Biomedical subjects

Martin Gleave

Publications and source records attributed to Martin Gleave.

At least 19 recordsLinked to original sources

PubMed2007

Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells.

Heat shock protein 27 (Hsp27) is a cytoprotective chaperone that is phosphoactivated during cell stress that prevents aggregation and/or regulate activity and degradation of certain client proteins. Recent evidence suggests that Hsp27 may be involved in tumor progression and the development of treatment resistance in various tumors, including bladder cancer. The purpose of this study was to examine, both in vitro and in vivo, the effects of overexpression of Hsp27 and, correspondingly, the down-regulation of Hsp27 using small interfering (si) RNA and OGX-427, a second-generation antisense oligonucleotide targeting Hsp27. Hsp27 overexpression increased UMUC-3 cell growth and resistance to paclitaxel. Both OGX-427 and Hsp27 siRNA decreased Hsp27 protein and mRNA levels by >90% in a dose- and sequence-specific manner in human bladder cancer UMUC-3 cells. OGX-427 or Hsp27 siRNA treatment induced apoptosis and enhanced sensitivity to paclitaxel in UMUC-3 cells. In vivo, OGX-427 significantly inhibited tumor growth in mice, enhanced sensitivity to paclitaxel, and induced significantly higher levels of apoptosis compared with xenografts treated with control oligonucleotides. Collectively, these findings suggest that Hsp27 knockdown with OGX-427 and combined therapy with paclitaxel could be a novel strategy to inhibit the progression of bladder cancer.

Animals↗

PubMed2006

Expression of clusterin in prostate cancer correlates with Gleason score but not with prognosis in patients undergoing radical prostatectomy without neoadjuvant hormonal therapy.

OBJECTIVES: To determine whether the expression level of clusterin in prostate cancer could be used as a prognostic predictor in patients who have undergone radical prostatectomy (RP). METHODS: This study included 172 consecutive patients undergoing RP for clinically organ-confined prostate cancer without neoadjuvant hormonal therapy. Immunohistochemical staining was performed in RP specimens obtained from these patients to evaluate the expression level of clusterin protein. The cell proliferative activities and apoptotic features in these specimens were investigated using Ki-67 immunostaining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, respectively. RESULTS: Varying levels of clusterin expression were noted in 169 of 172 prostate cancer specimens; 32 of the 172 normal prostatic tissue specimens did not exhibit any clusterin staining. Clusterin expression in prostate cancer tissue was significantly related to the Gleason score, but not to the other parameters, including age, serum prostate-specific antigen level, pathologic stage, perineural invasion, tumor volume, and lymph node metastasis. In addition, cell proliferative activity in the prostate cancer specimens was significantly associated with clusterin expression; however, no correlation was found between the apoptotic index and clusterin expression. In this series, 34 (19.8%) of 172 patients developed biochemical recurrence. No significant difference was found in biochemical/recurrence-free survival between patients with strong clusterin expression and those with weak expression. CONCLUSIONS: Despite its detection in most prostate cancer tissue, clusterin expression failed to show a significant association with prognosis in patients undergoing RP without neoadjuvant hormonal therapy. This suggests a limited role for clusterin in the progression of clinically organ-confined prostate cancer in the absence of proapoptotic stimuli.

Aged↗

PubMed2006

Cluster-based network model for time-course gene expression data.

We propose a model-based approach to unify clustering and network modeling using time-course gene expression data. Specifically, our approach uses a mixture model to cluster genes. Genes within the same cluster share a similar expression profile. The network is built over cluster-specific expression profiles using state-space models. We discuss the application of our model to simulated data as well as to time-course gene expression data arising from animal models on prostate cancer progression. The latter application shows that with a combined statistical/bioinformatics analyses, we are able to extract gene-to-gene relationships supported by the literature as well as new plausible relationships.

Animals↗

PubMed2006

Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro.

