Hormone Ablation Research Articles

Abstract 130: Regulatory role of miR-29b in prostate cancer metastasis

Abstract Prostate cancer remains the second leading cause of cancer deaths among American men. Earlier diagnosis increases survival rate in patients. However, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment are necessary for inhibiting progression of the disease. We have shown previously that microRNA-29b (miR-29b) expression was lower in prostate cancer cells as compared to prostate epithelial cells. Among the prostate cancer cell lines, metastatic prostate cancer cells displayed lowest expression of miR-29b. In this study, we have observed that PC-3M cells that constitutively overexpressed miR-29b failed to colonize the lungs and other organs of SCID mice after intravenous injection, while PC-3M cells expressing a control miRNA formed multiple nodules in the lung. PC-3M cells expressing miR-29b inhibited wound healing and invasiveness of cancer cells. Epithelial cell marker E-cadherin expression was enhanced in prostate cancer cells expressing miR-29b as compared to control cells. On the other hand, N-Cadherin and Snail1 expression were downregulated in PC-3M cells expressing miR-29b. Together these results suggested that miR-29b is an anti-metastatic miRNA in prostate cancer that acts at multiple steps of the metastatic cascade. Therefore, miR-29b could be a potentially new attractive target for therapeutic intervention in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 130. doi:1538-7445.AM2012-130

Quality of life in men receiving radiotherapy and neo‐adjuvant androgen deprivation for prostate cancer: results from a prospective longitudinal study

To report a study measuring the quality of life and side effects in men receiving radiotherapy and hormone ablation for prostate cancer up to 1 year after treatment. Prostate cancer incidence is increasing with the result that more men are living longer with the disease and the side effects of treatment. It is important to know the effects this has on their quality of life. Survey. Between September 2006-September 2007, all men who were about to undergo radical conformal radiotherapy ± neo-adjuvant androgen deprivation for localized prostate cancer were invited to participate in the study; 149 men were recruited. They completed the European Organization on Research and Treatment of Cancer quality of life questionnaire C-30 and Prostate Cancer module PR25 at four time-points. At 4-6 weeks after radiotherapy, participants experienced the biggest relative decline in global quality of life, social, physical, and role functioning and an increase in treatment side effects. At 6 months postradiotherapy the majority of men experienced an improvement in their side effects. However, a minority of men were experiencing severe side effects of radiotherapy at 1 year post-treatment. Single men and men who had a low quality of life prior to radiotherapy, reported a lower quality of life at 1 year after treatment in comparison to married men. Men with prostate cancer suffer limitations due to the symptoms they experience and disruption to their quality of life. It is essential that nurses develop and deliver follow-up care which is flexible and appropriate to the individual needs of these men.

Nuclear factor κB predicts poor outcome in patients with hormone-naive prostate cancer with high nuclear androgen receptor

Despite recent advances in prostate cancer treatments, disease recurrence is common and associated with significant morbidity and mortality. The need for more effective antitumor agents has led researchers to target signaling pathways that drive tumorigenesis by modulating or bypassing androgen receptor signaling--attenuation or blockade of which current treatments aim to effect. The transcription factor nuclear factor κB/p65 has been implicated in prostate cancer progression; however, few studies have examined the involvement of nuclear factor κB in hormone-naive disease. We used immunohistochemistry to investigate expression of p65, androgen receptor, Ki-67, and phosphorylation status of p65 at serine 536, in 154 tumor samples taken from patients before hormone ablation or radical treatment. Nuclear p65 expression was significantly associated with disease-specific mortality: P = .005; hazard ratio, 2.2. When patients were stratified according to androgen receptor status, this relationship was abolished in low androgen receptor-expressing patients and potentiated in high androgen receptor-expressing patients: P = .002; hazard ratio, 3.1. Ki-67 expression was also prognostic of shorter disease-specific mortality: P = .001; hazard ratio, 2.3. When the cohort was stratified according to androgen receptor status, this relationship held for high androgen receptor expressers but not low expressers: P = .0003; hazard ratio, 3.5. Neither androgen receptor nor p65 phosphorylated at S536 were significantly prognostic when considered individually. These data suggest that future prostate cancer treatments that target nuclear factor κB signaling should be assigned primarily to patients with concomitant high nuclear p65 and androgen receptor expression.

