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PubMed2026

Integrated signatures define mutational processes in prostate cancer.

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Journal Article↗

PubMed2006

Therapeutic vaccines for prostate cancer.

Prostate cancer is the most common, noncutaneous cancer for men in the U.S., leading to more than 30,000 deaths a year. Vaccines for prostate cancer, which for several years have been shown to generate immunologic responses, are beginning to show significant clinical promise. At present, numerous therapeutic options are being investigated, including autologous and allogeneic whole-tumor cell vaccines, dendritic cell vaccines, and poxvirus-based vaccines. Advances in basic immunology have translated into new, more complex therapeutic strategies. The findings from current trials and the demonstrated potential to combine vaccines with conventional therapies herald a promising future for the treatment of prostate cancer. This review highlights recent advances and clinical trials in immunotherapy for prostate cancer, along with current thoughts on immunologic and clinical monitoring of these trials.

Cancer Vaccines↗

PubMed1996

Epidemiology of prostate cancer.

Prostate cancer is currently one of the most common malignancies worldwide. The incidence of prostate cancer has risen dramatically over the last decade, more so than can be explained by increasing longevity. Mortality rates have also risen, though not as dramatically. There is a wide geographic variation in the incidence of clinical prostate cancer, with higher rates in the United States than in China. One risk factor which could explain this variation is the high fat intake associated with a Western diet. It is also apparent that prostate cancer is now being detected at less advanced stages than in the past. Increased awareness of the disease and improved detection methods are thought to contribute to this earlier detection.

Diet↗

PubMed1999

Androgen receptor gene mutations in hormone-refractory prostate cancer.

Prostate cancer is considered to be one of the most hormone-dependent human malignancies. As a key mediator of hormonal response, the androgen receptor (AR) is believed to have an important role in the progression of prostate cancer. Mutations in the coding region of the AR gene have been found in both untreated and hormone-refractory prostate cancer, but the frequency of such mutations at different stages of the disease is poorly documented and even contradictory results have been published. In the present study, the frequency of AR gene mutations was determined in 30 locally recurrent and two metastatic hormone-refractory prostate tumours using the polymerase chain reaction (PCR), non-radioactive single strand conformation polymorphism (SSCP), and sequencing. The length of the polymorphic CAG repeat, which is inversely correlated with the ability of the AR to activate transcription, was also analysed as well as the GGC repeat. Twelve samples were known to contain an AR gene amplification. Altogether, one point mutation (Gly(674)-->Ala) and one microsatellite mutation (CAG(20)-->CAG(18)) were found, both in cancers containing the AR gene amplification. The mean lengths of the polymorphic CAG and GGC repeats were similar to those observed in the normal population. These results favour the view that mutations in the AR gene are rare in hormone-refractory prostate cancer and do not play an important role, at least, in local relapse. Instead, the amplification and consequent overexpression of the wild-type AR gene seem to be the most common alteration involving the AR in hormone-refractory prostate cancer.

Carcinoma↗

PubMed2000

[Clinical features of multiple primary cancers including prostate cancer].

We analyzed the clinical features of multiple primary cancers (MPCs) that included prostate cancer. MPCs were observed in 93 (15.2%) of the patients suffering from prostate cancer. In the MPC group, the organ most commonly involved was the stomach, followed by bladder, colon and lungs. The median age at diagnosis of the first, second and third cancers was 72, 74, and 75 years old, respectively, and the duration between the first and second cancers (median: 20 months) was longer than that between the second and third cancers (median: 8 months). In the 37 MPC patients whose cause of death was obvious, 29 (78.4%) died of a cancer; prostate cancer was not so common (6 patients) as the cause of death. Age at diagnosis and grade distribution of prostate cancer were not significantly different between the MPC and single primary cancer (SPC) groups. However, the proportion of earlier stage was significantly (p < 0.01) higher in the MPC group than in the SPC group, and this trend was more obvious in patients whose prostate cancer was diagnosed as the second cancer. The prostate cancer-specific survival rates were significantly higher in the patients with MPC, and this trend was more obvious in the patients with stage D or moderately differentiated cancer. It is important in the follow up of prostate cancer patients to be aware of the possibility of the occurrence of a second cancer.

