Advanced Stage Prostate Research Articles

Evaluation of thresholding methods for the quantification of [68Ga]Ga-PSMA-11 PET molecular tumor volume and their effect on survival prediction in patients with advanced prostate cancer undergoing [177Lu]Lu-PSMA-617 radioligand therapy

PurposeThe aim of this study was to systematically evaluate the effect of thresholding algorithms used in computer vision for the quantification of prostate-specific membrane antigen positron emission tomography (PET) derived tumor volume (PSMA-TV) in patients with advanced prostate cancer. The results were validated with respect to the prognostication of overall survival in patients with advanced-stage prostate cancer.Materials and methodsA total of 78 patients who underwent [177Lu]Lu-PSMA-617 radionuclide therapy from January 2018 to December 2020 were retrospectively included in this study. [68Ga]Ga-PSMA-11 PET images, acquired prior to radionuclide therapy, were used for the analysis of thresholding algorithms. All PET images were first analyzed semi-automatically using a pre-evaluated, proprietary software solution as the baseline method. Subsequently, five histogram-based thresholding methods and two local adaptive thresholding methods that are well established in computer vision were applied to quantify molecular tumor volume. The resulting whole-body molecular tumor volumes were validated with respect to the prognostication of overall patient survival as well as their statistical correlation to the baseline methods and their performance on standardized phantom scans.ResultsThe whole-body PSMA-TVs, quantified using different thresholding methods, demonstrate a high positive correlation with the baseline methods. We observed the highest correlation with generalized histogram thresholding (GHT) (Pearson r (r), p value (p): r = 0.977, p < 0.001) and Sauvola thresholding (r = 0.974, p < 0.001) and the lowest correlation with Multiotsu (r = 0.877, p < 0.001) and Yen thresholding methods (r = 0.878, p < 0.001). The median survival time of all patients was 9.87 months (95% CI [9.3 to 10.13]). Stratification by median whole-body PSMA-TV resulted in a median survival time from 11.8 to 13.5 months for the patient group with lower tumor burden and 6.5 to 6.6 months for the patient group with higher tumor burden. The patient group with lower tumor burden had significantly higher probability of survival (p < 0.00625) in eight out of nine thresholding methods (Fig. 2); those methods were SUVmax50 (p = 0.0038), SUV ≥3 (p = 0.0034), Multiotsu (p = 0.0015), Yen (p = 0.0015), Niblack (p = 0.001), Sauvola (p = 0.0001), Otsu (p = 0.0053), and Li thresholding (p = 0.0053).ConclusionThresholding methods commonly used in computer vision are promising tools for the semiautomatic quantification of whole-body PSMA-TV in [68Ga]Ga-PSMA-11-PET. The proposed algorithm-driven thresholding strategy is less arbitrary and less prone to biases than thresholding with predefined values, potentially improving the application of whole-body PSMA-TV as an imaging biomarker.

Abstract 2270: Hyperlipidemia promotes aggressive variant prostate cancer via RNA-binding protein Quaking