Abstract C3: Receptor tyrosine kinase(s) modulate androgen receptor signaling in castrate-resistant prostate cancer

Abstract This study is designed to investigate the mechanisms underlying effects of receptor tyrosine kinase(s) on androgen receptor (AR) in castrate resistant prostate cancer (CRPC). Hormone ablation therapies remain the mainstay of treatment for metastatic prostate cancer, but disease eventually reoccurs as CRPC where AR has been reactivated despite castrate androgen levels. Amongst ways that facilitate restoration of AR activity in CRPC, receptor tyrosine kinases (RTKs) have been reported to activate AR and induce CRPC growth through as of yet unclear mechanisms. Our investigative studies revealed that lapatinib (inhibits Her2/Her3 heterodimer and EGFR) treatment inhibited endogenous AR expression and activity in C4-2 CRPC cells. Lapatinib induced destabilization and proteosomal degradation of the AR with minimal effect on AR mRNA transcript levels. To further investigate if this effect was dependent on Her2/Her3 or EGFR, an EGFR inhibitor erlotinib was used. It produced modest effects on AR, indicating that effects of lapatinib are predominantly through Her2/Her3. As AKT, a serine/threonine kinase, functions downstream of Her2/Her3, we then directly investigated the effects of AKT on AR in CRPC cells. Our studies revealed that inhibition of AKT decreased endogenous AR expression through proteosomal degradation. Moreover AKT inhibition decreased endogenous AR activity and C4-2 cell survival, indicating that AKT positively regulates AR and CRPC growth. As many groups have previously reported conflicting effects of AKT on AR, we are now focused on the molecular basis for this positive effect of AKT on AR expression and function in CRPC. Preliminary studies indicate that AKT inhibition may be decreasing levels of heat shock proteins (Hsp70, Hsp90) that serve as chaperones for cytoplasmic AR, and may by another mechanism be decreasing AR accumulation in the nucleus. We anticipate that these studies will provide a clear mechanistic view of effects of RTKs and AKT on AR in CRPC and highlight molecules that may be targeted for novel therapeutic interventions. Citation Format: Ankur Sharma, Steven P. Balk. Receptor tyrosine kinase(s) modulate androgen receptor signaling in castrate-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C3.

▼Denosumab for postmenopausal osteoporosis?

Osteoporosis is the most common clinical disorder of bone metabolism, and is characterised by low bone mass and deterioration of the microarchitecture of bone tissue that results in increased bone...

Treatment-induced bone loss and fractures in cancer patients undergoing hormone ablation therapy: efficacy and safety of denosumab.

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.

Androgen Receptor and Nutrient Signaling Pathways Coordinate the Demand for Increased Amino Acid Transport during Prostate Cancer Progression

L-Type amino acid transporters such as LAT1 and LAT3 mediate the uptake of essential amino acids. Here, we report that prostate cancer cells coordinate the expression of LAT1 and LAT3 to maintain sufficient levels of leucine needed for mTORC1 signaling and cell growth. Inhibiting LAT function was sufficient to decrease cell growth and mTORC1 signaling in prostate cancer cells. These cells maintained levels of amino acid influx through androgen receptor-mediated regulation of LAT3 expression and ATF4 regulation of LAT1 expression after amino acid deprivation. These responses remained intact in primary prostate cancer, as indicated by high levels of LAT3 in primary disease, and by increased levels of LAT1 after hormone ablation and in metastatic lesions. Taken together, our results show how prostate cancer cells respond to demands for increased essential amino acids by coordinately activating amino acid transporter pathways vital for tumor outgrowth.

P1-13-03: Zoledronic Acid Induces an Immune Response in Breast Cancer Patients through Stimulation of Central Memory and Effector Memory gamma/delta T-Cells.

