Vascular Targeted Photodynamic Therapy for Localized Prostate Cancer

Survival for men diagnosed with prostate cancer directly depends on the stage and grade of the disease at diagnosis. Prostate cancer screening has greatly increased the ability to diagnose small and low-grade cancers that are amenable to cure. However, widespread prostate-specific antigen screening exposes many men with low-risk cancers to unnecessary complications associated with treatment for localized disease without any survival advantage. One challenge for urological surgeons is to develop effective treatment options for low-risk disease that are associated with fewer complications. Minimally invasive ablative treatments for localized prostate cancer are under development and may represent a preferred option for men with low-risk disease who want to balance the risks and benefits of treatment. Vascular targeted photodynamic therapy (VTP) is a novel technique that is being developed for treating prostate cancer. Recent advances in photodynamic therapy have led to the development of photosynthesizers that are retained by the vascular system, which provides the opportunity to selectively ablate the prostate with minimal collateral damage to other structures. The rapid clearance of these new agents negates the need to avoid exposure to sunlight for long periods. Presented herein are the rationale and preliminary data for VTP for localized prostate cancer.Key words: Prostate cancer, localized; Minimally invasive ablative treatment for prostate cancer; Photodynamic therapy; WST-09; WST-11; Vascular targeted photodynamic therapy; Padoporfin; Palladium bacteriopheophorbideProstate cancer represents the second most common cause of cancer-related deaths in American men; it is estimated that 27,000 men in the United States died from the disease in 2007.¹ Survival for men with prostate cancer directly depends on the stage and grade of the disease at the time of diagnosis.² These sobering mortality statistics and the more favorable prognosis associated with early detection provide the primary justification for prostate cancer screening, which is performed by measuring the level of serum prostate-specific antigen (PSA) and conducting a digital rectal examination (DRE). It is estimated that 50% of men over the age of 50 years are screened annually for prostate cancer.³Despite widespread acceptance, prostate cancer screening is debated,^4,5 and recommendations for prostate cancer screening are inconsistent. Screening protagonists emphasize that radical prostatectomy increases prostate cancer survival in men with localized disease,⁶ and that the recently observed progressive and significant decline in prostate cancer mortality rates is the direct result of PSA screening and aggressive intervention.⁷ Screening antagonists emphasize the indolent natural history of most prostate cancers detected by screening,⁸ and that the vast majority of men who are treated for prostate cancer do not recognize any survival advantage from early detection and are simply left suffering the ravages of treatment.⁹Both sides of the screening debate have valid arguments. In the absence of widespread screening, many men are denied an opportunity to cure their disease. These men will experience the otherwise preventable consequences of disease progression, which include the development of androgen-insensitive disease¹⁰ and death. However, widespread screening exposes many men to unnecessary complications associated with treatment for localized disease. The challenges are to identify and treat only those cancers that have the biological potential to cause serious and preventable consequences, or to develop treatment options that are associated with fewer complications.     

The Case for Hypofractionation of Localized Prostate Cancer

An optimal treatment regimen for localized prostate cancer (PCa) is yet to be determined. Increasing evidence reveals a lower α/β ratio for PCa with hypofractionated radiation therapy (HFRT) regimens introduced to exploit this change in therapeutic ratio. HFRT also results in shortened overall treatment times of 4 to 5 weeks, thus reducing staffing and machine burden, and, more importantly, patient stress. This review evaluates pretreatment characteristics, outcomes, and toxicity for 15 HFRT studies on localized PCa. HFRT results in comparable or better biochemical relapse-free survival and toxicity and is a viable option for localized PCa.Key words: Localized prostate cancer, Hypofractionation, Short-course radiotherapy, Dose escalation, Biologic equivalenceMultiple randomized dose-escalation trials for localized prostate cancer (PCa) have shown improved biochemical relapse-free survival (bRFS) rates for higher total doses using conventionally fractionated radiotherapy (CFRT), though at a cost of longer treatment duration.^1–4 The increased treatment time requires increased access to radiation treatment facilities, with additional burden on both patients and staff. To address the issue of prolonged treatment duration while maintaining equivalent bRFS, an increasing number of studies have pursued the role of hypofractionated radiotherapy (HFRT) with higher daily doses delivered in a shorter total amount of time. This treatment paradigm assumes a low α/β ratio for PCa, as demonstrated in several recent studies, with higher α/β ratios for normal surrounding tissues.^5–7 By employing HFRT, the increased daily radiation doses exploit the aforementioned α/β ratios by allowing equivalent tumor kill as with CFRT, while also allowing for normal tissue repair.With longer-term and randomized HFRT data now reported in the literature, it seems appropriate to address whether the time has come to make HFRT the new standard. This article seeks to review the current literature and the role of HFRT in the modern era of radiotherapy for localized PCa.     