Abstract Introduction: Hyperlipidemia has been associated with increased risk of advanced stage and high Gleason grade prostate cancer (PCa), yet the underlying mechanism is not completely understood. Quaking (QKI) is an RNA-binding protein (RBP) that regulate lipid metabolism. For PCa, QKI overexpression has been associated with increased chance of metastatic recurrence. Method: We performed RNA sequencing of prostate cancer tissues of hyperlipidemia (n = 12) and normolipidemia (n=32). Tissue samples were acquired by MRI-US fusion targeted biopsy. DESeq2 and GSEA was used to identify differently expressed genes and enriched genesets. A web-based RBP motif screening tool TRANSITE was utilized to identify active RBPs in hyperlipidemia-associated PCa. Results: PCa samples of hyperlipidemia patients exhibited poorer histology than normolipidemia PCA. RNA sequencing found that hyperlipidemia-associated PCa is enriched of Myc-regulated genes as well as interferon or innate immunity-associated genes. Interestingly, hyperlipidemia-associated PCa gene expression signature identified PCa samples devoid of common PCa genetic alterations - TMPRSS2-ERG fusion and PTEN deletion/mutation. RBP motif screening found QKI as one of the top enriched RBP in hyperlipidemia-associated PCa transcriptome. In a separate a consecutive radical prostatectomy series (n=190), we found that QKI-high (immunohistochemistry staining score 2-3) tumors had significantly higher serum cholesterol than QKI-low (score 0-1) tumors. Overexpression and knockdown experiments proved that QKI is responsible of rapid cell proliferation and interferon-related inflammatory gene expressions, In silico analysis predicted QKI overexpressing cancer cells are susceptive to stain-mediated ferroptosis-like cell death. Mechanistically, QKI regulates expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which dictates the sensitivity of QKI overexpressing cells to ferroptosis. Conclusion: Hyperlipidemia was associated with aggressive pathologic characteristics of PCa without TMPRSS2-ERG fusion or PTEN deletion/mutation, and high tissue expression of QKI, an RNA-binding protein. QKI overexpression in PCa increased sensitivity to ACSL4-mediated ferroptosis by statins. This explains the epidemiological associations between hyperlipidemia and PCa, and will guide molecular subtype-driven drug repurposing studies. Citation Format: Hyun Ho Han, Jin Sol Sung, Dong Wook Song, Cheol Keun Park, Nam Hoon Cho, Young Deuk Choi, Woo Jin Ko. Hyperlipidemia promotes aggressive variant prostate cancer via RNA-binding protein Quaking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2270.

A Multi-Center Retrospective Analysis Examining the Effect of Dipeptidyl Peptidase-4 Inhibitors on Progression-Free Survival in Patients With Prostate Cancer.

BackgroundCluster of differentiation 26/dipeptidyl peptidase-4 (DPP4) is a cell surface glycoprotein with multifaceted roles, including immune regulation, glucose metabolism, and tumorigenesis. Recent literature has identified DPP4 inhibitors to improve survival in diabetic patients with prostate cancer. DPP4 inhibitors have been proposed to play a role in prostate cancer, as DPP4 is found at higher levels in malignant prostate tissue compared to benign and correlates with PSA levels and cancer stage. In this multi-center retrospective study, we aim to define the effects of DPP4 inhibitors on progression-free survival (PFS) in diabetic patients with advanced-stage prostate cancer.MethodologyWe performed a retrospective analysis of 161 patients with diabetes and advanced-stage (III or IV) prostate cancer at the University of Florida Health Cancer Center and Moffitt Cancer Center. Our cohort included 120 patients on metformin (control group) and 41 on a DPP4 inhibitor (study group).ResultsNo significant difference in progression of prostate cancer was identified between those on DPP4 inhibitors versus metformin (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.64-1.61; p = 0.955). Median time to progression was 3.5 years (range: 2.4-4.6 years).ConclusionsDespite prior literature indicating survival benefit of DPP4 inhibitors in prostate cancer, our study did not identify a statistically significant improvement of PFS in diabetic patients with advanced prostate cancer. Additional analysis with larger sample sizes and prospective investigation with study of tumor microenvironment are needed to evaluate clinical impact and potential survival benefit of DPP4 inhibitors in prostate cancer.

Abstract 4097: Enhanced synergistic efficacy of simvastatin and metformin on enzalutamide resistant prostate cancer cells