Abstract Background Zoledronic acid (ZA) in combination with endocrine therapy (ET) and ovarian ablation (OA) reported a DFS advantage in premenopausal women with early stage breast cancer (EBC) in ABCSG-12. Emerging evidence from pre-clinical studies suggests that ZA increases gamma/delta T-cells (GDT), an immune cell population with anti-tumor activity. This study examined immune responses to a single dose of ZA in patients with either EBC or metastatic breast cancer (MBC) through sequential measurement of T-cells and immune regulatory cytokines. Methods Women with EBC/MBC, both pre- and post-menopausal, and no history of immune dysregulation who were scheduled to receive their first-ever dose of ZA were eligible. Blood was collected for serum and blood mononuclear cells at Day 0 (pre-ZA), Day 1 (18-48 hours post-ZA), Day 7 (Day 5–8 post ZA), and Day 28 (Day 25–32 post-ZA). GDT populations and cytokine responses were assayed using flow cytometry and multi-analyte profiling beads (Luminex), respectively. Relative changes from baseline at days 1, 7 and 18 were quantified using log-ratios and analyzed using the Wilcoxon signed-rank test. Results 24 patients were enrolled from Oct 2009 to Mar 2011. 75% of pts had MBC, and 25% had EBC, while 75% received ET, 17% received chemo (C), and 8% received other. Following ZA administration, a transient decrease in total GDT (CD3+/Vdelta2+) at Day 1 was seen (p<0.0003). This was followed by an increase in both effector (CD3+/Vdelta2+/CD45RA-/CD27-) (P<0.005) and central memory GDT (CD3+/Vdelta2+/CD45RA-/CD27+)(P<0.007) and a decrease in naïve GDT (CD3+/Vdelta2+/CD45RA+/CD27+) (P<0.006) at day 7; total GDT unchanged. The change in naïve GDT and effector GDT appeared to persist at Day 28. IL-1RA (P<0.003), IL-12 (P<0.0005), MIP-1b (P<0.0005), IP-10 (P<0.00002) and MIG (P<0.00006), were increased at Day 1 compared to baseline. By day 28, these cytokine levels returned to baseline except IP-10 which appeared to remain elevated. In this limited patient sample, no differences were observed between patients with EBC vs. MBC, ET vs. C, and pre- vs. post-menopausal. Conclusion: ZA appears to induce a highly significant change in immune effector cells in both EBC and MBC patients receiving ET or C. Mobilization of anti-tumor T-cells with a decrease in total (non-specific) GDT followed by a marked increase post-ZA in specific central and effector memory GDT was seen at day 7. Significant increases in cytokine levels, like those seen in this study including those associated with Th1 responses or cell-mediated immunity, as well as IL-12 levels, have been implicated in direct anti-tumor activity. This apparent cytokine and cellular response to ZA could offer an important biologic mechanism for the anti-cancer activity reported in ABCSG-12. Further studies should be performed to determine which subsets of BC patients might achieve these described immune benefits from ZA. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-13-03.

Bitter Melon Extract Impairs Prostate Cancer Cell-Cycle Progression and Delays Prostatic Intraepithelial Neoplasia in TRAMP Model

Prostate cancer remains the second leading cause of cancer deaths among American men. Earlier diagnosis increases survival rate in patients. However, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment and prevention are necessary for inhibiting disease progression to a hormone refractory state. One of the approaches to control prostate cancer is prevention through diet, which inhibits one or more neoplastic events and reduces the cancer risk. For centuries, Ayurveda has recommended the use of bitter melon (Momordica charantia) as a functional food to prevent and treat human health related issues. In this study, we have initially used human prostate cancer cells, PC3 and LNCaP, as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. We observed that prostate cancer cells treated with BME accumulate during the S phase of the cell cycle and modulate cyclin D1, cyclin E, and p21 expression. Treatment of prostate cancer cells with BME enhanced Bax expression and induced PARP cleavage. Oral gavage of BME, as a dietary compound, delayed the progression to high-grade prostatic intraepithelial neoplasia in TRAMP (transgenic adenocarcinoma of mouse prostate) mice (31%). Prostate tissue from BME-fed mice displayed approximately 51% reduction of proliferating cell nuclear antigen expression. Together, our results suggest for the first time that oral administration of BME inhibits prostate cancer progression in TRAMP mice by interfering cell-cycle progression and proliferation.