Multifunctional Nanoparticles for Prostate Cancer Therapy

The relapse of cancer after first line therapy with anticancer agents is a common occurrence. This recurrence is believed to be due to the presence of a subpopulation of cells called cancer stem cells in the tumor. Therefore, a combination therapy which is susceptible to both types of cells is desirable. Delivery of this combinatorial approach in a nanoparticulate system will provide even a better therapeutic outcome in tumor targeting. The objective of this study was to develop and characterize nanoparticulate system containing two anticancer agents (cyclopamine and paclitaxel) having different susceptibilities toward cancer cells. Both drugs were entrapped in glyceryl monooleate (GMO)-chitosan solid lipid as well as poly(glycolic-lactic) acid (PLGA) nanoparticles. The cytotoxicity studies were performed on DU145, DU145 TXR, and Wi26 A4 cells. The particle size of drug-loaded GMO-chitosan nanoparticles was 278.4 ± 16.4 nm with a positive zeta potential. However, the PLGA particles were 234.5 ± 6.8 nm in size with a negative zeta potential. Thermal analyses of both nanoparticles revealed that the drugs were present in noncrystalline state in the matrix. A sustained in vitro release was observed for both the drugs in these nanoparticles. PLGA blank particles showed no cytotoxicity in all the cell lines tested, whereas GMO-chitosan blank particles showed substantial cytotoxicity. The types of polymer used for the preparation of nanoparticles played a major role and affected the in vitro release, cytotoxicity, and uptake of nanoparticles in the all the cell lines tested.KEY WORDS: cancer stem cells, cyclopamine, glyceryl monooleate, nanoparticles, PLGA     

Focal Laser Ablation for Localized Prostate Cancer: Principles,Clinical Trials,and Our Initial Experience

Focal therapy of prostate cancer is an evolving treatment strategy that destroys a predefined region of the prostate gland that harbors clinically significant disease. Although long-term oncologic control has yet to be demonstrated, focal therapy is associated with a marked decrease in treatment-related morbidity. Focal laser ablation is an emerging modality that has several advantages, most notably real-time magnetic resonance imaging (MRI) compatibility. This review presents the principles of laser ablation, the role of multiparametric MRI for delineating the site of significant prostate cancer, a summary of published clinical studies, and our initial experience with 23 patients, criteria for selecting candidates for focal prostate ablation, and speculation regarding future directions.Key words: Laser ablation, Prostate cancer, Focal therapy, Targeted therapyProstate cancer is the most common solid organ malignancy and the second most common cause of cancer death among men living in the Western world.¹ Widespread prostate-specific antigen (PSA) testing and decreased thresholds for prostate biopsy have led to both a reduction in the proportion of men diagnosed with advanced disease and disease-specific mortality. The consequence of widespread PSA screening has been a dramatic increase in both the detection of low-risk disease and the proportion of men diagnosed with prostate cancer undergoing radical prostatectomy (RP) or radiation therapy (RT).² In many cases, the complications associated with treating low-risk disease by RP or RT outweigh the benefits.^3,4 Although active surveillance (AS) is an appealing alternative for managing low-risk disease, it potentially decreases long-term survival rates.⁵ Due to the unreliability of disease risk stratification at the time of diagnosis, 14% to 41% of men assigned to AS will cross over to RP or RT due to upgrading or upstaging.⁶There is increasing evidence that multiparametric magnetic resonance imaging (mpMRI) localizes the site(s) of clinically significant prostate cancer prior to prostate biopsy.⁷ These suspicious MRI focal abnormalities can be biopsied directly in the MRI unit or under transrectal ultrasound (TRUS) guidance using software that co-registers and fuses the MRI and ultrasound (US) images.⁸ In many cases, MRI image-guided biopsy identifies a single clinically significant cancer. Although prostate cancer is typically a multifocal disease, the index, or dominant, lesion is typically predictive of extraprostatic extension and disease progression.^9–11 The majority of the secondary tumor sites are composed of small Gleason 6 disease, which represent no immediate threat.¹² It is theoretically possible to focally ablate only the index lesion, thereby achieving oncologic control while minimizing treatment-related morbidity by minimizing collateral damage to adjacent structures.Focal ablation of prostate cancer is an evolving treatment strategy that destroys a predefined region (or target) of the prostate that harbors the clinically significant cancer. A number of energy sources have been investigated for focal ablation of the prostate, including cryotherapy,¹³ high-intensity focused ultrasound (HIFU),¹⁴ photodynamic therapy,¹⁵ and laser ablation.¹⁶ Although long-term oncologic control has yet to be demonstrated, all of these targeted ablative options are associated with marked decrease in treatment-related complications. One of the advantages of laser technology is that the ablation can be performed with real-time MRI imaging. Because the target lesion are almost always defined by the MRI, laser ablation is currently the most accurate way to deliver ablative energy to the intended target. Other advantages of laser ablation include its homogeneous tissue necrosis, relatively low cost, and wide availability.¹⁷ MRI-guided focal ablation allows treatment monitoring using MR thermometry and real-time visualization of the targeted treatment zone.^18,19This review presents the principles of laser ablation, the role of mpMRI for delineating the site of significant prostate cancer, a summary of published clinical studies and the New York University Langone Medical Center (NYULMC)/Sperling Prostate Cancer Center experience on focal laser ablation of prostate cancer, criteria for selecting candidates for focal prostate ablation, and speculation regarding future directions of focal laser ablation for the treatment of localized prostate cancer.     