Abstract Androgen deprivation therapy (ADT) continues to be the mainstay therapy for advance-stage prostate cancer. Although malignant cells respond to ADT initially, subsequently colonize and re-emerge as castration-resistant prostate cancer (CRPC). Enzalutamide (ENZU), a second-generation AR antagonist exhibits survival advantage in CRPC patients, however, ~30% of patients develop resistance after ENZU treatment, activating AR in these tumors. These ENZU-resistant tumors poorly respond to chemotherapy and other treatment modalities. Therefore, identification of an effective low-cost therapeutic alternative with fewer side effects may lead to increased survival and greatly benefit the quality-of-life of these patients. Activation of aerobic glycolysis and biomass production is implicated, in part, to be responsible for CRPC cells to acquire androgen resistance. Previous studies from our laboratory have demonstrated that synergistic combination of simvastatin (SIM), a drug for the treatment of hypercholesterolemia and metformin (MET), a glucose-lowering drug inhibits CRPC growth, invasiveness and migration with minimal effect on normal prostate epithelial cells (Mol Cancer Ther. 13(10):2288-2302, 2014). Here we examine whether the combination of SIM and MET could be effective in the treatment of ENZU-resistant prostate cancer cells. Human CRPC cells viz. C4-2B and its variant C4-2B-ENZU (C4-2B enzalutamide resistant) and 22Rv1 were used for the experiments. C4-2B-ENZU cells were generated by growing C4-2B cells in 20µM ENZU over 6 months and maintained in 5µM ENZU in the cell culture medium. 22Rv1 cells were inherently resistant to ENZU treatment. Both cells were treated with SIM (4µM) and MET (2mM) individually and in combination, followed by the assessment of cell viability, crystal violet assay, cell cycle analysis, migration, invasion, and expression of various target genes by Western blotting. C4-2B-ENZU and 22Rv1 cells were treated with a combination of SIM and MET at pharmacological dose range (500nM-4µM SIM and 250µM-2mM MET). Combination treatment with 4μM SIM and 2mM MET (SIM+MET) led to significant and synergistic inhibition of cell viability, migration, invasion and cell cycle blockade in both cancer cell lines. The individual treatments of SIM and MET exhibited little or no effect on these cells. Furthermore, SIM+MET combination decreased the expression of AR, AR-V7, p-Akt (Ser473), p-AMPKα1/α2 (Ser-485/491) and simultaneously increased p-AMPKα1 (Thr-172) and AMPKα kinase activity in these cells. We demonstrate, for the first time, that synergistic combination of SIM and MET may be an effective regimen for treatment ENZU-resistant prostate cancer cells. Citation Format: Eswar Shankar, Pingfu Fu, Gregory T. MacLennan, Sanjay Gupta. Enhanced synergistic efficacy of simvastatin and metformin on enzalutamide resistant prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4097.

Variation in TRMT11 gene as a prognostic marker in advanced-stage castrate-resistant prostate cancer (CRPC) patients.

Variation in <i>TRMT11 </i>gene as a prognostic marker in advanced-stage castrate-resistant prostate cancer (CRPC) patients.

Variation in TRMT11 gene as a prognostic marker in advanced-stage castrate-resistant prostate cancer (CRPC) patients.

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS&lt;7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C&gt;G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]

Abstract 320: New metastatic murine prostate cancer cell lines and preclinical model of human prostate cancer.

Abstract Defining oncogene-specific molecular pathways required for the induction and maintenance of prostate cancer is essential for the rational design of new therapies. Identifying molecular predictors of prostate cancer patient survival is important for patient therapeutic substratification. We generated murine prostate cancer cell lines via selective transduction with a single oncogene (c-Myc, Ha-Ras, NeuT, and v-Src). These cell lines demonstrate contact-independent growth characteristics in soft agar, and have the substantial growth advantage over primary prostate epithelial cells. Each of the prostate lines grew tumor in immune competent mice after subcutaneous injection, and develop lung metastasis in c-Myc, Ha-Ras, and v-Src cell line groups. RNA samples were prepared from the these cell lines, Microarray analysis identified a total of 2635 out of 22115 genes that were significantly altered in expression (at least two-fold change) in oncogene over-expressing cell lines when compared with prostate epithelial cell control samples. The distinct oncogene expression signature was compared to gene signatures obtained from other published databases to identify similarities to human prostate cancer phenotypes. Comparisons were performed against gene signatures representative of differential expression in advanced state vs. early stage prostate cancer, high grade vs low grade prostate cancer, recurrent vs. nonrecurrent, the results indicate a significant degree of similarity between the prostate oncogene expression signature and high-grade disease; between the oncogene expression signature and the advanced stage disease phenotype. Interrogation of two distinct cohorts of Prostate cancer patient samples using the oncogene signature demonstrated an ability to distinguish tumor from normal prostate with a predictive value for prostate cancer of 98 - 99%. The signature provided in blinded study independent substratification of reduced recurrence free survival by Kaplan-Meier analysis. The generation of new oncogene-specific prostate cancer cell lines that recapitulate human prostate cancer gene expression, that metastasize in immune-competent mice, are a valuable new resource for testing targeted therapy. The molecular signatures identified herein provide further value over current markers of prediction and outcome. Citation Format: Xiaoming Ju, Richard G. Pestell. New metastatic murine prostate cancer cell lines and preclinical model of human prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2013-320

