poor androgens. Researchers thus have focused on methods oxygenation into a survival advantage. Thus, the authors of controlling AR signaling to improve the survival rates conclude that novel therapies that target the hypoxic areas of patients, in particular before the disease becomes of tumors not only may improve the therapeutic ratio hormone refractory. However, only reducing the levels of when conventional treatments fail, but also may be useful circulating androgens or using antiandrogens may not be as preventative treatments or for tumors detected at an sufficient to ablate AR signaling entirely. To investigate early stage. the use of nontoxic phytochemicals in achieving such effects on AR signaling, Deep and colleagues examined the antiandrogenic activity of isosilybin B, a flavono- Review article lignan derived from milk thistle seeds. Their results appear in Oncogene. Marignol L et al. Hypoxia in prostate cancer: a powerful Of all the flavonolignans isolated and purified from shield against tumor destruction? Cancer Treat Rev 2008; milk thistle seeds, researchers have shown that isosilybin e-pub ahead of print 9 March 2008. B is the most potent, particularly in inhibiting PSA

Prostate Cancer and Prostatic Diseases secretion. Thus the authors carried out detailed mechan- but not the stromal, compartment of normal prostate and 111 istic studies using isosilybin B and three of its isomers in ovarian tissues and that the levels are decreased in androgen-dependent LNCaP, LAPC4 and 22Rv1 prostate advanced prostate and ovarian cancer metastases. The cancer cells, all of which demonstrate functional AR authors investigated whether decreased MKK4 protein signaling. Not only did isosilybin B prove to be the most expression resulted from posttranscriptional regulatory effective in decreasing both intracellular and secreted events by examining the mechanisms that control its PSA levels in all of the cells lines, but it also did not alter expression in the high MKK4-expressing cancer cells AR or PSA levels in nonneoplastic human prostate lines LNCaP and C4-2 and in the low MKK4-expressing epithelial cells, indicating that isosilybin B has a selective lines DU145, PC3, DuPro. Northern blot analysis showed response only toward prostate cancer cells. The effect that comparable levels of MKK4 mRNA are present in persisted even after isosilybin B withdrawal. Further, the both high- and low-expressing prostate cancer cell lines. researchers found strong G1 arrest and growth inhibition However, the differences between relative levels of by isosilybin B in LNCaP cells, which they suggest may MKK4 protein and mRNA suggests that a posttranscrip- be the result of antagonism of AR signaling. The results tional mechanism regulates the steady-state level of also showed that isosilybin B increases Akt-mediated MKK4 protein. The investigators used Northern blotting phosphorylation of Mdm2. The authors suggest that to determine whether the decreased MKK4 protein further investigation into the role of activated Akt in AR production in cancer cells is the result of mechanisms degradation as a result of phytochemical action is involving RNA transport or translation and found that needed, as is investigation of the role of isosilybin B. MKK4 mRNA is nuclear in both PC3 and LNCaP lines. They further report that MKK4 mRNA in high MKK4- expressing cells (LNCaP and C4-2) was preferentially Original research paper associated with polysomes of a higher molecular weight compared with that of low MKK4-expressing cells Deep G et al. Isosilybin B causes androgen receptor (PC3 and DuPro), thus establishing that translational degradation in human prostate carcinoma cells via PI3K- regulation is crucial in the control of MKK4 protein levels Akt-Mdm2-mediated pathway. Oncogene 2008; e-pub in metastatic cells. The authors’ future goals include ahead of print 10 March 2008. identifying the regulatory elements of the MKK4 mRNA sequence and the translation-regulatory molecules that function by interacting with MKK4 mRNA. Regulation of a kinase kinase The search to understand the regulatory mechanisms of signaling kinases involved in the regulation of metastatic Original research paper growth are particularly important in prostate cancer, Robinson VL et al. Mitogen-activated protein kinase given the inevitable consequences of the disease when it kinase 4/c-Jun NH2-terminal kinase kinase 1 protein becomes metastatic. One dual-specificity kinase that has expression is subject to translational regulation in been identified as having a role in the regulation of prostate cancer cell lines. Mol Cancer Res 2008; 6: 501–508. metastases is mitogen-activated protein kinase kinase 4/ c-Jun NH2-terminal kinase kinase 1 (MKK4). Robinson and colleagues investigated the presence and regulatory mechanisms of MKK4 in prostate cancer cell lines and Acknowledgment report their results in Molecular Cancer Research. Previous immunohistochemical studies found that Research Highlights is sponsored by an educational high levels of MKK4 protein are present in the epithelial, grant from AstraZeneca.

Prostate Cancer and Prostatic Diseases