OBJECTIVES: To evaluate synthetic small interference RNA (siRNA) compounds targeting heat-shock protein 27 (Hsp27) as an alternative approach to Hsp27 'knockdown' in prostate cancer cells, as Hsp27 expression is highly up-regulated in prostate cancer cells after androgen withdrawal or chemotherapy, to become uniformly highly expressed in androgen-independent (AI) prostate cancer. MATERIALS AND METHODS: We recently showed that targeting Hsp27 by a 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide, OGX-427, inhibits Hsp27 expression and enhances hormone- and chemotherapy in prostate cancer xenograft models. In the present study, a 'gene walk' screening different siRNAs was initially used in PC-3 and LNCaP cells to determine the most potent sequence to down-regulate Hsp27 mRNA and protein levels. The effects of Hsp27 silencing on in vitro growth rates were studied by tetrazolium-blue and crystal violet assays. Apoptosis was determined by single-stranded DNA nuclear and cleaved caspase-3 immunostaining, as well as flow cytometry. Spotted microarrays with 14,000 human oligonucleotides were used to examine changes in gene expression. RESULTS: Low concentrations of 1 nm siRNA decreased Hsp27 mRNA levels by 19-fold and suppressed protein expression to undetectable levels. Silencing of Hsp27 in prostate cancer cells by siRNA # 2 increased apoptotic rates 2.4-4 fold and caused 40-76% inhibition of cell growth in LNCaP and PC-3 cells. Characteristic cleavage of caspase-3 occurred after treatment with Hsp27 siRNA (1 nm). cDNA microarray analysis from LNCaP and PC-3 cell lines revealed differential gene expression profiles after Hsp27 down-regulation that could be used to identify various survival pathways involved in androgen-dependent and AI growth. CONCLUSIONS: These findings illustrate the potential utility of Hsp27-silencing therapy and highlight Hsp27 siRNA strategies as a novel and highly effective tool, with the potential for future targeted therapy in enhancing the efficacy of chemotherapy in advanced prostate cancer.

Apoptosis↗

PubMed2006

Expression and nuclear localization of ErbB3 in prostate cancer.

PURPOSE: The ErbB1 and ErbB2 receptors have been implicated in prostate cancer progression, but less is known about the role and biology of other ErbB receptor family members in prostate cancer. The aim of this study was to analyze the expression and localization of ErbB3 in prostate tissues and prostate cancer cell lines. EXPERIMENTAL DESIGN: Immunohistochemistry of ErbB3 was done on prostate cancer tissue sections from 143 patients and on a tissue microarray containing 390 cores of radical prostatectomy-derived specimens representing normal, prostatic intraepithelial neoplasia, and malignant tissues from 81 patients. ErbB3 subcellular localization was studied by Western blot analysis in LNCaP, 22Rv1, PC-3, and DU145 prostate cancer cell lines. RESULTS: Immunohistochemistry analysis of prostate cancer tissues revealed that >90% of prostate cancer tissues displayed cytoplasmic ErbB3 staining. Minimal ErbB3 nuclear staining was observed in normal prostate tissues and benign prostatic hyperplasia tissues; in contrast, ErbB3 was frequently localized in the nucleus of cancerous tissues. This nuclear localization was more frequent (P < 0.001) in hormone-refractory tissues (17 of 17, 100%) compared with hormone-sensitive samples (37 of 92, 40.2%). Additionally, in the tissue microarray, increased nuclear ErbB3 was associated with increasing Gleason grade. Interestingly, Western blot analysis of cytoplasmic and nuclear subcellular fractions showed that ErbB3 nuclear localization was more prevalent in hormone-sensitive prostate cancer cell lines (LNCaP and 22Rv1) compared with hormone-insensitive cell lines (PC-3 and DU145). CONCLUSIONS: ErbB3 nuclear localization discriminates normal from malignant prostate tissues and between tumors from hormone-sensitive versus hormone-refractory prostate cancer. ErbB3 nuclear staining seems to be associated with risk of disease progression. The high frequency of ErbB3 nuclear localization in hormone-refractory tissues indicates that ErbB3 warrants further study to understand its association with prostate cancer disease progression.

Cell Nucleus↗

PubMed2006

Cyclin G-associated kinase: a novel androgen receptor-interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer.