Association of germ-line genetic variation in the NK3 homeobox 1 gene with overall survival in advanced-stage castrate-resistant prostate cancer (CRPC).

75 Background: We investigated the association of germline variation in ten candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with overall survival (OS) in a cohort of metastatic CRPC stage patients. Methods: Patients (N=497) were enrolled at the time of androgen deprivation therapy failure for D2 stage prostate cancer. Candidate genes were selected from the literature and pilot studies. Genes were tagged using SNPs from HapMap with minor allele frequency (MAF) of &gt;5% and r2≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was OS, defined as time from development of CRPC to death. Principle components analysis was used for gene-levels tests. To account for multiple testing we calculated the false discovery rate (FDR). For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and adjusted for age and Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 497 Caucasian subjects. The median age of the CRPC cohort was 71 years (range 43,93). The GS distribution was 51% subjects with GS≥8; 32% with GS7 and 17% with GS&lt;7. After a median follow up of 2.1 years (IQ range: 1.2-3.6), 297 subjects had died. In unadjusted gene level analyses, NKX3-1 (p=0.04; FDR=0.03) was associated with OS. After adjusting for age and GS the result remained significant (p=0.03). Two of the 5 genotyped SNPs in this gene were associated with OS after adjustment for age and GS: rs10503733 (dominant model p=0.03, HR=0.77; 95 CI=0.60-0.98; A&gt;C; MAF = 0.22) and rs7005368 (dominant model p=0.05, HR=1.38, 95CI=1.0-1.92; G&gt;A; MAF=0.07). Both SNPs are in Hardy Weinberg Equilibrium and in complete LD (D'=1), although r2 is low (r2=0.025) due to different allele frequencies. Conclusions: Variation in the homeobox NKX-1 gene, a prostate specific tumor suppressor gene involved in prostate development and carcinogenesis is significantly associated with OS in CRPC after accounting for age and GS. Further validation is needed to develop these as prognostic biomarkers.

Capturing Treatment Decision Making Among Patients With Solid Tumors and Their Caregivers

To examine the feasibility and acceptability of using a decision aid with an interactive decision-making process in patients with solid tumors and their caregivers during cancer-related treatment. A phenomenologic approach was used to analyze qualitative data, with a focus on the meaning of participants' lived experiences. Interviews were conducted by telephone or in person. Outpatient clinics at two regional cancer centers. 160 total individuals; 80 patients with newly diagnosed breast (n = 22), advanced-stage prostate (n = 19), or advanced-stage lung (n = 39) cancer, and their caregivers (n = 80). Twenty-seven of the 80 pairs engaged in audio recorded interviews that were conducted using a semistructured interview guide. Continuous text immersion revealed themes. Validity of qualitative analysis was achieved by member checking. Significant findings included three themes: (a) the decision aid helped patients and caregivers understand treatment decisions better, (b) the decision aid helped patients and caregivers to be more involved in treatment decisions, and (c) frequent contact with the study nurse was valuable. Decision making was more complex than participants expected. The decision aid helped patients and caregivers make satisfying treatment decisions and become integral in a shared treatment decision-making process. Decision aids can help patients and their caregivers make difficult treatment decisions affecting quantity and quality of life during cancer treatment. The findings provide valuable information for healthcare providers helping patients and their caregivers make treatment decisions through a shared, informed, decision-making process. Decision aids can be helpful with treatment choices. Caregivers' understanding about treatment is just as important in the decision-making process as the patients' understanding. Incorporating decision aids that are delivered by healthcare providers or trained personnel has the potential to improve patients' decision satisfaction.