Oncological outcomes of the prostate cancer patients registered in 2004: Report from the Cancer Registration Committee of the JUA

In 2001, the Cancer Registration Committee of the Japanese Urological Association initiated a data collection of prostate cancer patients into a computer-based database. The aim of the present study is to report the clinical and pathological characteristics and outcomes of prostate cancer patients diagnosed in 2004 in Japan. Overall, 11,385 patients from 239 institutions were registered into the database. After excluding 1105 patients because of insufficient data, duplication or insufficient follow up, 10,280 patients were eligible for the analysis. Most of them (10,198, 99.2%) were Japanese and 1195 (11.6%) had metastatic disease at the time of diagnosis. The mean and median follow up was 53.2 months and 61.5 months, respectively. The 5-year overall and prostate cancer-specific survival rate was 89.7% and 94.8%, respectively. The 5-year prostate cancer-specific survival rate of M0 and M1 disease was 98.4% and 61.1%, respectively. For 8424 cases of organ-confined or regional disease, Japanese urologists used as the initial treatment hormone ablation therapy alone (3360, 39.9%), radical prostatectomy (3140, 38.1%), radiation therapy (1530, 18.2%) and watchful waiting (394, 4.7%) including active surveillance or palliative observation. This is the first large population report of survival data in Japanese prostate cancer patients. In Japan, the disease population, survival period with metastatic disease and ratio of patients having hormone ablation therapy differ from those in Western countries.

Cancer epigenetics: a perspective on the role of DNA methylation in acquired endocrine resistance

Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.

Opposing roles of ERα and ERβ in the genesis and progression of adenocarcinoma in the rat ventral prostate

Prostate cancer is a common malignancy in men and although hormone ablation therapy is effective, men develop hormone resistance. There is need for therapies applicable earlier, such as treatment of prostatic intraepithelial neoplasia (PIN). Estrogens besides androgens play a role in prostate cancer pathogenesis via two receptors ERα and ERβ and both receptors are thought to play different, opposing, roles with ERα having proliferative properties and ERβ having anti-proliferative properties. To differentiate between the roles both receptors play in prostate cancer an ERα and an ERβ agonist, ERA-45 and ERB-26, have been tested in a rodent model for prostate carcinogenesis. The influence of ERα on prostate cancer progression was studied in intact male rats treated with testosterone in combination with the ERα agonist, ERA-45 for either a long-term (20-week) period or a shorter term (6-week) period. The ERβ agonist was tested in the shorter term model in intact male rats treated with testosterone in combination with the ERα agonist, ERA-45, followed by administration of the ERβ agonist, ERB-26, during the last 2 weeks. Treatment of rats with testosterone in combination with ERA-45 induced mild PIN lesions at 6 weeks and severe precancerous PIN lesions at 20 weeks. The ERβ agonist prevented the onset of PIN lesions at 6 weeks. Moreover, prostate epithelial cell apoptosis was increased and proliferation was decreased. These findings confirm the opposing roles ERα and ERβ play in prostate carcinogenesis and suggest a therapeutic opportunity of ERβ for treating precancerous PIN lesions.

Whole Pelvic Radiotherapy With Hypofractionated Simultaneous Integrated Boost And Hormonal Therapy For NCCN High Risk Prostate Adenocarcinoma: Implications For The Alpha/Beta Ratio

The alpha/beta ratio for adenocarcinoma of the prostate may vary by Gleason score or tumor growth rate. In this study we seek to determine the response of aggressive (NCCN high risk) prostate adenocarcinoma to radiotherapy to the pelvis with a simultaneous hypofractionated boost to the prostate in combination with hormonal ablation.

Androgen-Independent Molecular Imaging Vectors to Detect Castration-Resistant and Metastatic Prostate Cancer

