Long-term aspirin use and intratumoral gene expression in prostate cancer.

106 Background: Pharmacoepidemiologic studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that prostate cancer tissue from regular aspirin users at cancer diagnosis compared to nonusers is characterized by specific transcriptional changes. Methods: We analyzed tumor whole-transcriptome data from men diagnosed with prostate cancer during prospective follow up of the Physicians Health Study 1 (PHS1, n1 = 150), initially a randomized-controlled trial of aspirin for prevention of cardiovascular disease and cancer. We compared the expression of putative aspirin target genes ( PTGS2, CTNNB1, MYC, AXIN2, PTGER3) between regular aspirin users ( ≥ 3 x 324 mg/week) and non-users at cancer diagnosis. We used Gene Set Enrichment Analysis to identify Gene Ontology biological process gene sets (total, 3609) associated with aspirin use. Leading edge genes of ≥ 3 functionally related gene sets were summarized in a meta-gene score. Results were validated among prostate cancer patients from the Health-Professionals Follow-up Study (HPFS, n2 = 254; aspirin use, ≥ 2 x/week). Results: Regular aspirin use was common (65% in PHS1; 45% in HPFS) and not associated with age, stage, and Gleason grade. In PHS1, none of the predefined genes were associated with aspirin use (all p > 0.05). 26 gene sets were downregulated in aspirin users at a false discovery rate (FDR) < 0.25 (9 at FDR < 0.05). 11 gene sets were clustered functionally around ribosome function and protein translation. A “ribosome” score of 96 genes was higher in aspirin users compared to nonusers (difference, 35.5 standard deviations [SD]; p = 0.0001). There was no dose-dependency for cumulative duration of aspirin use before cancer diagnosis ( ptrend = 0.17) or time since stopping use among non-users at diagnosis ( p = 0.32). In HPFS, neither the pre-defined target genes (all p > 0.18) nor the score were associated with aspirin use (difference, –9.8 SD; p = 0.18). Conclusions: Although RNA acetylation and resulting intratumoral gene expression changes due to aspirin use may be biologically plausible, we were unable to corroborate this association in two-long term prospective studies. Short-term trials might assess if aspirin has direct effects on tumor gene expression.

Download Full-text

Differential gene expression in prostate tissue according to vasectomy.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.298 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 298-298

Author(s):

Kathryn M Wilson ◽

Travis Gerke ◽

Ericka Ebot ◽

Jennifer A Sinnott ◽

Jennifer R. Rider ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cancer Diagnosis ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Prostate Tissue ◽

Gene Set Enrichment ◽

Normal Prostate ◽

Gene Sets ◽

Normal Prostate Tissue

298 Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.

Download Full-text

Prospective evaluation of fexapotide triflutate injection treatment of Grade Group 1 prostate cancer: 4-year results

World Journal of Urology ◽

10.1007/s00345-020-03127-w ◽

2020 ◽

Vol 38 (12) ◽

pp. 3101-3111

Author(s):

Neal Shore ◽

Steven A. Kaplan ◽

Ronald Tutrone ◽

Richard Levin ◽

James Bailen ◽

...

Keyword(s):

Prostate Cancer ◽

Gleason Grade ◽

Grade Group ◽

Serious Adverse Events ◽

Total Incidence ◽

Grade Increase ◽

Fexapotide Triflutate ◽

Group 1

Abstract Purpose This study was undertaken to determine the safety and efficacy of fexapotide triflutate (FT) 2.5 mg and 15 mg for the treatment of Grade Group 1 prostate cancer. Methods Prospective randomized transrectal intraprostatic single injection FT 2.5 mg (n = 49), FT 15 mg (n = 48) and control active surveillance (AS) (n = 49) groups were compared in 146 patients at 28 U.S. sites, with elective AS crossover (n = 18) to FT after first follow-up biopsy at 45 days. Patients were followed for 5 years including biopsies (baseline, 45 days, and 18, 36, and 54 months thereafter), and urological evaluations with PSA every 6 months. Patients with Gleason grade increase or who elected surgical or radiotherapeutic intervention exited the study and were cumulatively included in the data analysis. Percentage of normal biopsies in baseline focus quadrant, tumor grades, and volumes; and outcomes including Gleason grade in entire prostate as well as treated prostate lobe, interventions associated with Gleason grade increase and total incidence of interventions were assessed. Results Significantly improved long-term clinical outcomes were found after 4-year follow-up, with percentages of patients progressing to interventions with and without Gleason grade increase significantly reduced by FT single treatment. Results in the FT 15-mg group were superior to the FT 2.5-mg dose group. There were no drug-related serious adverse events (SAEs). Conclusions FT showed statistically significant long-term efficacy in the treatment of Grade Group 1 patients regarding clinical and pathological progression. FT 15 mg showed superior results to FT 2.5 mg. There were no drug-related SAEs; FT injection was well tolerated.