Abstract PR04: Prostate cancer risk and dietary folate in a multiethnic population: Higher intake increases risk in the California Collaborative Prostate Cancer Study.

Abstract Background: High intake of dietary folate has been associated with both increased and decreased risk of prostate cancer in some previous epidemiologic studies which included mostly non-Hispanic white men. Timing of high folate intake may determine its impact on lesion development. In studies of colon cancer, for instance, high dietary folate appears protective in prelesion men, whereas high folate consumption in postlesion men accelerates cancer cell proliferation. We investigated the association between dietary folate intake and risk of advanced and localized prostate cancer among African American and White men from the California Collaborative Prostate Cancer Study. Methods: We examined 737 African American cases (233 advanced stage at diagnosis; 264 localized) and controls (N=240); and 1357 White cases (905 advanced stage; 452 localized) and controls (N=855). Folate intake during the reference year (1 year prior to diagnosis for cases or study selection for controls) was assessed by modified Block Food Frequency Questionnaire and categorized by quartiles. Risk was estimated by fitting conditional logistic regression models adjusted for race/ethnicity, age, and family history of prostate cancer. Results: Dietary folate intake was linearly related to risk of prostate cancer (p&amp;lt;0.001). Risk increased by 16% for each increase of one quartile. Men in the upper quartile of intake (&amp;gt;632 mg/day) were at 45% increased risk compared to men in the lowest quartile (OR=1.45, 95% CI 1.16-1.81). The associations for advanced (OR=1.41, 95% CI 1.11, 1.81) and localized (OR=1.57, 95% CI 1.17, 2.11) disease were similar. The results were similar for African Americans and Whites. Conclusions: Recent high folate intake appears to be a risk factor. Men who consume high levels of dietary folate in the postlesion period may be at substantially greater risk for both advanced stage and localized prostate cancer in this multi-ethnic study. This abstract is also presented as Poster B43. Citation Format: Glovioell W. Rowland, Esther M. John, Sue A. Ingles. Prostate cancer risk and dietary folate in a multiethnic population: Higher intake increases risk in the California Collaborative Prostate Cancer Study. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PR04.

Sun Exposure and the Risk of Prostate Cancer in the Singapore Prostate Cancer Study: a Case-control Study

Most of the epidemiology studies on the effects of sun exposure and prostate cancer were conducted among the temperate countries of North America and Europe. Little is known about the influence on Asian populations. The purpose of current study was to evaluate any association of sun exposure with risk of prostate cancer in Chinese, Malays and Indians who reside in the tropics. The Singapore Prostate Cancer Study is a hospital-based case-control study of 240 prostate cancer incident cases and 268 controls conducted in Singapore between April 2007 and May 2009. Detailed information on outdoor activities in the sun, skin colour, sun sensitivity and other possible risk factors were collected in personal interviews. Cases were further classified by Gleason scores and TNM staging. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression analysis, adjusted for age, ethnicity, education, family history of any cancers, BMI and skin colour. We found that prostate cancer risk was increased in subjects with black/dark-brown eyes (OR 5.88, 95%CI 3.17-10.9), darker skin colour e.g. tan/dark brown/black (OR 7.62, 95%CI 3.41-17.0), frequent sunburn in lifetime (OR 4.30, 95%CI 1.7-11.2) and increased general sun exposure in adulthood per week (OR 2.03, 95%CI 1.09-3.81). The increased risk was consistent for high grade tumours and advanced stage prostate cancers. The findings from this study suggest that excessive sun exposure is a risk factor for prostate cancer in Asians.

Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on multifunctional T-cell responses in ovarian, breast, and prostate cancer patients.

2588 Background: To increase the efficacy of peptide cancer vaccines, we developed a novel vaccine platform called DepoVax, an adjuvanted water-free depot formulation with the ability to generate enhanced immune responses. Naturally processed HLA-A2 restricted peptides that are selectively presented by breast, ovarian and prostate cancer cell lines, but not by normal HLA-A2+ cells, were used as antigens with a proprietary adjuvant and a T helper peptide epitope to create a therapeutic cancer vaccine, DPX-0907. Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose volume cohorts in a three immunization clinical protocol. Results: DPX-0907 proved to be safe with no serious adverse effects related to the vaccine reported. Of those evaluable for immunogenicity, all breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated immune response to one or more of seven antigenic peptides, resulting in a 61% response rate. Immune responses correlated with achievement of CR, PR or SD to last treatment. No difference in immune response rate or magnitude was seen between the two dose groups. DPX-0907 displayed strong immune induction potential, with 73% of immune responders showing responses with just one dose of vaccine. In 83% of responders, immune responses were detected at ≥2 time points post vaccination and 64% had a persistent immune response at one month post last vaccination. Immune monitoring showed peptide-specific CD8 T cells, and these T cells were able to secrete multiple Th1 cytokines indicating their multifunctionality, a feature attributable to cells that mediate protective responses. Conclusions: These data support the ability of DPX-0907 to elicit Th1 dominated, specific immunity and support the rationale for further testing in immunologically competent cancer patients. The novel DepoVax formulation may promote multifunctional memory responses with peptides from other tumor associated antigens.

Abstract 165: The anticarcinogenic effects of melatonin on inhibition of fatty acid transport and 13-HODE production in HT29 human colorectal cancer occurs via receptor-mediated signal transduction

Abstract Over 620,000 people in the U.S. alone this year will be diagnosed with either breast, prostate, or colorectal cancers, which represent nearly 50% of all reported malignancies. Patients with advanced stage breast, prostate, or colorectal cancer have only a 35% survival rate at 5 years. Epidemiological studies have indicated that the risk of these cancers is increased in persons exposed to excessive sunlight or, interestingly, ocular light at night, as experienced by night-shift workers. This latter finding was shown to be associated with a suppression of the nighttime production of the circadian neurohormone melatonin. Previous work from this laboratory using perfused, tissue-isolated human breast and prostate tumors showed that tumor growth and metabolism in vivo is dependent upon uptake of linoleic acid (LA), the most prominent fatty acid in our western diet, and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE). In tissue-isolated human MCF-7 (steroid responsive and non-responsive) and PC3 prostate tumors perfused in situ with arterial blood, melatonin inhibits LA-uptake and conversion to 13-HODE, a lipoxygenase product that stimulates EGF mitogenesis. The present study explores the effects in vivo of melatonin (500 pM) on perfused, tissue isolated HT29 colorectal carcinomas in nude rats. HT29 colorectal carcinoma latency-to-onset and growth rates, respectively, of 12 days and 0.12 ± 0.01 g/day; mean tumor weights were 5.6 ± 0.2 g (n = 20). Colorectal carcinomas perfused in situ with donor rodent blood for 2 hours (Controls) revealed a tumor LA uptake and 13-HODE release of 0.86 ± 0.08 μg/min/g (20.0 ± 1.6% of arterial supply) and 3.23 ± 0.81 ng/min/g, respectively. Incorporation of 3H-thymidine into tumor DNA and DNA content, respectively were 25.9 ± 1.6 dpms/μg DNA and 2.7 ± 0.1 μg/g tumor. Carcinomas perfused with arterial donor blood augmented with physiological nocturnal levels of 500 pM melatonin showed a complete inhibition of LA uptake, 13-HODE release, ERK 1/2, MEK, Akt, and GSK3β activities, and over a 90% reduction in tumor cAMP levels and [3H]thymidine incorporation into tumor DNA. Addition of the non-selective MT1/MT2 melatonin antagonist S20928, forskolin, 8-Bromo-cyclic-AMP, or pertussis toxin completely reversed the tumor growth inhibitory response. Also, addition of 13-HODE reversed the inhibition of 3H-thymidine incorporation into tumor DNA, while having no effect on LA uptake. These results are the first to demonstrate in HT29 colorectal carcinoma that nocturnal melatonin levels suppress tumor growth via a melatonin receptor-mediated signal transduction mechanism. An understanding of this signaling pathway for the control of LA uptake in cancer could lead to new approaches for therapeutic intervention and/or chemoprevention. 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 165. doi:1538-7445.AM2012-165