Neoadjuvant Therapy for Prostate Cancer: An Oncologist's Perspective

With increasing use of prostate-specific antigen as a screening tool, diagnosis of prostate cancer has undergone a stage migration toward early-stage disease. Although this has increased the proportion of men who are candidates for definitive, potentially curative therapy, it has also made clear the limitations of our current standard of care. Specifically, despite adequate local therapy, a significant proportion of men go on to develop progressive disease. Neoadjuvant systemic therapy is one approach that continues to be studied as a way to maximize cure rates in the setting of early-stage disease. This article reviews the current data regarding neoadjuvant therapy, both hormonal and chemotherapy, and discusses which men are appropriate candidates for this option.     

A New Formulation of Calcitriol (DN-101) for High-Dose Pulse Administration in Prostate Cancer Therapy

Although the antineoplastic activity of calcitriol in prostate cancer has been known for many years, the agent's use in oncology has been prevented because of the occurrence of hypercalcemia with daily administration. High-dose pulse administration of calcitriol has the potential to improve the therapeutic index of calcitriol. Results of a phase II study of calcitriol and docetaxel (Taxotere(R)) suggest that this combination may have utility in androgen-independent prostate cancer (AIPC). DN-101, a high-dose (15 mug) formulation of calcitriol suitable for use in oncology, is now being tested in a randomized trial (AIPC Study of Calcitriol Enhancing Taxotere). This formulation of calcitriol could become an important new tool for improving the efficacy of docetaxel in the treatment of AIPC and would join the ranks of other nuclear receptor ligands in cancer treatment. Investigations of DN-101 in the treatment of a broad range of tumor types and in combination with a variety of agents are an exciting new area of research.     

Widespread and Functional RNA Circularization in Localized Prostate Cancer

1. Download high-res image (265KB)
2. Download full-size image

     

Therapeutic Strategies for Localized Prostate Cancer II: Perineal Prostatectomy, X-Rays, Protons, Neutrons, and Combination Brachytherapy

Application of improved imaging, diagnostic, and computer techniques is beginning to have an impact on the management of localized prostate cancer. It is possible to perform a range of surgical and radiation procedures with less morbidity than in the past. The changes in therapy for patients with localized disease derive from better knowledge of anatomy for invasive procedures and optimization of virtual planning for noninvasive methods. Perineal prostatectomy and combinations of beam and seed radiation offer both patient and physician reasonable therapeutic options.     

Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.     

Analysis of Prostate Deformation during a Course of Radiation Therapy for Prostate Cancer

Purpose

Accurate analysis of the correlation between deformation of the prostate and displacement of its center of gravity (CoG) is important for efficient radiation therapy for prostate cancer. In this study, we addressed this problem by introducing a new analysis approach.

Method

A planning computed tomography (CT) scan and 7 repeat cone-beam CT scans during the course of treatment were obtained for 19 prostate cancer patients who underwent three-dimensional conformal radiation therapy. A single observer contoured the prostate gland only. To evaluate the local deformation of the prostate, it was divided into 12 manually defined segments. Prostate deformation was calculated using in-house developed software. The correlation between the displacement of the CoG and the local deformation of the prostate was evaluated using multiple regression analysis.