The androgen receptor (AR), a steroid receptor family member, is a ligand-dependent transcription factor that has an integral role in normal prostate development. Alterations in AR-mediated activity can result in abnormal gene expression, dysregulated cell growth and prostate cancer. Coregulator proteins that interact with AR to influence activity and specificity of the AR-response may also have an important role in prostate cancer progression. Since the NH(2)-terminal domain (NTD) of AR encodes the ligand-independent activation function (AF)-1, this domain is incompatible with conventional yeast two-hybrid systems. Therefore, we have used the Tup1 repressed transactivator (RTA) system, which exploits the intrinsic transactivation properties of AR.NTD, for identification of novel AR-interacting proteins. Using this system, cyclin G-associated kinase (GAK) was identified as an AR interacting protein, and GST pull-down assays were used to confirm the interaction. GAK was shown to enhance the AF-1 function of AR activity in a ligand-dependent manner. Additionally, GAK enhanced the AR transcriptional response even at low concentrations of androgens, which is relevant to AR activity in androgen-independent prostate cancer. Finally, neo-adjuvant hormone therapy (NHT) tissue microarray analysis demonstrated that GAK expression increased significantly with prostate cancer progression to androgen independence, which suggests a prognostic role for GAK in advanced disease.

Androgens↗

PubMed2006

Rh2 synergistically enhances paclitaxel or mitoxantrone in prostate cancer models.

PURPOSE: We explored the efficacy of the ginsenoside Rh2 and examined its impact on the effective dose of paclitaxel and mitoxantrone in the LNCaP prostate tumor model. MATERIALS AND METHODS: Cultured LNCaP cell viability was assessed following treatment (48 hours) with Rh2 (0 to 40 microM) alone or in combination with paclitaxel and mitoxantrone. Synergism or antagonism observed when combining treatment was calculated using CalcuSyn software (Biosoft). In addition, the inhibition of LNCaP human xenograft tumor growth was examined in vivo when Rh2 treatment was combined with chemotherapy. Harvested tumors were immunohistochemical stained with p27kip and Ki67. RESULTS: Rh2 and paclitaxel act synergistically in cultured LNCaP cells to lower ED50 and ED75 values. Rh2 and mitoxantrone are also synergistic. However, when combined as ED95, an antagonistic effect was observed in this cell line. Treatment of LNCaP tumors by Rh2 plus paclitaxel produced a significant decrease in tumor growth and serum prostate specific antigen. Immunohistochemical analysis revealed an apparent but nonsignificant effect on proliferation markers in LNCaP tumors. When Rh2 and mitoxantrone were combined in vivo, there was no significant benefit observed. CONCLUSIONS: These results indicate that the combination of Rh2 and paclitaxel has an effect on growth inhibition that is greater and synergistic, as demonstrated in a cultured LNCaP cell line. Conversely combining Rh2 with mitoxantrone appears to elicit no benefit. Therefore, combination therapy using chemotherapy and Rh2 requires further investigation.

Animals↗

PubMed2006

The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase.

Signaling through the insulin-like growth factor I receptor (IGF-IR) axis is essential for transformation by many dominantly acting oncoproteins. However, the mechanism by which IGF-IR contributes to oncogenesis remains unknown. To examine this, we compared transformation properties of the oncogenic ETV6-NTRK3 (EN) chimeric tyrosine kinase in IGF-IR-null R- mouse embryo fibroblasts with R- cells engineered to reexpress IGF-IR (R+ cells). We previously showed that R- cells expressing EN (R- EN cells) are resistant to transformation but that transformation is restored in R+ cells. We now show that while R- EN cells have intact Ras-extracellular signal-regulated kinase signaling and cell cycle progression, they are defective in phosphatidylinositol-3-kinase (PI3K)-Akt activation and undergo detachment-induced apoptosis (anoikis) under anchorage-independent conditions. In contrast, R+ cells expressing EN (R+ EN cells) suppress anoikis and are fully transformed. The requirement for IGF-IR in R- EN cells is overcome by ectopic expression of either activated Akt or a membrane-targeted form of EN. Moreover, compared to R- EN cells, R+ EN cells show a dramatic increase in membrane localization of insulin receptor substrate 1 (IRS-1) in association with EN. Since EN is known to bind IRS-1 as an adaptor protein, our findings suggest that IGF-IR may function to localize EN/IRS-1 complexes to cell membranes, in turn facilitating PI3K-Akt activation and suppression of anoikis.

Animals↗

PubMed2006

Surgical wait times for patients with urological cancers: a survey of Canadian surgeons.