Prostate-specific promoters are frequently employed in gene-mediated molecular imaging and therapeutic vectors to diagnose and treat castration-resistant prostate cancer (CRPC) that emerges from hormone ablation therapy. Many of the conventional prostate-specific promoters rely on the androgen axis to drive gene expression. However, considering the cancer heterogeneity and varying androgen receptor status, we herein evaluated the utility of prostate-specific enhancing sequence (PSES), an androgen-independent promoter in CRPC. The PSES is a fused enhancer derived from the prostate-specific antigen (PSA) and prostate-specific membrane antigen gene regulatory region. We augmented the activity of PSES by the two-step transcriptional amplification (TSTA) system to drive the expression of imaging reporter genes for either bioluminescent or positron emission tomography (PET) imaging. The engineered PSES-TSTA system exhibits greatly elevated transcriptional activity, androgen independency, and strong prostate specificity, verified in cell culture and preclinical animal experimentations. These advantageous features of PSES-TSTA elicit superior gene expression capability for CRPC in comparison with the androgen-dependent PSA promoter-driven system. In preclinical settings, we showed robust PET imaging capacity of PSES-TSTA in a castrated prostate xenograft model. Moreover, intravenous administrated PSES-TSTA bioluminescent vector correctly identified tibial bone marrow metastases in 9 of 9 animals, whereas NaF- and FDG-PET was unable to detect the lesions. Taken together, this study showed the promising utility of a potent, androgen-independent, and prostate cancer-specific expression system in directing gene-based molecular imaging in CRPC, even in the context of androgen deprivation therapy.

Prostate cancer with Paneth cell-like neuroendocrine differentiation and extensive perineural invasion: Coincidence or causal relationship?

The case of a 74-year-old man is reported who suffered from a locally advanced prostate cancer treated by neoadjuvant hormonal ablation, followed by prostatectomy. Histological examination of the prostatectomy specimen disclosed an adenocarcinoma with partial, Paneth-like, neuroendocrine differentiation. Extensive perineural tumor invasion was found with a total of 921 perineural tumor foci. Neuroendocrine differentiation of tumor cells was accentuated in perineural locations and was associated with an elevated expression of N-CAM and vimentin, and a reduced expression of E-Cadherin and Ki-67. We hypothesize that neuroendocrine differentiation may promote perineural invasion of prostate cancer cells by a “catherin-switch” and by mechanisms involving epithelial-mesenchymal transition.

Patient reported incontinence after radical prostatectomy is more common than expected and not associated with the nerve sparing technique: Results from the center for prostate disease research (CPDR) database

The reported incidence of urinary incontinence (UI) after radical prostatectomy (RP) ranges from 2.5 to 87%. We reviewed data from the Center for Prostate Disease Research (CPDR) to determine the incidence of patient reported UI after RP (postRPUI) and establish risk factors for postRPUI. We obtained IRB approval to query the CPDR database on all patients undergoing RP between 1990 and 2007. We assessed patient age, nerve sparing status, blood loss, margin status, stage, and patient self-reported incontinence status as entered into the database. Patients were counted as having UI only if the database showed patient reported UI in every follow-up encounter. Patients were counted as permanently dry if at any time in the follow-up they answered that they had no UI. Four thousand three hundred seventy four patients underwent RP without radiation therapy or hormonal ablation between 1990 and 2007. Complete data were available for 1,616 (37%) and 1,459 (90.3%) reported UI more than 1 year after RP with a median follow-up of 50.7 months. Older age is an independent risk factor for UI (OR = 1.021, P ≤ 0.0003). Nerve sparing, blood loss, stage of cancer, and margin status were not predictive for UI. Our data indicate that patient reported post-RPUI is higher than expected but is not related to the nerve sparing technique, stage of cancer nor blood loss at the time of surgery.

Neoadjuvante Therapie vor radikaler Prostatektomie – Indikationen und Protokolle

As neoadjuvant chemotherapy is established for a variety of nonorgan confined malignancies, neoadjuvant hormone ablation for hormone sensitive prostate cancer has demonstrated encouraging results. Neoadjuvant therapy not only provides possible early systemic treatment for subclinical distant disease, but also aims to improve local disease control and to increase the number of patients eligible for definitive local therapy via downstaging. However, only limited, heterogenous studies are available. Therefore, prospective high quality studies are urgently needed to assess the future role of neoadjuvant hormone ablation.

Localized but Biochemicaly Progressing Prostate Cancer Under Long-Term Hormonal Ablation Treated by Therapeutic High-Intensity Focal Robotic Ultrasound

Treatment of hormone-refractory prostate cancer (HRPCa) is challenging and rewarding at the same time. Use of high-intensity focal ultrasound (HIFU) as primary prostate cancer therapy is still judged to be experimental, ignoring the fact that already more than 30.000 men worldwide have been treated and that 10 years data are available. Early onset of androgen deprivation therapy (ADT) and general longer patient survival lead to an increase in the number of patients requiring post-hormonal therapy resulting in increasing numbers of biochemical PSA relapse after few years.