Download Full-text

Contrary Functions of NF-κB Signaling in Anti-Cancer Treatment Outcome

Blood ◽

10.1182/blood.v118.21.1652.1652 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1652-1652

Author(s):

Julia Kase ◽

Hua Jing ◽

Jan R Dörr ◽

Maja Milanovic ◽

Dido Lenze ◽

...

Keyword(s):

Gene Expression ◽

Treatment Outcome ◽

Cancer Treatment ◽

B Cell ◽

Target Genes ◽

Gene Set Enrichment Analysis ◽

Term Outcome ◽

Long Term Outcome ◽

Anti Cancer

Abstract Abstract 1652 Nuclear factor-κB (NF-κB) transcription factors are involved in cancer-relevant processes such as suppression of apoptosis, growth promotion, enhanced migration and invasiveness, although their actual role as oncogenic or tumor-suppressive activities remains controversial. Moreover, NF-κB-mediated suppression of apoptosis has been linked to chemoresistance. Interestingly, cellular senescence, a terminal cell-cycle arrest initiated via DNA-damaging chemotherapy as well, and known to improve long-term outcome, is associated with the massive induction of secretable NF-κB target genes, which, in turn, potentially reinforce the senescence phenotype. In this study, primary Eμ-myc transgenic mouse lymphomas as a well established model for human aggressive B-NHL, and information from human diffuse large B-cell lymphomas (DLBCL) were used in a cross-species approach to identify oncogenic networks in which chemotherapy-activated NF-κB signaling no longer mediates resistance but promotes therapy-induced senescence (TIS) and contributes to the outcome of anti-cancer treatment. Primary Myc-driven lymphoma cells, stably bcl2-transduced to block apoptosis, were exposed to the DNA-damaging chemotherapeutic agent adriamycin (ADR) to induce TIS. Gene set enrichment analysis of microarray-based gene expression profiles from drug-senescent vs. untreated cells found NF-κB target genes strongly skewed towards the TIS group, and multiplex ELISA-based analysis detected significantly higher DNA binding activities for the NF-κB family subunits p50, p52, p65 (RelA) and RelB in senescent cells. Inactivation of NF-κB by stable expression of the NF-κB super-repressor IκBα-δN (SR) lowered expression levels of NF-κB target genes in ADR-treated lymphomas. Matched pairs of individual primary lymphomas differing only in their SR status displayed compromised senescence induction in vivo when expressing the SR, indicating that TIS depends on intact NF-κB function. To assess the contribution of endogenous NF-κB signaling to long-term outcome, we grouped primary Myc-lymphomas by their NF-κB activity levels as “NF-κB low” (NL) or “NF-κB high” (NH). ADR-treated NH, but not NL lymphomas presented selective vulnerability to the SR moiety. Recapitulating the clinical outcome of patients suffering from DLBCL, around 60% of the mice harboring Eμ-myc lymphomas achieved long-term remissions, while the remaining 40% encountered a relapse after chemotherapy. Relapsing Myc-lymphomas exhibited substantially higher expression of the NF-κB targets IκBα and bcl2, reminiscent of activated B-cell-like (ABC) DLBCL, the clinically inferior subtype characterized by constitutively active NF-κB signaling. In contrast, germinal center B-cell-like (GCB) DLBCL rarely possess activating NF-κB mutations, but frequently develop in the context of a t(14;18) translocation that drives Bcl2 overexpression independent of NF-κB. Induced NF-κB target gene expression and increased TIS induction after overexpression of an NF-κB-activating CARD11 mutant suggested that higher NF-κB activity may contribute to treatment outcome via TIS promotion. Indeed, stratifying a large dataset of untreated GEP and corresponding clinical data after immunochemotherapy from 233 DLBCL patients by a 63-gene NF-κB expression signature (Shaffer-AL et al, Immunol Rev, 2006; Lenz-G et al, N Eng J Med, 2008), confirmed for the subset of GCB patients with above-median Bcl2 expression – the group whose genetic features we modeled before in the mouse – a significantly superior progression-free survival. In essence, our “cross-species” investigations demonstrate opposing roles of NF-κB in treatment outcome and have important ramifications for clinical trials that aim at inhibiting NF-κB signaling in DLBCL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