Results

The mean value and standard deviation (SD) of the prostate deformation were 0.6 mm and 1.7 mm, respectively. For the majority of the patients, the local SD of the deformation was slightly lager in the superior and inferior segments. Multiple regression analysis revealed that the anterior-posterior displacement of the CoG of the prostate had a highly significant correlation with the deformations in the middle-anterior (p < 0.01) and middle-posterior (p < 0.01) segments of the prostate surface (R² = 0.84). However, there was no significant correlation between the displacement of the CoG and the deformation of the prostate surface in other segments.

Conclusion

Anterior-posterior displacement of the CoG of the prostate is highly correlated with deformation in its middle-anterior and posterior segments. In the radiation therapy for prostate cancer, it is necessary to optimize the internal margin for every position of the prostate measured using image-guided radiation therapy.     

Focal Therapy: A New Paradigm for the Treatment of Prostate Cancer

Focal therapy has been proposed in recent years as a means of bridging the gap between radical prostatectomy and active surveillance for treatment of prostate cancer. The rationale for focal therapy comes from its success in treating other malignancies. One of the challenges in applying such an approach to the treatment of prostate cancer has been the multifocal nature of the disease. This review addresses the selection of potentially ideal candidates for focal therapy and discusses which modalities are currently being used and proposed for focal therapy. Setting and meeting guidelines for oncologic efficacy is a challenge we must embrace to safely deliver this potentially revolutionary approach to treating men with prostate cancer.Key words: Focal therapy, Photodynamic therapy, Prostatic neoplasms, Prostate-specific antigen, Prostatectomy, Ultrasound, high-intensity focused, transrectal, CryosurgeryWith the advent of prostate-specific antigen (PSA) screening there has been a stage migration, with radical prostatectomy (RP) being performed with increasing frequency in men with low-risk disease.¹ Whole gland treatment of prostate cancer carries a significant risk of incontinence and sexual dysfunction. Even in the most experienced centers, the rate of potency following RP is approximately 60%.^2–4 Stage migration has led many to recommend active surveillance (AS) as a means to decrease the number of men who may be overtreated; however, AS has been slow to gain acceptance in the United States.An analysis of over 5300 men from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) National Prostate Cancer Registry⁵ showed that only 7% of men with clinically localized prostate cancer chose AS as an initial option. Aside from the anxiety that stems from not treating a diagnosed cancer, the greater difficulty with AS lies in selection of candidates and appropriate parameters for surveillance, allowing prompt intervention without compromising cure rates.Focal therapy has been proposed in recent years as a means of bridging the gap between whole gland treatment and AS. Many believe that for patients with low-risk disease, focal therapy is the ideal option for maximizing quality of life by avoiding the effects of whole gland radiation or surgery while alleviating the anxiety and uncertainty of AS. The definition of focal therapy itself is not well established and includes lesion-targeted therapy (LAT), hemiablative therapy (HAT), or subtotal gland therapy (STAT), sparing at least 1 neurovascular bundle.⁶The rationale for focal therapy comes from its success in treating other malignancies. In breast cancer treatment, for example, radical mastectomy has been replaced in many instances by local excision and Mohs surgery has led to less radical surgery for the treatment of melanoma.⁷ In our own field, the push for nephron-sparing surgery has led to the favoring of partial nephrectomy in tumors less than 7 cm, with oncologic outcomes similar to those of radical nephrectomy.⁸The challenge in applying such an approach to the treatment of prostate cancer has been the multifocal nature of prostate cancer and the fact that most cancers are detected without identifying a lesion on palpation or imaging studies.^9,10In this review, we revisit the current status of focal therapy in the treatment of prostate cancer. We discuss whether there are ideal candidates for focal therapy; we then discuss how these candidates should be selected. We review which modalities are currently being used and proposed for focal therapy. Finally, we discuss potential definitions of successful treatment. As this article shows, there are still many aspects of focal therapy that are yet to be defined, that warrant a great need for further research.     

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。     

Short-Term Soy Isoflavone Intervention in Patients with Localized Prostate Cancer: A Randomized,Double-Blind,Placebo-Controlled Trial

Purpose

We describe the effects of soy isoflavone consumption on prostate specific antigen (PSA), hormone levels, total cholesterol, and apoptosis in men with localized prostate cancer.

Methodology/Principal Findings

We conducted a double-blinded, randomized, placebo-controlled trial to examine the effect of soy isoflavone capsules (80 mg/d of total isoflavones, 51 mg/d aglucon units) on serum and tissue biomarkers in patients with localized prostate cancer. Eighty-six men were randomized to treatment with isoflavones (n = 42) or placebo (n = 44) for up to six weeks prior to scheduled prostatectomy. We performed microarray analysis using a targeted cell cycle regulation and apoptosis gene chip (GEArrayTM). Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol were analyzed at baseline, mid-point, and at the time of radical prostatectomy. In this preliminary analysis, 12 genes involved in cell cycle control and 9 genes involved in apoptosis were down-regulated in the treatment tumor tissues versus the placebo control. Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared to men receiving placebo were not statistically significant.