A phase I study of the safety and immunogenicity of a therapeutic vaccine, DPX-0907 in patients with advanced-stage ovarian, breast, or prostate cancer.

e13050 Background: Immunovaccine Inc. (IMV) has developed a novel liposome-in-oil depot vaccine platform called DepoVax (DPX), which increases the potency of peptide-based vaccines. DPX-0907 is a D...

Abstract B92: Serum total and HDL cholesterol and risk of prostate cancer

Abstract Background: There has been growing support for the hypothesis that low cholesterol may protect against prostate cancer with a poorer prognosis. Studies suggest a decreased risk of high-grade prostate cancer in men with lower circulating total cholesterol, and that statin drugs may protect against aggressive prostate cancer. Confirmation of these findings in additional populations and examination of lipoprotein subfractions is needed. We prospectively examined prostate cancer risk and serum total and HDL cholesterol in the ATBC Study cohort. Methods: The ATBC Study was a randomized controlled trial conducted among male smokers in Finland to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence. Fasting blood samples were collected at baseline (1985 — 1988), and total and HDL cholesterol were measured for all participants (n=29,133). Cohort follow-up continues through the Finnish Cancer Registry and the Register of Causes of Death. Cox proportional hazards models were used to estimate the relative risk of overall (n=2,041), high stage (≥ TNM stage III or AJC stage 3; n=412), high grade (Gleason sum ≥ 7; n=231), aggressive (either high stage or high grade; n=461), and non-aggressive (neither high stage nor high grade; n=829) prostate cancer by categories of total (&amp;lt;200, 200 — &amp;lt;240, ≥240 mg/dL) and HDL (&amp;lt;40, 40 — &amp;lt;60, ≥60 mg/dL) cholesterol. Multivariable models adjusted for age, serum α-tocopherol, family history of prostate cancer, education, and urban residence. Further adjustment for the following factors did not alter the results: α-tocopherol and β-carotene supplementation group, serum β-carotene, cigarettes per day, years smoked, physical activity, marital status, and intake of total energy, total fat, fruits and vegetables, red meat, alcohol, vitamin A, vitamin D, and calcium. Results: Men with high serum total cholesterol were at increased risk of prostate cancer, particularly high stage disease (≥240 vs. &amp;lt;200 mg/dl: HR=1.26, 95% CI 0.92 — 1.71, p-trend = 0.03). Stratification by follow-up time showed that the increased risk of prostate cancer for men with higher total cholesterol was limited to cases diagnosed at least 10 years after baseline. After excluding the first 9 years of follow-up, men with higher serum total cholesterol were at an increased risk of overall (≥240 vs. &amp;lt;200: HR=1.22, 95% CI 1.03 — 1.44, p-trend=0.01) and advanced-stage (≥240 vs. &amp;lt;200: HR=1.85, 95% CI 1.13 — 3.03, p-trend=0.05) prostate cancer. Higher HDL cholesterol appeared related to decreased risk of prostate cancer, overall and all clinical subtypes, throughout the follow-up period. Conclusion: In this population of male smokers with a low prevalence of PSA screening, high serum total cholesterol was associated with an increased risk of advanced prostate cancer, but only among cases diagnosed at least 10 years after baseline. Further, there was a suggestion that high HDL cholesterol reduced the risk of all clinical subtypes of prostate cancer. These results support previous studies and, indirectly, support the hypothesis that statin drugs may reduce the risk of prostate cancer with a poorer prognosis by lowering cholesterol concentrations. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B92.