Age Factors↗

PubMed2003

Strategies for the development of PSA-based vaccines for the treatment of advanced prostate cancer.

Prostate cancer is the second leading cause of cancer death in males in the USA. Vaccine strategies represent a novel therapeutic approach. One potential target for a prostate cancer vaccine is prostate-specific antigen (PSA), due to its restricted expression in prostate cancer and normal prostatic epithelial cells. A number of PSAspecific epitopes have been identified that can activate cytotoxic T-lymphocytes (CTLs) and in turn lead to the killing of tumor targets by the peptide-specific CTLs. Strategies have now been employed in clinical trials using RNA-pulsed dendritic cell vaccines, recombinant protein vaccines, and recombinant viral vector delivery of vaccines. Newer approaches incorporating costimulatory molecules that enhance Tcell activation are also being investigated.

Cancer Vaccines↗

PubMed2001

Androgen receptor signaling in androgen-refractory prostate cancer.

Prostate cancer is the second most prevalent cancer in males in the United States. Standard therapy relies on removing, or blocking the actions of, androgens. In most cases, this therapy results in a regression of the cancer because the prostate and most primary prostate tumors depend on androgens for growth and the avoidance of apoptosis. However, a portion of the cancers eventually relapse, at which point they are termed "androgen refractory" and can no longer be cured by conventional therapy of any type. The precise molecular events that lead from androgen-sensitive prostate cancer to androgen-refractory prostate cancer are, therefore, of great interest. This review seeks to identify specific molecular events that may be linked directly to the progression to androgen-refractory cancer. Some of the mechanisms appear to involve the androgen receptor (AR) directly and include mutations in, or amplification of, the AR gene in a manner that allows the AR to respond to low doses of androgens, other steroids, or antiandrogens. In a less direct manner, coactivators may increase the sensitivity of the AR to androgens and even other nonandrogenic substances through a number of mechanisms. Additional indirect mechanisms that do not result from mutation of the AR may involve activation of the AR by peptide growth factors or cytokines or may involve bypassing the AR entirely via other cellular pathways. Identification of the role of these mechanisms in the progression to androgen-refractory prostate cancer is critical for developing therapies capable of curing this disease.

Androgens↗

PubMed2005

Exisulind in the treatment of prostate cancer.

Prostate cancer represents the most common noncutaneous malignancy in men. With the widespread use of prostate-specific antigen screening, as many as one in six men in the USA will be diagnosed with prostate cancer. Significant healthcare resources are currently devoted to the treatment of this disease, specifically aimed at improving the side effects of successful treatment. Surgery or radiation therapy provides the best chance of cure from this disease. However, as many as 50% of patients treated with curative intent will develop a recurrence 10-15 years following treatment. Hormonal ablation via medical or surgical castration provides disease control, but is associated with significant hot flushes, loss of libido and impotence. Selective, apoptotic antineoplastic drugs, such as exisulind, may provide an alternative method to treating or preventing prostate cancer. This drug profile reviews the evidence for the use of exisulind in the treatment of prostate cancer.

Antineoplastic Agents↗

PubMed1996

Molecular cytogenetics of prostate cancer.

Prostate cancer is the most common malignancy among men in many developed countries. One-fourth of prostate cancers are diagnosed at metastatic stage but there is no curative treatment for such disease and palliative androgen withdrawal therapy remains the most used one. Thus, understanding the molecular events that underlie the development and progression of prostate cancer could help to answer many clinical questions on its treatment. In this review article, I want to illustrate some of the most interesting findings (by fluorescence in situ hybridization and comparative genomic hybridization) in the molecular cytogenetics of prostate cancer.

Aneuploidy↗

PubMed1996

APC gene mutations in human prostate cancer.

Prostate cancer is the most common cancer in aged men. Although ras and p53 gene mutations have been detected in some prostate cancers, the major genetic alterations involved in its carcinogenesis are not well understood. Mutation of the APC gene is responsible for colorectal tumors in which ras and p53 mutations are also often involved. Using PCR-SSCP analysis and sequencing, we examined 31 human primary prostate cancers (three cases at stage A, 10 at stage B, five at stage C and 13 at stage D) and four cases of lymph node metastasis from the stage D cases, for mutations in the APC gene. A mutation was detected in only one of the 35 samples (3%). This mutation, present in a primary stage B cancer, had a T to C transition in exon 15 at the first position of codon 956, resulting in substitution of histidine for tyrosine. This study clarified that APC gene mutations are not largely involved in the development of clinical prostate cancer.