BACKGROUND: The wait times for urological cancer surgeries in Canada has increased over the past 2 decades. This is of concern to patients, physicians and other key stakeholders because there is evidence that delaying surgery beyond a recommended threshold could have a negative impact on clinical outcomes. To address these trends, a Canadian surgical wait times (SWAT) initiative has been undertaken to develop a consensus document and make recommendations on appropriate wait times. As a first step, the SWAT steering committee determined that current wait times estimates were required for the four key disease sites; prostate, bladder, kidney and testes. To obtain such data, a survey of Canadian urological surgeons was undertaken. METHODS: A structured electronic mailing strategy was adopted as recommended by Dillman (1978). Standardized data collection forms were sent to members of the Canadian Urological Association (CUA) and attendees to the 2005 CUA meeting. Survey items consisted of respondent demographic data, information on surgical wait times for the four key disease sites and potential barriers to timely cancer surgery. RESULTS: One hundred and five urological surgeons responded to the survey. There was considerable variation in wait times between and within the four disease sites with bladder and kidney cancer surgeries displaying the widest range. Operating room availability and staging tests were identified as the most significant barriers to efficient cancer surgery. CONCLUSIONS: The wide variation in wait times identified in this study suggest that the overall time to treatment from referral is beyond the duration considered by many experts and by the Canadian Society of Surgical Oncology to be acceptable. These issues need to be addressed through a partnership between the key stakeholders in order to reduce the potentially negative impact on clinical outcomes and patient quality of life.

Appointments and Schedules↗

PubMed2006

Does prolonging the time to prostate cancer surgery impact long-term cancer control: a systematic review of the literature.

BACKGROUND: The wait times for prostate cancer surgery in Canada has increased over the past 2 decades. Prolonged wait times have a negative impact on patient quality of life but the effect on long-term cancer control is undefined. We conducted a systematic literature review to examine the best available evidence addressing the following key questions: . What is the reported time interval for prostate cancer patients from the decision to operate until the day of cancer surgery? . Are there recommendations/guidelines in the urological cancer literature and, if so, how do the Canadian times compare? . Is there a known association between duration of wait time beyond the recommended standard and clinical outcome (i.e. recurrence free survival, overall survival)? METHODS: A structured literature search of Medline, Pubmed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, the Cochrane Database of Abstracts of Reviews of Effects, Healthstar and Google Scholar was performed from January 1980 to January 2006 for published epidemiological studies and international guidelines/consensus documents that evaluated surgical wait times for prostate cancer. Data extracted from eligible studies included median time to prostate cancer surgery from the point of patient contact and adjusted hazard ratios (HR) for wait times. All HR from the included studies were examined for the possibility of statistical pooling via meta analytic techniques. RESULTS: Thirteen studies evaluating wait times for prostate cancers were identified, six of which measured the HR for prostate specific antigen (PSA) recurrence in patients with prolonged wait times. Differences in study data availability, method of analysis and wait time definitions precluded statistical pooling of the findings. Median wait times from various points of patient contact ranged from 42 days to 244 days. In the six Canadian studies identified, wait times ranged from 42 days (consultation to operation) to 83 days (consultation to hospital admission). This was in contrast to national and international guidelines, which recommended a maximum wait time for prostatectomy between 2 to 4 weeks. The association between surgical delay and disease recurrence remained controversial where only two of six epidemiological studies reported at least a statistical trend for an increased risk of PSA recurrence free survival in patients with surgical delays of 3 months or more. CONCLUSIONS: Unlike comparable countries, surgical wait times in Canada appear to be increasing and are well beyond the threshold recommended by national and international expert bodies. Even though the association between surgical delay and disease recurrence remains unclear, there is an ongoing concern that the psychological impact of prolonged waiting could negatively impact patient outcomes. To address these important issues, the surgical wait times (SWAT) initiative is mandated to provide the necessary guidance and recommendations to the federal and provincial governments. Through a partnership of the key stakeholders, it is the vision of SWAT to ultimately improve the care and quality of life of prostate cancer patients and their families.

Appointments and Schedules↗

PubMed2005

Increased Hsp27 after androgen ablation facilitates androgen-independent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis.