Development of a novel poly bisphosphonate conjugate for treatment of skeletal metastasis and osteoporosis

Advanced stage prostate and breast cancer frequently metastasize to the skeleton (approximately 75%). An additional complication in these patients, that further affects the bones, is that their hormonal treatment, induces osteoporosis. Bisphosphonates (bpns) are standard drugs against osteoporosis and have been shown to have clinically significant anti-tumor effects. This study describes the development of a new polybisphosphonate conjugate (ODX) with enhanced dual efficacy i.e. with anti-bone resorption and anti-tumor properties. Zoledronic acid (Zometa) was used as a positive control (at equimolar concentrations). Alendronic acid and aminoguanidine were conjugated to oxidized dextran with subsequent reductive amination (on average approximately 8 alendronate and approximately 50 guanidine moieties per conjugate). ODX was tested in a bone resorption assay for its capacity to inhibit bone resorbing osteoclasts (bone organ culture from neonatal mice, 45Ca labelled bone mineral). Tumor cell toxicity was studied on prostate (PC3) and breast cancer (MDA231, MDA453) cell cultures. Two methods were employed, a fluorescent cytotoxicity assay (FMCA) and an apoptosis assay (Annexin V assay). In the bone resorption assay, Zometa and ODX showed very similar potency with 50% osteoclast inhibition at approximately 20 nM and 100% at 0.2 microM. In the FMCA, IC50 for ODX was at approximately 2 microM and 25 microM for Zometa (PC3). In the apoptosis assay, ODX induced approximately 85-97% apoptosis at 10 microM in both cell lines, while Zometa failed to induce any significant apoptosis in any of the cell lines at the tested concentration range (10 nM-10 microM). ODX appears to be a promising drug candidate with high dual efficacy for the treatment of bone metastasis and osteoporosis. It has both potent osteoclast inhibiting properties and enhanced anti-tumor efficacy.

Thrombin receptor expression is upregulated in prostate cancer

Aberrant expression of protease-activated receptors (PARs) has been associated with increased angiogenesis, tumor growth, and metastasis of various cancers. We assessed the status of PAR1 expression in prostate cancer. The study compared the abundance levels of PAR1 RNA and protein using real-time reverse-transcriptase polymerase chain reaction and immunoblotting in freshly resected prostate tissues from early localized-stage disease (n=9) to those from patients with advanced metastatic disease (n=7). PAR1 expression and localization was evaluated using immunohistochemical staining of prostate specimens with benign prostatic hyperplasia (n=27), early- (n=32) and advanced-stage (n=22) prostate cancer. Association analyses of PAR1 expression with expression of VEGF-family of growth factors, their receptors, and clinicopathological characteristics of the patients were also performed. PAR1 RNA expression in advanced-stage prostate was 2.39-fold higher (P=0.024) and its protein expression was 2.75-fold higher (P=5.89x10(-5)) when compared with early-stage prostate cancer. PAR1 expression was localized to endothelial cells in vascular network of prostate tumor areas. The expression of PAR1 correlated statistically significantly with advanced disease stage (P=0.0006) and pre-operative PSA levels (P=0.005) in these samples. These findings demonstrate that PAR1 expression is increased in prostate cancer. Its predominant expression in vascular network suggests that it may play a direct and crucial role in angiogenesis and could be a relevant target for therapeutic interventions to control or to prevent disease progression.

Overexpression of FGF8B in advanced stage and high grade prostate cancer

Overexpression of FGF8B in advanced stage and high grade prostate cancer