Adult↗

PubMed2006

Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer.

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.

Calcium↗

PubMed2004

Newer therapies in advanced prostate cancer.

Prostate cancer is a leading cause of morbidity and mortality among males. Androgen ablation as initial therapy for advanced prostate cancer provides high response rates but does not cure disease, as nearly all men with metastases will eventually progress to hormone-refractory prostate cancer (HRPC). Present chemotherapy regimens for HRPC can provide palliation and have recently demonstrated an increase in overall survival. Over the past 2 decades, these regimens represent clear advances in the treatment of metastatic prostate cancer but also demonstrate that newer therapies are needed. Studies are ongoing to provide viable alternatives among traditional cytotoxic therapies as well as among novel agents targeting specific molecular pathways. This article reviews some of the newer therapies being developed and evaluated, including the epothilone analogues, human epidermal growth factor receptor pathway inhibitors, angiogenesis inhibitors, and endothelin receptor antagonists.

Angiogenesis Inhibitors↗

PubMed1997

Prostate cancer.

Prostate cancer accounted for over 41,000 deaths in the United States in 1996. Prostate-specific antigen (PSA) screening is capable of detecting prostate cancer and appears to detect cancers that are both clinically significant as well as organ-confined, and therefore potentially curable. The positive predictive value of PSA value has been increased by the use of the free-to-total PSA ratio. The early detection of a large number of nonpalpable tumors has mandated the development of new risk assessment schemas, which include nomograms and equations in which Gleason score, PSA, and clinical stage play a prominent role. Definitive answers to the question of watchful waiting versus intervention await conclusion of the prostate cancer intervention-versus-observation trial. For both radical prostatectomy and radiation therapy, one means of potentially reducing the risk of relapse is the use of androgen deprivation. Neoadjuvant androgen deprivation prior to surgery results in a lower incidence of positive surgical margins, but impact on survival is unknown. By contrast, the use of concurrent androgen deprivation appears to be associated with enhanced survival in patients treated with definitive radiotherapy. For good risk tumors, modem brachytherapy results in freedom from biochemical relapse rates similar to those observed with surgery and external beam radiation therapy. The best therapy for patients with positive margins or serologic progression, including radiation therapy, remains to be identified. The widespread availability of PSA testing has led to an empirically driven redefinition of advanced disease and includes patients with earlier stage disease in which primary treatment has failed. In these patients, debate remains as to whether combined androgen deprivation is superior to monotherapy. A comparison of flutamide with bicalutamide awaits maturation of survival data. The utility of antiandrogen withdrawal in patients with progressive disease despite androgen deprivation has been confirmed. Thereafter, second-line hormonal maneuvers may be appropriate. In patients with truly hormone refractory prostate cancer, a variety of nonhormonal agents, including estramustine-based therapy, suramin, mitoxantrone, and doxorubicin-based regimens have demonstrated activity and remain as options.

Antineoplastic Agents↗

PubMed1992

[Epidemiology of prostate cancer].

Prostatic cancer is frequent in elderly men. The incidence of "clinical" cancer varies greatly in different regions of the world. The highest incidences have been reported in black populations in North America and the lowest incidences are observed in Asian populations. "Subclinical" cancer is much more frequent than "clinical" cancer. Among the subclinical forms, the prevalence of carcinoma in situ varies only slightly from one region to another and is constant beyond the age of 40 years. Different aetiological factors are therefore probably involved in these two forms of prostatic cancer. The corrected 5-year survival for all patients with prostatic cancer in France is 41 to 47%. These poor results can probably be attributed to the very advanced stage of the disease at the time of diagnosis. Dietary, toxic, infectious, hormonal and genetic factors have been suggested in the aetiology of prostatic cancer, but the results of the various studies conducted are sometimes contradictory. In the absence of any known risk factors, primary prevention cannot be envisaged. Secondary prevention by means of screening raises certain problems due to the poor understanding of the natural history of the disease.