One strategy to improve therapies in prostate cancer involves targeting cytoprotective genes activated by androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. The objectives of this study were to define changes in Hsp27 levels after androgen ablation and to evaluate the functional relevance of these changes in AI progression. Using a tissue microarray of 232 specimens of hormone-naïve and post-hormone ablation-treated prostate cancer, we found that Hsp27 levels increase after androgen ablation to become highly expressed (>4-fold, P < or = 0.01) in AI tumors. Hsp27 overexpression rendered LNCaP cells highly resistant to androgen withdrawal both in vitro and in vivo. Tumor volume and serum prostate-specific antigen levels increased 4.3- and 10-fold faster after castration when Hsp27 was overexpressed. Treatment of LNCaP tumor cells in vitro with Hsp27 antisense oligonucleotides (ASO) or short-interfering RNA suppressed Hsp27 levels in a dose-dependent and sequence-specific manner increased the apoptotic sub-G0-G1 fraction and caspase-3 cleavage >2-fold, as well as decreased signal transducers and activators of transcription 3 (Stat3) levels and its downstream genes, c-fos and sPLA-2. The cytoprotection afforded by Hsp27 overexpression was attenuated by Stat3 knockdown using specific Stat3 ASO. Coimmunoprecipitation and immunofluorescence confirmed that Hsp27 interacts with Stat3 and that Stat3 levels correlated directly with Hsp27 levels. Hsp27 ASO treatment in athymic mice bearing LNCaP tumors significantly delayed LNCaP tumor growth after castration, decreasing mean tumor volume and serum prostate-specific antigen levels by 57% and 69%, respectively. These findings identify Hsp27 as a modulator of Stat3-regulated apoptosis after androgen ablation and as a potential therapeutic target in advanced prostate cancer.

Animals↗

PubMed2005

Clusterin as a therapeutic target for radiation sensitization in a lung cancer model.

PURPOSE: Clusterin plays important roles in cell survival and death. Inactivation of clusterin enhances the therapeutic efficacy of chemotherapy in lung cancer models. The purpose of this study was to determine whether inhibition of clusterin by an antisense-based investigative drug enhances radiation sensitization in a lung cancer model. METHODS AND MATERIALS: Cells were transfected with an antisense oligonucleotide (ASO) against clusterin (OGX-011). Apoptosis was determined by 7-aminoactinomycin D staining. Cell survival was examined by 3-(4, 5-methylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and clonogenic assay. Xenograft model was used to demonstrate tumor growth and tumor blood flow. RESULTS: OGX-011 specifically attenuated the expression of secreted clusterin (prosurvival), with no apparent effect on the expression of nuclear clusterin (proapoptotic). Apoptosis was significantly increased when H460 lung cancer cells were treated with OGX-011 plus radiation. Inhibition of clusterin followed by radiation greatly decreased cell survival. H460 xenografts that were treated with OGX-011 plus radiotherapy demonstrated growth delay beyond 17 days. Doppler studies showed that tumor blood flow was compromised when mice bearing H460 xenografts were treated with OGX-011 and radiation. CONCLUSION: A combination of radiotherapy and OGX-011 improved control of tumor growth and vascular regression in the H460 lung cancer model.

Animals↗

PubMed2005

High-risk localized prostate cancer: a case for early chemotherapy.

High-risk tumors exhibit a more aggressive natural history and have higher positive margin and recurrence rates after radical prostatectomy or radiotherapy alone, where unimodality therapy likely represents undertreatment. Hence, the therapeutic ratio (patients who actually realize a survival benefit from a therapeutic intervention) may, therefore, be greater in high-risk disease if its natural history can be altered by multimodality therapy. It is, thus, important to investigate therapies that optimize complete extirpation of all cancer cells and reduce the incidence of positive surgical margins and disease recurrence. Neoadjuvant therapy extends the logic of early adjuvant therapy further by applying systemic therapy earlier in the course of the disease before definitive locoregional therapy. In prostate cancer, outcomes have not been improved significantly when neoadjuvant hormone therapy is used before surgery; although outcomes are improved when androgen ablation is combined with radiotherapy, many patients remain at risk for systemic recurrence. With recent data confirming improved survival data with docetaxel chemotherapy in metastatic disease, future trials are now focusing on earlier combinations of chemohormonal or biologic therapies in high-risk patients.

Antineoplastic Agents, Hormonal↗

PubMed2005

Loss of functional E-cadherin renders cells more resistant to the apoptotic agent taxol in vitro.

Experimental evidence supports a role for E-cadherin in suppressing invasion, metastasis, and proliferation. Germline mutations of the E-cadherin represent the genetic cause of hereditary diffuse gastric cancer (HDGC). In this type of tumor, isolated cancer cells permeate the basal membrane and paradoxically survive in the gastric wall in the absence of contact with neighbor epithelial cells or with the extracellular matrix. This suggests that upon E-cadherin deregulation, cells acquired resistance to apoptosis. To test this hypothesis, CHO cells stably expressing either wild-type E-cadherin or the HDGC-related germline mutations T340A and V832M were seeded either on a thin layer of collagen type I or on plastic and then subjected to the apoptotic agent taxol. We found that in vitro functional E-cadherin renders cells more sensitive to the effect of taxol. Our results also indicate that this effect is associated to decreased level of the anti-apoptotic bcl-2 protein.

