Clinical experience with gene therapy for the treatment of prostate cancer

Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients.     

Hormonal therapy combined with radiotherapy in locally advanced prostate cancer

At present radiation therapy and radical prostatectomy are considered to be the treatment of choice for clinical T1-T2 prostate cancer. In a more advanced stage of the disease (T3) 10-year overall survival is observed in approximately 40% of patients treated with conventional radiotherapy. So far only a few methods for improving the efficacy of radiotherapy have been introduced. One of them is a three-dimensional conformal radiotherapy with 3 dimensional treatment planning. These novel methods make it possible to escalate the dose to the target and protect healthy tissue at the same time. The optimal volume of irradiation, total dose, fraction dose, techniques of radiotherapy, and the end points used during the follow-up are open to debate. In recent years a few clinical trials involving hormonal therapy and radiotherapy have been carried out. The most important of these are: RTOG 8307, RTOG 8610, RTOG 9202, and EORTC 22863.In the RTOG 8307 trial the comparison of outcomes of a combined treatment with a matched-control group of patients treated by radiotherapy alone has shown that adding hormonal therapy to radiotherapy resulted in a better outcome. Another trials RTOG 8531 and RTOG 8610 produced benefit due to the implementation of hormonal therapy in radiotherapy. The EORTC trial No. 22863 showed improvement in the 5-year overall survival when hormonal therapy after the completion of radiotherapy was continued for 3 years in the investigational arm. The RTOG 9202 study indicated benefit obtained from 2 years of adjuvant hormonal therapy.The results of these trials have had a substantial impact on the management of locally advanced prostate cancer, but there are still questions that have to be answered. There is no doubt that hormonal therapy is an important component of the management of locally advanced prostate cancer. Still the optimal combination of drugs and the timing of such treatment remains controversial. Considering the potential side effects of a combined treatment on the quality of life of patients and care costs, additional properly designed randomised trials are needed to identify the subgroup of patients who will obtain the greatest benefit. Currently, it can be concluded that in the group of patients with a high risk of relapse by adding hormonal therapy to radiotherapy the outcome of treatment in patients with prostate cancer has improved.     

Cancer and bone repair mechanism: clinical applications for hormone refractory prostate cancer

It is a long-standing clinical observation that the bone corresponds to the prevalent site for metastatic growth of prostate cancer. In addition, bone metastases of this malignancy produce a potent blastic reaction, in contrast to the overwhelming majority of other osteotropic neoplasms, whose metastases are generally associated with an osteolytic reaction. Osteoblastic metastases represent almost always the first and, frequently, the exclusive site of disease progression to hormone refractory stage, stage D3. Moreover, the number of skeletal metastatic foci is the most powerful independent prognostic factor associated with a limited response to hormone ablation therapy and poor survival of advanced prostate cancer. It is noteworthy that disease progression to hormone refractory stage occurs almost always in osteoblastic metastases. These clinical observations suggested that the osteoblastic reaction is possibly not an innocent bystander of the metastatic prostate tumour growth, simply suffering its consequences, but it may in fact facilitate the efforts of metastatic cells to expand their population. An extensive line of research in the pathophysiology of osteoblastic metastases has established that the local blastic reaction involves the uPA/plasmin/IGF/IGFBP-3/TGFbs bioregulation system which can stimulate both the growth of osteoblasts and prostate cancer cells. Furthermore, we were the first to characterize osteoblast-derived 'survival factors' able to rescue metastatic prostate cancer cells from chemotherapy-induced apoptosis. These data resulted in the development of a novel concept of an anti-survival factor therapy, namely an anti-IGF-1 therapy, which has provided encouraging preliminary data in a phase II clinical trial with terminally-ill hormone/chemotherapy-resistant prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Success and failure of single-modality treatment for early prostate cancer

Many men who undergo radical prostatectomy or radiotherapy for early prostate cancer have an excellent outcome; however, a significant proportion subsequently experience disease recurrence and/or cancer-related death. Adjuvant hormonal therapy after treatment of curative intent is given with the aim of eradicating undetected cancer cells outside the surgical margins or radiation field and/or micrometastatic disease. In the analogous setting of early breast cancer, adjuvant hormonal therapy is already established as standard care. Efficacy and tolerability data from the ongoing bicalutamide ('Casodex') Early Prostate Cancer program are expected to determine the role of adjuvant hormonal therapy with antiandrogens in early prostate cancer.     