Immunotherapy of prostate cancer: should we be targeting stem cells and EMT?

Cancer stem cells have been implicated in a number of solid malignancies including prostate cancer. In the case of localised prostate cancer, patients are often treated with surgery (radical prostatectomy) and/or radiotherapy. However, disease recurrence is an issue in about 30% of patients, who will then go on to receive hormone ablation therapy. Hormone ablation therapy is often palliative in a vast proportion of individuals, and for hormone-refractory patients, there are several immunotherapies targeting a number of prostate tumour antigens which are currently in development. However, clinical responses in this setting are inconsistent, and it is believed that the failure to achieve full and permanent tumour eradication is due to a small, resistant population of cells known as 'cancer stem cells' (CSCs). The stochastic and clonal evolution models are among several models used to describe cancer development. The general consensus is that cancer may arise in any cell as a result of genetic mutations in oncogenes and tumour suppressor genes, which consequently result in uncontrolled cell growth. The cancer stem cell theory, however, challenges previous opinion and proposes that like normal tissues, tumours are hierarchical and only the rare subpopulation of cells at the top of the hierarchy possess the biological properties required to initiate tumourigenesis. Furthermore, where most cancer models infer that every cell within a tumour is equally malignant, i.e. equally capable of reconstituting new tumours, the cancer stem cell theory suggests that only the rare cancer stem cell component possess tumour-initiating capabilities. Hence, according to this model, cancer stem cells are implicated in both tumour initiation and progression. In recent years, the role of epithelial--mesenchymal transition (EMT) in the advancement of prostate cancer has become apparent. Therefore, CSCs and EMT are both likely to play critical roles in prostate cancer tumourigenesis. This review summarises the current immunotherapeutic strategies targeting prostate tumour antigens taking into account the need to consider treatments that target cancer stem cells and cells involved in epithelial--mesenchymal transition.

Abstract 5574: mTOR is a target for omega-3 fatty acid modulation of prostate cancer progression

Abstract Prostate cancer is the second leading cause of cancer related deaths in men. The primary obstacle in effective treatment of prostate cancer is the progression of the disease from a hormone-dependent to a hormone-independent state. Previous studies indicate that activation of the mammalian Target of Rapamycin (mTOR) signaling pathway may be involved in progression of prostate cancer to androgen independence. Recent data indicate that the combination of androgen deprivation with mTOR inhibition provides an additive anti-tumor effect in vivo. mTOR activity is regulated by both growth factors and nutrients, suggesting that certain dietary interventions may have anti-cancer effects through regulation of mTOR. Epidemiological studies indicate an inverse relation between dietary intake of omega-3 fatty acids and prostate cancer risk. Omega-3 fatty acids have been shown to inhibit prostate cell growth both in vitro and in vivo. Preliminary data from our laboratory demonstrated that treatment of LNCaP prostate cancer cells with omega-3 fatty acids, specifically docosahexaonoic acid (DHA), delayed development of androgen independence in vitro. This delay correlated with a decrease in protein expression of downstream targets of mTOR regulation, including phosphorylated S6, Bcl-2, and cyclin D. We hypothesize that omega-3 fatty acids may prevent prostate cancer progression to a hormone independent phenotype in part through modulation of mTOR. To test this hypothesis, we established stable transfectant LNCaP cell lines that express a constitutively active mTOR. These clones displayed less sensitivity to hormone deprivation, resembling the response observed in our previously generated hormone refractory LNCaP cell line. Importantly, these clones with constitutively active mTOR also showed resistance to the inhibitory effects of DHA. Ongoing studies are using these clones to determine if omega-3 fatty acids mediate their effect on mTOR in an Akt-independent manner to delay progression of prostate cancer to a hormone refractory phenotype. We will investigate alternative pathways through which mTOR activity is modulated in prostate cancer signaling, These studies indicate that mTOR is critical for cellular response to hormone ablation, and that mTOR may be a viable target for delaying progression to a hormone refractory disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5574. doi:10.1158/1538-7445.AM2011-5574