Animals↗

PubMed2005

A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer.

PURPOSE: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy. EXPERIMENTAL DESIGN: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment. RESULTS: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m(2) i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (C(ss)) was a significant determinant of antitumor activity; mean C(ss) values were higher in responders compared with nonresponders (6.24 +/- 1.68 versus 4.27 +/- 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen C(ss) or response. CONCLUSIONS: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen C(ss).

Adult↗

PubMed2005

Mechanisms of the development of androgen independence in prostate cancer.

The effectiveness of androgen ablation in the management of advanced prostate cancer is of limited duration, with the median length of response being only 18-24 months. The transition of the prostate cancer cell to an androgen independent phenotype is a complex process that involves selection and outgrowth of pre-existing clones of androgen-independent cells (clonal selection) as well as adaptive up-regulation of genes that help the cancer cells survive and grow after androgen ablation (adaptation). These two mechanisms share an important pre-requisite characteristic: prostate cancers are heterogeneous tumours comprised of various subpopulations of cells that respond differently to androgen withdrawal therapy. This tumour heterogeneity may reflect either a multifocal origin, adaptation to environmental stimuli, and/or genetic instability of the initial cancer. This review will reexamine the different mechanisms that enable prostate cancer cells to proliferate in an androgen depleted environment.

Androgens↗

PubMed2005

Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer.

The discovery and targeting of genes mediating androgen-independence may lead to the development of novel therapies that delay progression of hormone refractory prostate cancer (HRPC). Clusterin is a stress-associated cell survival gene that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the use of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer models. Immunostaining of tissue microarrays constructed from untreated and post-hormone treated radical prostatectomy specimens confirm that clusterin is highly expressed in virtually all HRPC cells, 80% of prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Overexpression of clusterin in LNCaP cells confers resistance to both androgen ablation and chemotherapy. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels, accelerated apoptotic tumor regression, and significantly delayed the recurrence of androgen-independent tumors. A human clusterin ASO targeting the translation initiation site and incorporating MOE-gapmer backbone (OGX-011) synergistically enhanced the cytotoxic effects of paclitaxel in human xenografts of prostate, renal cell, bladder, and lung cancer. Clusterin, is an anti-apoptosis protein upregulated in an adaptive cell survival manner by androgen ablation and chemotherapy that confers resistance to various cell death triggers. Suppression of clusterin levels using ASOs enhances cell death following treatment with androgen ablation, radiation, and chemotherapy.

Androgens↗

PubMed2005

Beyond simple castration: targeting the molecular basis of treatment resistance in advanced prostate cancer.

Over the past 20 years, research on hormonal treatments for prostate cancer focused on maximizing androgen ablation through combination therapy. Unfortunately, maximal androgen ablation increases treatment-related side effects and expense and has not significantly prolonged time to androgen-independent (AI) progression. Intermittent androgen suppression (IAS) is based on the hypothesis that if tumor cells surviving androgen withdrawal can be forced along a normal pathway of differentiation by androgen replacement, then apoptotic potential might be restored, androgen dependence may be prolonged and progression to androgen independence may be delayed. Observations from animal model studies suggest that progression to androgen independence is delayed by IAS and this strategy is now being evaluated in phase III trials. Another strategy for improving therapies in advanced prostate cancer involves targeting genes that are activated by either androgen withdrawal or chemotherapy to delay or prevent the emergence of the resistant AI phenotype. Targeted inhibition of stress-associated increases in gene expression precipitated by androgen withdrawal or chemotherapy may enhance treatment-induced apoptosis and delay progression to AI disease. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, clusterin, Hsp27, and IGFBP-2 and IGFBP-5. The purpose of this paper is to review the rationale and progress in using targeted gene therapies to enhance tumor cell death after androgen withdrawal or taxane chemotherapy. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those not amenable to small molecule or antibody inhibition. The current status and future direction of several antisense oligonucleotides that have potential clinical use in cancer are also reviewed.

Clusterin↗