Current status of androgen suppression and radiotherapy for patients with prostate cancer

Analogous to the impact of anti-estrogen therapy in breast cancer, anti-androgen therapy may have a greater impact on the castrate male with non-metastatic disease. The use of castration or a LHRH drug alone, does not appear to adequately suppress intra-prostatic DHT (Dihydrotestosterone) levels. Normal prostate elements appear to be more efficient than metastatic elements at converting DHT precursors to active DHT. Thus, blocking this step may be more critical for clinically localized disease. Laverdiere et al. reported a 2 year positive (+) biopsy rate of 65% with XRT alone compared to 28% when 3 months of NHT preceded radiotherapy, but 5% if NHT was continued for a total of 10.5 months of combined androgen blockade (CAB). Bolla et al. incorporated one month of NHT prior to XRT followed by 3 years of an LHRH drug. An improvement in local control, disease free survival and overall survival of nearly 20% was noted at 5 years. Thus far, these important studies demonstrate that a survival benefit may require long term adjuvant hormonal therapy. There is a need for further studies to define the optimal timing and duration of CAB and the role of XRT. Long term data recently provided by the Radiation Therapy Oncology Group (RTOG) may provide insights into criteria for defining which patients are likely to benefit the most from long term CAB.     

A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients

Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.     

Managing bone loss and bone metastases in prostate cancer patients: a focus on bisphosphonate therapy

Androgen deprivation therapy (ADT) and bone metastases are the most important risk factors for developing skeletal complications (eg, bone loss, pathologic fractures) in prostate cancer (PC) patients with locally advanced and metastatic disease. Bisphosphonates, which inhibit excessive osteoclast activity caused by ADT and bone metastases, have proven to be safe and effective in preventing skeletal complications and presently are the standard of care in patients with metastatic disease. Bisphosphonates should be considered for use in all PC patients with locally advanced disease initiating ADT for an intended duration of at least 1 year, especially those with a low baseline bone mineral density.     

Prospects for gene therapy in human prostate cancer

Prostate cancer is the most common neoplasm in men and a significant cause of mortality in affected patients. Despite significant advances, current methods of treatment are effective only in the absence of metastatic disease. Gene therapy offers a renewed hope of using the differential characteristics of normal and malignant tissue in constructing treatment strategies. Several clinical trials in prostate cancer gene therapy are currently under way, using immunomodulatory genes, anti-oncogenes, tumor suppressor genes and suicide genes. A continued understanding of the etiological mechanisms involved in the establishment and progression of prostate cancer, along with advances in gene therapy technology, should make gene therapy for prostate cancer therapeutically valuable in the future.     

Prostate cancer proteomics

Proteomics has offered the hope of biomarker discovery to improve the management of prostate cancer. Markers are needed for screening and diagnosis, distinguishing latent from aggressive disease, defining the men who will benefit from therapy, differentiating localized from metastatic disease, predicting outcome and identifying new targets for therapy. There are many potential sources of proteins derived from the prostate, including urine, prostatic fluid (expressed or ejaculate), serum, and plasma or tissue, each with distinct advantages and limitations. Equally, there are many methodological platforms for proteomic studies of the prostate. Despite the promise, protoemics has yielded little of relevance to the management of prostate cancer, and most of the work that has been published is either irreproducible or of no clinical value.     

Prostate cancer: Re-focusing on androgen receptor signaling

Prostate cancer is the most common, non-dermatologic cancer in men. Since prostate cancer is highly associated with increased age, the incidence of this disease is expected to increase as the population ages. In its initial stages prostate cancer depends upon the actions of androgen, and androgen deprivation therapy induces tumor regression. Currently, androgen deprivation is achieved by either surgical or chemical androgen blockade. Unfortunately, nearly all prostate cancer patients develop tumors that grow despite androgen blockade and ultimately relapse. Many alterations in prostate cancer cells contribute to this state. Although chemotherapy induces short remissions in some patients, there are no curative therapies for metastatic disease. This review summarizes our current understanding in androgen signaling and the mechanisms that allow tumor cells to bypass androgen manipulation therapy. The identification of novel survival pathways and effector molecules that drive androgen independent growth is necessary to develop effective therapies for advanced prostate cancers.     