Conclusions/Significance

These data suggest that short-term intake of soy isoflavones did not affect serum hormone levels, total cholesterol, or PSA.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255125","term_id":"NCT00255125"}}NCT00255125     

Chemo-Cryo Combination Therapy: An Adjunctive Model for the Treatment of Prostate Cancer

Despite continuing research and the development of alternate therapeutic options, prostate cancer remains problematic. Chemotherapy has played a minor role as a treatment option due to its lack of efficacy. Whereas cryotherapy has received renewed attention as a treatment modality, it too fails to offer an absolute curative option. Previously, we reported on the utilization of a therapeutic model, which, in combination, increases cell death in a canine renal cell model. Based upon that study, we investigated a combination therapy model as an alternative for the treatment modality for prostate cancer. We hypothesized that the combination of chemotherapy and cryosurgery would result in enhanced cell death, thereby presenting a more effective treatment of prostate cancer. A human prostate cancer cell (PC-3) model was exposed to 5-fluorouracil (5-FU) for 2 and 4 days (prefreeze), freezing (-5 to -100 degrees C), or a combination of the two treatments, and each was assessed for effectiveness over a 2-week posttreatment period. Additionally, investigation into the mechanisms of cell death initiated by the respective therapies was performed through DNA cleavage analysis. For chemotherapy, cultures exposed to 5-FU (2-4 days) yielded a 15-25% loss in cell survival. For cryotherapy, cultures exposed to a temperature window of -5 to -20 degrees C yielded an initial 5-70% loss of viability but cells propagated over time. Cultures exposed to temperatures of -25 to -80 degrees C yielded a 90-99% (+/-4.5%) initial loss in viability with repopulation observed by 12 days postthaw. Cells frozen to -100 degrees C yielded 100% (+/-0.3%) loss of viability and exhibited no signs of propagation. For chemo-cryo therapy, combination treatment at milder temperatures (-5 to -25 degrees C) resulted in an enhanced loss of cell viability compared to that for either treatment alone. Combination treatment at lower temperatures (-40 to -80 degrees C) resulted in a complete loss of cell viability. DNA fragmentation analysis at 48 h posttreatment revealed that dead (detached) cells treated with 5-FU died primarily through apoptosis, whereas dead cells from freezing (-15 degrees C) alone died primarily through freeze-rupture and necrosis. Detached cell analysis from combination treatment at -15 degrees C revealed the presence of apoptotic, necrotic, and freeze-rupture cell death. Scanning electron micrographs of cells exposed to freezing contributing to cell death. These data demonstrate that the combination of 5-FU at sublethal doses and freezing temperatures improves human prostate cancer cell death efficacy. Further, we suggest that chemo-cryo therapy offers a potential alternative treatment for the control and eradication of prostate cancer.     

靶向蛋白质泛素修饰及降解在前列腺癌治疗中的机遇与挑战

前列腺癌是中国发病率增长最快的男性肿瘤,抗雄激素治疗耐药是导致前列腺癌患者预后差的主要原因。因此,解决耐药性难题是前列腺癌转化研究的关键问题。哺乳动物细胞利用泛素-蛋白酶体系统实现蛋白质的靶向降解。因此,前列腺癌中关键的癌基因如雄激素受体（AR）的上游泛素化调控因子（如去泛素化酶）是潜在的治疗靶点。然而,这些酶具有较广的底物谱系,存在脱靶的可能性。近来,基于泛素-蛋白酶体系统开发的蛋白质降解靶向嵌合体（proteolysis-targeting chimeras,PROTAC）技术是最具前景和革命性的新型抗癌药物研发技术,能够利用特定E3泛素连接酶对靶蛋白进行降解而不影响其他底物。与传统小分子抑制剂相比,PROTAC分子在克服耐药性以及针对不可成药的靶点方面拥有巨大优势。目前,针对AR的PROTAC降解剂已在II期临床取得了成功,靶向蛋白质泛素化及降解途径的新技术将有望为前列腺癌的临床治疗带来新的突破。     

Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy

Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non-malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three-dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non-malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can facilitate cell death using a pro-drug approach, and shows promise as a vector for the treatment of prostate cancer.