8: Predictors of HRQOL Duirng Long-Term Follow-Up of Men Treated for Prostate Cancer

The Journal of Urology ◽

10.1016/s0022-5347(18)30273-8 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 3-4

Author(s):

George J. Huang ◽

Natalia Sadetsky ◽

Peter R. Carroll ◽

David F. Penson

Keyword(s):

Prostate Cancer ◽

Long Term Follow Up

Download Full-text

Development of Internet-Accessible Prediction Models for Prostate Cancer Diagnosis, Treatment, and Follow-Up

10.21236/ada413542 ◽

2003 ◽

Author(s):

Leon Sun ◽

Judd W. Moul ◽

Hongyu Wu ◽

Fatiha Bensouda ◽

Holly Wu

Keyword(s):

Prostate Cancer ◽

Cancer Diagnosis ◽

Prediction Models ◽

Prostate Cancer Diagnosis

Download Full-text

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1574888x13666180105125347 ◽

2018 ◽

Vol 21 (2) ◽

pp. 74-83

Author(s):

Tzu-Hung Hsiao ◽

Yu-Chiao Chiu ◽

Yu-Heng Chen ◽

Yu-Ching Hsu ◽

Hung-I Harry Chen ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Therapy ◽

Cancer Treatment ◽

Cancer Survival ◽

Expression Profiles ◽

Functional Gene ◽

Gene Set Enrichment Analysis ◽

Gene Set ◽

Gene Sets

Aim and Objective: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, “repositioning” of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures. Materials and Methods: First, a “gene set–compound” network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A “cancer–functional gene set– compound” network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained. Results: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment. Conclusion: Our method can effectively identify compounds with a potential to be “repositioned” for cancer treatment according to their active mechanisms and their association with patients’ survival time.

Download Full-text

Carbon ion radiotherapy for prostate cancer with bladder invasion

BMC Urology ◽

10.1186/s12894-021-00871-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yuhei Miyasaka ◽

Hidemasa Kawamura ◽

Hiro Sato ◽

Nobuteru Kubo ◽

Tatsuji Mizukami ◽

...

Keyword(s):

Prostate Cancer ◽

Locally Advanced ◽

Therapeutic Benefit ◽

Carbon Ion Radiotherapy ◽

Safety And Efficacy ◽

Carbon Ion ◽

Grade 3 ◽

Bladder Invasion

Abstract Background The optimal management of clinical T4 (cT4) prostate cancer (PC) is still uncertain. At our institution, carbon ion radiotherapy (CIRT) for nonmetastatic PC, including tumors invading the bladder, has been performed since 2010. Since carbon ion beams provide a sharp dose distribution with minimal penumbra and have biological advantages over photon radiotherapy, CIRT may provide a therapeutic benefit for PC with bladder invasion. Hence, we evaluated CIRT for PC with bladder invasion in terms of the safety and efficacy. Methods Between March 2010 and December 2016, a total of 1337 patients with nonmetastatic PC received CIRT at a total dose of 57.6 Gy (RBE) in 16 fractions over 4 weeks. Among them, seven patients who had locally advanced PC with bladder invasion were identified. Long-term androgen-deprivation therapy (ADT) was also administered to these patients. Adverse events were graded according to the Common Terminology Criteria for Adverse Event version 5.0. Results At the completion of our study, all the patients with cT4 PC were alive with a median follow-up period of 78 months. Grade 2 acute urinary disorders were observed in only one patient. Regarding late toxicities, only one patient developed grade 2 hematuria and urinary urgency. There was no grade 3 or worse toxicity, and gastrointestinal toxicity was not observed. Six (85.7%) patients had no recurrence or metastasis. One patient had biochemical and local failures 42 and 45 months after CIRT, respectively. However, the recurrent disease has been well controlled by salvage ADT. Conclusions Seven patients with locally advanced PC invading the bladder treated with CIRT were evaluated. Our findings seem to suggest positive safety and efficacy profiles for CIRT.

Download Full-text