Cancer de prostate métastatique : prise en charge

Current data have demonstrated that the incidence and mortality induced by prostate cancer increases with age. Natural history of prostate cancer extends on 10 to 15 years. As shown by randomized trials on screening, PSA measurements lead to early detection of localised cancer and explain the decrease number of metastatic disease which remains frequent in the elderly. However, patients with bone metastasis present painful symptomatology and a poor quality of life. This disease is hormone-sensitive during 18 to 24 months, before it becomes androgen-resistant. Considering epidemiologic and life expectancy data, we can expect an increasing number of patients with an hormonal blocking and it is important to develop alternative treatments to improve the prognosis of this disease which remains poor at the metastatic stage.     

The Impact of Prostate Cancer and Hormonal Therapy on Bone

Large-scale studies agree that the observed decline in prostate cancer mortality that began in the early 1990s, shortly after prostate-specific antigen testing was introduced in the United States, is most likely explained by more widespread treatment of prostate cancer, including hormonal therapy. Practitioners should be aware of the risk of the development of osteoporosis and of skeletal side effects related to hormonal therapy to optimize the care of men with prostate cancer.Key words: Hormone deprivation therapy, Androgen deprivation therapy, Bone destruction, Osteoporosis, OsteopeniaProstate cancer is the most commonly diagnosed cancer among men in the United States, with approximately 192,280 cases anticipated in 2009.¹ It also remains a common cause of cancer death, with 27,360 deaths anticipated in 2009. Moreover, the declining US death rates from cardiovascular and smoking-related disease coupled with the aging of the population associated with the Baby Boom generation may beget an anticipated increase in prostate cancer diagnoses in the coming years. It has been estimated that about 10% of the US population was over the age of 65 years in 2000 and that this proportion will approximately double by 2030.² As a condition of aging men, prostate cancer is apt to remain a significant, if not growing, public health problem.Current efforts to reduce the mortality burden of prostate cancer have included prostate-specific antigen (PSA)-based screening, but its effect on mortality as assessed in randomized trials, particularly during the first 10 years of follow-up, is controversial.^3,4 But these large-scale studies agree that the observed decline in prostate cancer mortality that began in the early 1990s, shortly after PSA testing was introduced in the United States, is most likely explained by more widespread treatment of prostate cancer, including hormonal therapy.⁵ Given these considerations, it is quite likely that hormone deprivation therapy will remain an important treatment for men with prostate cancer. Therefore, a thorough understanding of its long-term side effects is necessary if we are to optimize the care of men with prostate cancer.     

Psoriasis exacerbation after hormonotherapy in prostate cancer patient—Case report

Psoriasis, as the most common inflammatory skin disorder, affects about 2–3% of the world''s population. Many non-dermatological conditions have been linked with psoriasis, including cardiovascular diseases, depression, inflammatory bowel disorders, and some cancers, i.e. lung, colon and kidney cancers. Among systemic factors are endocrine and metabolic disturbances as well as many drugs. Erythrodermic psoriasis, the most severe form of the disease, is characterized by diffuse erytrema and scaling, often accompanied by fever, chills, and malaise.A 57-year-old Caucasian man was admitted for curative radiation therapy of adenocarcinoma of the prostate after 3 months of initial hormonal therapy. The management comprised the combined androgen blockade (CAB). On admission the patient reported escalation of psoriasis symptoms, which he had been treated for since 2002. Due to a mild course of the disease he had not required any systemic treatment ever before, even during aggravation periods. The last exacerbation started appearing a month after hormonal therapy implementation. The cutaneous eruptions, already existing, become larger with new foci revealing, mainly on upper and lower limbs. During radiotherapy planning, there appeared a diffuse erythema and scaling on hands and feet with accompanying pruritis. We decided to start the previously planned radiation therapy which included the prostate gland with 1.5 cm margin and provided for the total dose of 72 Gy in 36 fractions. The irradiation was conducted with the four-field technique using a megavoltage linear accelerator. During radiotherapy we photo-documented skin lesions.To our best knowledge hormone therapy (androgen deprivation) of prostate cancer patients has not been reported as an aggravating factor. Thus, the aim of our work is to present the case of a prostate cancer patient who experienced psoriasis exacerbation after implementation of hormonal blockade as a neoadjuvant oncological treatment.     

前列腺癌的靶向治疗研究现状与展望

前列腺癌难以根治,研究雄激素非依赖型前列腺癌的靶向治疗具有实际的临床意义,涉及抗体靶向治疗、靶向抗前列腺癌药物研制、细胞生长信号转导通路抑制、微小RNA应用等多方面,而靶向清除肿瘤干细胞则是根治前列腺癌的有效策略。