Environmental Exposure↗

PubMed1998

Primary care screening for prostate cancer.

Prostate cancer is second only to lung cancer among killers of men in the United States. Researchers continue to develop tests that are more sensitive for diagnosing prostate cancer. At present, primary care assessment and evaluation of the disease are determined by physical evidence that may not be apparent and by laboratory values that may not be truly reflective of the underlying disease process. Men over the age of 40 need an annual evaluation for increased prostate-specific antigen (PSA) along with a digital rectal examination. Some data suggest that the digital rectal exam and PSA levels may be insensitive indicators of prostate cancer in men with low total or free testosterone levels. The synergistic effect of testosterone on PSA could mask indicators for evaluation of prostate cancer.

Humans↗

PubMed2006

CSR1 suppresses tumor growth and metastasis of prostate cancer.

Prostate cancer is frequent among men over 45 years of age, but it generally only becomes lethal with metastasis. In this study, we identified a gene called cellular stress response 1 (CSR1) that was frequently down-regulated and methylated in prostate cancer samples. Survival analysis indicated that methylation of the CSR1 promoter, and to a lesser extent down-regulation of CSR1 protein expression, was associated with a high rate of prostate cancer metastasis. Forced expression of CSR1 in prostate cancer cell lines DU145 and PC3 resulted in a two- to threefold decrease in colony formation and a 10-fold reduction in anchorage-independent growth. PC3 cells stably expressing CSR1 had an average threefold decrease in their ability to invade in vitro. Expression of CSR1 in PC3 cell xenografts produced a dramatic reduction (>8-fold) in tumor size, rate of invasion (0 versus 31%), and mortality (13 versus 100%). The present findings suggest that CSR1 is a potent tumor sup-pressor gene.

Adenocarcinoma↗

PubMed2002

Inhibition of angiogenesis: treatment options for patients with metastatic prostate cancer.

Prostate cancer is the most frequently diagnosed malignancy and the second most common cause of cancer-related death in men in the United States. Unfortunately, at the current time, no curative treatments are available for metastatic prostate cancer. As is the case for most solid tumors, the recruitment of blood vessels (angiogenesis) is key for the progression and metastasis of prostate cancer. Inhibition of this process is an attractive approach to treatment. Many antiangiogenic agents are currently in clinical development. The following discussion will outline the importance of angiogenesis in the metastasis and progression of prostate cancer, summarize the current surrogate markers of angiogenesis available for the drug development of antiangiogenic agents, and review examples of investigational agents that target tumor angiogenesis (e.g., TNP-470, Thalidomide, CC5013, Carboxyamido-triazole (CAI), Endostatin. SU5416, SU6668, Bevacizumab (Anti-VEGFrhuMAb), and 2-Methoxyestradiol).

Angiogenesis Inhibitors↗

PubMed2002

Prostate-specific antigen vaccines for prostate cancer.

Prostate cancer is the most common malignant tumour in men and there are few treatment options available once the tumour becomes refractory to hormonal manipulation. Prostate-specific antigen (PSA) is a secretory glycoprotein that is commonly expressed by prostatic epithelial cells and is found in elevated levels in the serum of men with prostate cancer. The identification of T cell specific epitopes within the coding sequence of PSA has led to the development of various vaccine strategies that target PSA in an attempt to treat established prostate cancer. These strategies have included human leukocyte antigen-restricted PSA peptides, dendritic cells pulsed with PSA, recombinant viruses expressing PSA and combinations of different vectors. In addition to PSA, several other antigens have been described that may be useful for targeting prostate tumours by vaccines. Animal studies have established the feasibility and safety for many of these agents and clinical trials are now in progress to evaluate the immunological and clinical responses of PSA vaccines. Further research in manipulating anti-PSA immunity with cytokines, costimulatory molecules and other immune modulating agents will likely improve the therapeutic effectiveness of PSA vaccines. Clinical trials designed to evaluate the effects of vaccination in different stages of disease and through different routes of administration need to be performed to define the optimal schedule for PSA vaccines in patients with prostate cancer, or for those at high risk of developing the disease.

Animals↗